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Congenital adrenal hypoplasia v4.7 ABCD1 Achchuthan Shanmugasundram Source NHS GMS was added to ABCD1.
Source Expert Review Green was added to ABCD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v4.3 RNF216 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: RNF216.
Hypogonadotropic hypogonadism (GMS) v4.3 FEZF1 Arina Puzriakova Tag Q3_24_promote_green was removed from gene: FEZF1.
Hypogonadotropic hypogonadism (GMS) v4.3 RNF216 Arina Puzriakova reviewed gene: RNF216: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v4.3 FEZF1 Arina Puzriakova reviewed gene: FEZF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hypogonadotropic hypogonadism (GMS) v4.2 RNF216 Arina Puzriakova Source Expert Review Green was added to RNF216.
Source NHS GMS was added to RNF216.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v4.2 FEZF1 Arina Puzriakova Source Expert Review Green was added to FEZF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cholestasis v3.14 PSKH1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: PSKH1.
Cholestasis v3.14 RINT1 Achchuthan Shanmugasundram Tag Q2_25_ demote_red was removed from gene: RINT1.
Tag Q2_25_expert_review was removed from gene: RINT1.
Renal tubulopathies v5.10 CLCN5 Eleanor Williams Tag Q2_25_ promote_green was removed from gene: CLCN5.
Tag Q2_25_ NHS_review was removed from gene: CLCN5.
Renal tubulopathies v5.10 ATP6V1B1 Eleanor Williams Tag Q2_25_ MOI was removed from gene: ATP6V1B1.
Tag Q2_25_ NHS_review was removed from gene: ATP6V1B1.
Cholestasis v3.14 RINT1 Achchuthan Shanmugasundram edited their review of gene: RINT1: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Cholestasis v3.14 PSKH1 Achchuthan Shanmugasundram commented on gene: PSKH1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Cholestasis v3.13 RINT1 Achchuthan Shanmugasundram Source NHS GMS was added to RINT1.
Source Expert Review Red was added to RINT1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Cholestasis v3.13 PSKH1 Achchuthan Shanmugasundram Source NHS GMS was added to PSKH1.
Source Expert Review Green was added to PSKH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.26 PAPPA2 Ida Ertmanska Tag Q3_24_promote_green was removed from gene: PAPPA2.
Tag Q3_24_NHS_review was removed from gene: PAPPA2.
Tag Q3_24_expert_review was removed from gene: PAPPA2.
Tag to_be_confirmed_NHSE tag was added to gene: PAPPA2.
Monogenic short stature v1.26 SPOUT1 Ida Ertmanska reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SMC5 Ida Ertmanska reviewed gene: SMC5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SLF2 Ida Ertmanska reviewed gene: SLF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 SLC13A1 Ida Ertmanska reviewed gene: SLC13A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RSPRY1 Ida Ertmanska reviewed gene: RSPRY1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RNPC3 Ida Ertmanska reviewed gene: RNPC3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 RECQL4 Ida Ertmanska reviewed gene: RECQL4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 PAPPA2 Ida Ertmanska commented on gene: PAPPA2
Monogenic short stature v1.26 MSTO1 Ida Ertmanska commented on gene: MSTO1
Monogenic short stature v1.26 GH1 Ida Ertmanska reviewed gene: GH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Monogenic short stature v1.26 FBXO22 Ida Ertmanska reviewed gene: FBXO22: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Renal tubulopathies v5.10 OCRL Eleanor Williams commented on gene: OCRL: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.10 CLCN5 Eleanor Williams commented on gene: CLCN5: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.10 ATP6V1B1 Eleanor Williams commented on gene: ATP6V1B1: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Renal tubulopathies v5.9 OCRL Eleanor Williams Source Expert Review Green was added to OCRL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Renal tubulopathies v5.9 CLCN5 Eleanor Williams Source Expert Review Green was added to CLCN5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Renal tubulopathies v5.9 ATP6V1B1 Eleanor Williams Mode of inheritance for gene ATP6V1B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary Erythrocytosis v2.16 JAK2 Arina Puzriakova Phenotypes for gene: JAK2 were changed from Hereditary erythrocytosis to Hereditary erythrocytosis; Erythrocytosis, somatic, OMIM:133100
Hereditary Erythrocytosis v2.15 JAK2 Arina Puzriakova Tag Q1_25_ NHS_review was removed from gene: JAK2.
Tag Q1_25_ promote_green was removed from gene: JAK2.
Cerebral vascular malformations v4.9 CBL Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: CBL.
Tag Q2_25_expert_review was removed from gene: CBL.
Tag Q2_25_ NHS_review was removed from gene: CBL.
Hereditary Erythrocytosis v2.15 SH2B3 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SH2B3.
Tag Q2_25_expert_review was removed from gene: SH2B3.
Tag Q2_25_ NHS_review was removed from gene: SH2B3.
Hereditary Erythrocytosis v2.15 SH2B3 Arina Puzriakova commented on gene: SH2B3: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: All GLH providers for this specialty agree that this should not be promoted to green rating - no definitive evidence for germline association with erythrocytosis
Hereditary Erythrocytosis v2.15 JAK2 Arina Puzriakova edited their review of gene: JAK2: Added comment: The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Hereditary Erythrocytosis v2.14 JAK2 Arina Puzriakova Source Expert Review Green was added to JAK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SPOUT1 Ida Ertmanska Source Expert Review Green was added to SPOUT1.
Source NHS GMS was added to SPOUT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SMC5 Ida Ertmanska Source Expert Review Green was added to SMC5.
Source NHS GMS was added to SMC5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SLF2 Ida Ertmanska Source Expert Review Green was added to SLF2.
Source NHS GMS was added to SLF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 SLC13A1 Ida Ertmanska Source Expert Review Green was added to SLC13A1.
Source NHS GMS was added to SLC13A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 RSPRY1 Ida Ertmanska Source Expert Review Green was added to RSPRY1.
Source NHS GMS was added to RSPRY1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 RNPC3 Ida Ertmanska Source Expert Review Red was added to RNPC3.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Monogenic short stature v1.25 RECQL4 Ida Ertmanska Source Expert Review Green was added to RECQL4.
Source NHS GMS was added to RECQL4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 MSTO1 Ida Ertmanska Mode of inheritance for gene MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Monogenic short stature v1.25 GH1 Ida Ertmanska Source Expert Review Green was added to GH1.
Source NHS GMS was added to GH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Monogenic short stature v1.25 FBXO22 Ida Ertmanska Source Expert Review Green was added to FBXO22.
Source NHS GMS was added to FBXO22.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cerebral vascular malformations v4.9 ANO1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ANO1.
Tag Q2_25_expert_review was removed from gene: ANO1.
Tag Q2_25_ NHS_review was removed from gene: ANO1.
Cerebral vascular malformations v4.9 CBL Achchuthan Shanmugasundram commented on gene: CBL: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Cerebral vascular malformations v4.9 ANO1 Achchuthan Shanmugasundram reviewed gene: ANO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cerebral vascular malformations v4.8 CBL Achchuthan Shanmugasundram Source Expert Review Green was added to CBL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cerebral vascular malformations v4.8 ANO1 Achchuthan Shanmugasundram Source NHS GMS was added to ANO1.
Source Expert Review Green was added to ANO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autosomal recessive primary hypertrophic osteoarthropathy v1.16 SLCO2A1 Achchuthan Shanmugasundram Tag Q2_25_ MOI was removed from gene: SLCO2A1.
Familial tumours of the nervous system v2.7 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from {Melanoma and neural system tumor syndrome}, OMIM:155755; MELANOMA; PANCREATIC CANCER; ASTROCYTOMA; GLIOBLASTOMA; SCHWANNOMA; NEUROFIBROMA; MENINGIOMA; MALIGNANT PERIPHERAL NERVE SHEATH TUMOURS to {Melanoma and neural system tumor syndrome}, OMIM:155755; Astrocytoma; Glioblastoma; Schwannoma; Neurofibroma; Meningioma; Malignant peripheral nerve sheath tumours
Autosomal recessive primary hypertrophic osteoarthropathy v1.16 SLCO2A1 Achchuthan Shanmugasundram commented on gene: SLCO2A1
Autosomal recessive primary hypertrophic osteoarthropathy v1.15 SLCO2A1 Achchuthan Shanmugasundram Mode of inheritance for gene SLCO2A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Familial tumours of the nervous system v2.6 CDKN2A Arina Puzriakova Publications for gene: CDKN2A were set to PMID 24884915; 8317504; 9622062; 10797439; 17440112; 26794401; 29263814; 28699883; 28754699; 35422439; 38936911
Familial tumours of the nervous system v2.5 CDKN2A Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: CDKN2A.
Tag Q2_25_ NHS_review was removed from gene: CDKN2A.
Familial tumours of the nervous system v2.5 CDKN2A Arina Puzriakova edited their review of gene: CDKN2A: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Familial tumours of the nervous system v2.4 CDKN2A Arina Puzriakova Source NHS GMS was added to CDKN2A.
Source Expert Review Green was added to CDKN2A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Osteopetrosis v1.37 TYROBP Eleanor Williams Tag Q3_24_NHS_review was removed from gene: TYROBP.
Tag Q3_24_demote_red was removed from gene: TYROBP.
Tag Q3_24_expert_review was removed from gene: TYROBP.
Autoinflammatory disorders v2.34 TBK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: TBK1.
Tag Q2_25_ NHS_review was removed from gene: TBK1.
Osteopetrosis v1.37 TYROBP Eleanor Williams edited their review of gene: TYROBP: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Osteopetrosis v1.36 TYROBP Eleanor Williams Source Expert Review Red was added to TYROBP.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Autoinflammatory disorders v2.34 RIPK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RIPK1.
Tag Q2_25_ NHS_review was removed from gene: RIPK1.
Autoinflammatory disorders v2.34 RELA Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: RELA.
Tag Q2_25_ NHS_review was removed from gene: RELA.
Autoinflammatory disorders v2.34 POMP Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: POMP.
Tag Q2_25_ NHS_review was removed from gene: POMP.
Autoinflammatory disorders v2.34 IKBKG Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: IKBKG.
Tag Q2_25_ NHS_review was removed from gene: IKBKG.
Autoinflammatory disorders v2.34 ELF4 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ELF4.
Tag Q2_25_ NHS_review was removed from gene: ELF4.
Autoinflammatory disorders v2.34 COPA Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: COPA.
Tag Q2_25_ NHS_review was removed from gene: COPA.
Autoinflammatory disorders v2.34 ALPK1 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: ALPK1.
Tag Q2_25_ NHS_review was removed from gene: ALPK1.
Autoinflammatory disorders v2.34 TBK1 Achchuthan Shanmugasundram commented on gene: TBK1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.34 RIPK1 Achchuthan Shanmugasundram commented on gene: RIPK1: The rating of this gene has been updated to green and the mode of inheritance set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.34 RELA Achchuthan Shanmugasundram reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 POMP Achchuthan Shanmugasundram reviewed gene: POMP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 IKBKG Achchuthan Shanmugasundram reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 ELF4 Achchuthan Shanmugasundram commented on gene: ELF4: The rating of this gene has been updated to green and the mode of inheritance set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.34 COPA Achchuthan Shanmugasundram reviewed gene: COPA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Autoinflammatory disorders v2.34 ALPK1 Achchuthan Shanmugasundram commented on gene: ALPK1: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Autoinflammatory disorders v2.33 TBK1 Achchuthan Shanmugasundram Source NHS GMS was added to TBK1.
Source Expert Review Green was added to TBK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 RIPK1 Achchuthan Shanmugasundram Source NHS GMS was added to RIPK1.
Source Expert Review Green was added to RIPK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 RELA Achchuthan Shanmugasundram Source NHS GMS was added to RELA.
Source Expert Review Green was added to RELA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 POMP Achchuthan Shanmugasundram Source NHS GMS was added to POMP.
Source Expert Review Green was added to POMP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 IKBKG Achchuthan Shanmugasundram Source NHS GMS was added to IKBKG.
Source Expert Review Green was added to IKBKG.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 ELF4 Achchuthan Shanmugasundram Source NHS GMS was added to ELF4.
Source Expert Review Green was added to ELF4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 COPA Achchuthan Shanmugasundram Source NHS GMS was added to COPA.
Source Expert Review Green was added to COPA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Autoinflammatory disorders v2.33 ALPK1 Achchuthan Shanmugasundram Source NHS GMS was added to ALPK1.
Source Expert Review Green was added to ALPK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.6 STX16 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: STX16.
Tag Q2_25_expert_review was removed from gene: STX16.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.6 STX16 Achchuthan Shanmugasundram edited their review of gene: STX16: Added comment: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GMS reviewers commented as follows: Only STX16 deletions are clinically relevant and STX16 probes are included in the MS-MLPA kit which is an essential component of R293 testing as STX16 deletions act on methylation only. Adding this gene to Panelapp could be missleading as would suggest analysis of SNVs.; Changed rating: AMBER
Acute intermittent porphyria v1.5 HMBS Achchuthan Shanmugasundram Tag Q2_25_ MOI was removed from gene: HMBS.
Acute intermittent porphyria v1.5 HMBS Achchuthan Shanmugasundram commented on gene: HMBS
Acute intermittent porphyria v1.4 HMBS Achchuthan Shanmugasundram Mode of inheritance for gene HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Skeletal dysplasia v8.21 H2AFY Julie Evans gene: H2AFY was added
gene: H2AFY was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: H2AFY was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: H2AFY were set to PMID: 30711920, PMID: 23587911
Phenotypes for gene: H2AFY were set to Liebenberg syndrome
Penetrance for gene: H2AFY were set to Complete
Review for gene: H2AFY was set to GREEN
Added comment: H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome
Sources: Literature
Hypertrophic cardiomyopathy v5.17 TBX1 Riyaad Aungraheeta gene: TBX1 was added
gene: TBX1 was added to Hypertrophic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: TBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TBX1 were set to PMID: 41130538
Phenotypes for gene: TBX1 were set to Hypertrophic cardiomyopathy
Review for gene: TBX1 was set to AMBER
Added comment: Sources: Literature
Mosaic skin disorders - deep sequencing v3.22 TP63 Arina Puzriakova Tag watchlist was removed from gene: TP63.
Mosaic skin disorders - deep sequencing v3.22 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mosaic skin disorders - deep sequencing v3.21 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to PMID:
Hereditary neuropathy or pain disorder v7.29 KIF21A Alexander Rossor gene: KIF21A was added
gene: KIF21A was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: KIF21A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21A were set to 39643435; 41282472
Phenotypes for gene: KIF21A were set to CFEOM; agenesis of the corpus callosum; peripheral neuropathy
Penetrance for gene: KIF21A were set to Complete
Mode of pathogenicity for gene: KIF21A was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KIF21A was set to AMBER
Added comment: Currently only two unrelated individuals reported with peripheral neuropathy
Sources: Expert list
Retinal disorders v8.74 EGFLAM Siying Lin gene: EGFLAM was added
gene: EGFLAM was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: EGFLAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EGFLAM were set to PMID: 41343198
Phenotypes for gene: EGFLAM were set to Congenital Stationary Night Blindness
Mode of pathogenicity for gene: EGFLAM was set to Other
Review for gene: EGFLAM was set to AMBER
Added comment: PMID 41343198 - 3 patients from 2 unrelated families with different homozygous LOF variants and CSNB phenotype
Sources: Literature
Mosaic skin disorders - deep sequencing v3.20 TSC2 Ida Ertmanska Phenotypes for gene: TSC2 were changed from to Tuberous sclerosis-2, OMIM: 613254; tuberous sclerosis 2, MONDO:0013199
Mosaic skin disorders - deep sequencing v3.19 TSC2 Ida Ertmanska Publications for gene: TSC2 were set to PMID: 37356622
Mosaic skin disorders - deep sequencing v3.18 TSC2 Ida Ertmanska Mode of inheritance for gene: TSC2 was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.17 TSC2 Ida Ertmanska Classified gene: TSC2 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.17 TSC2 Ida Ertmanska Gene: tsc2 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.16 TSC2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TSC2.
Tag Q4_25_NHS_review tag was added to gene: TSC2.
Mosaic skin disorders - deep sequencing v3.16 TSC2 Ida Ertmanska commented on gene: TSC2: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC2 variants. Variants are sometimes detected in skin biopsy samples only - not in blood or saliva. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (down to <1%). Based on the available evidence, TSC2 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.16 TSC2 Ida Ertmanska reviewed gene: TSC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26540169, 31160751, 31114024, 32461669, 37141891, 37356622; Phenotypes: Tuberous sclerosis-2, OMIM: 613254; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.; to: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants are sometimes detected in skin biopsy samples only - not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska changed review comment from: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, and shagreen patch (PMID: 37141891).

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%).
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of 53 patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method. All 53 TSC patients had skin involvement.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).; to: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, and shagreen patch (PMID: 37141891).

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%). Variants are sometimes detected in skin biopsy samples only - not in blood or saliva.
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of 53 patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method. All 53 TSC patients had skin involvement.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska Deleted their comment
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.; to: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.16 TSC1 Ida Ertmanska Phenotypes for gene: TSC1 were changed from Cutaneous pigmentary abnormalities, and/or other aspects of germline TSC disease to Tuberous sclerosis-1, OMIM:191100; tuberous sclerosis 1, MONDO:0008612
Mosaic skin disorders - deep sequencing v3.15 TSC1 Ida Ertmanska Publications for gene: TSC1 were set to PMID: 37356622
Mosaic skin disorders - deep sequencing v3.14 TSC1 Ida Ertmanska Mode of inheritance for gene: TSC1 was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.13 TSC1 Ida Ertmanska Added comment: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.13 TSC1 Ida Ertmanska Mode of inheritance for gene: TSC1 was changed from Other to Other
Mosaic skin disorders - deep sequencing v3.12 TSC1 Ida Ertmanska Classified gene: TSC1 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.12 TSC1 Ida Ertmanska Gene: tsc1 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TSC1.
Tag Q4_25_NHS_review tag was added to gene: TSC1.
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska commented on gene: TSC1: Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring mosaic TSC1 variants. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (3-5%). Variants may be detected in skin biopsy samples but not in blood or saliva. Based on the available evidence, TSC1 should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska changed review comment from: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, shagreen patch.

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%).
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).; to: Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, and shagreen patch (PMID: 37141891).

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%).
Patients with TSC1 variants:
10 non-mosaic heterozygous cases;
Patient 6: mosaic variant TSC1:c.994del, p.Ser332Profs∗6; variant detected in saliva (36%) and affected skin (42%); blood sequencing not performed
Patient 12: mosaic variant TSC1:c.2101_2107del, p.Gln701Serfs∗21 - 4% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of 53 patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method. All 53 TSC patients had skin involvement.
Reported 4 patients with non-mosaic heterozygous TSC1 variants (allele freq = 50%), as well as 4 mosaic cases (allele freq <50%):
P53: 22yo male; TSC1 c.1776delG - 30% mutant allele in saliva and blood
P2: 20yo male; c.2689C>T; p.Q897* in TSC1 - 15% mutant allele in blood
P6: 4yo male; TSC1 c.2111_2112delAT - 4.7% in blood and normal skin
P5f: 57yo female; TSC1 c.2374C>T; p.Q792* - 3.3% in blood

This gene is associated with AD Tuberous sclerosis-1, MIM:191100 in OMIM (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.11 TSC1 Ida Ertmanska reviewed gene: TSC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26540169, 31160751, 31114024, 32461669, 37141891, 37356622; Phenotypes: Tuberous sclerosis-1, OMIM:191100, tuberous sclerosis 1, MONDO:0008612; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tubulointerstitial kidney disease v3.10 APOA4 Nour Elkhateeb gene: APOA4 was added
gene: APOA4 was added to Tubulointerstitial kidney disease. Sources: Literature
Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOA4 were set to PMID 38096951
Phenotypes for gene: APOA4 were set to tubulointerstitial kidney disease; Chronic kidney disease
Penetrance for gene: APOA4 were set to unknown
Review for gene: APOA4 was set to GREEN
Added comment: Kmochova et al. (2024) (PMID: 38096951) reported 35 patients from 5 large unrelated families with onset of tubulointerstitial kidney disease in late adulthood associated with mutations in the APOA4 gene.
Sources: Literature
Mosaic skin disorders - deep sequencing v3.11 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Split hand foot malformation with whorl-like pigmentary pattern to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292
Mosaic skin disorders - deep sequencing v3.10 TP63 Ida Ertmanska Publications for gene: TP63 were set to 18792980
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TP63.
Tag Q4_25_NHS_review tag was added to gene: TP63.
Tag Q4_25_expert_review tag was added to gene: TP63.
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska commented on gene: TP63: Comment on list classification: There is only one reported case of a confirmed mosaic TP63 variant in a parent, which has been passed on to offspring in an autosomal dominant manner (PMID:18792980). PMID: 34703865 reports another individual described as mosaic, but variant details are not specified. Both patients presented with linear hypopigmented patches following Blaschkoid lines - usually indicative of cutaneous mosaicism. In addition, 3 unrelated sets of siblings, harbouring the same rare 'de novo' TP63 mutations, have been described - suggestive of undetected mosaicism in parents (PMIDs: 22740388; 27351625; 28977327). Based on available evidence, this gene will be tagged for promotion to Green on Mosaic skin disorders - deep sequencing. Expert Review will be requested regarding the evidence for mosaicism in four cases (suspected but not confirmed through sequencing).
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska changed review comment from: PMID: 34703865 Chen, Issa and Schmidt, 2021
Report of a 31 yo African American man harbouring a 'TP63 gene copy number variant' (not specified) with a mosaic distribution (ratio not given). Putative diagnosis: ectodermal dysplasia (ED). Phenotype: patterned skin hypopigmentation (including linear hypopigmented patches following Blaschkoid lines), alopecia, and dental anomaly (one hypoplastic, conical tooth). Variant identified through an ED-associated gene panel.

PMID: 28977327 Rosa et al., 2017
3 siblings with Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, parents unaffected. Germline mosaicism hypothesised, but no DNA sequencing described.

PMID: 27351625 Enriquez et al., 2016
Report of two sibling fetuses with urogenital abnormalities, split hand and foot malformation, and bilateral cleft lip and palate. Both het for c.1051G > A; p.D351N in TP63. Both parents were unaffected. 'Parental lymphocyte DNA showed no evidence of the TP63 mutation but germline mosaicism in a parent is assumed' - only TP63 sequenced, parents are WT. Mosaicism presumed due to recurrence in the two siblings. The same missense mutation was reported de novo in other families (PMID: 21434540 Ergin et al., 2010 and PMID: 16691622 Rinne et al., 2006).

PMID: 22740388 Barbaro et al., 2012
Two sisters with Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Both sisters were heterozygous for TP63 c.1568T>C p.L523P (NM_003722.5: c.1574T>C, p.Leu525Pro) - not in gnomAD v4.1.0. Parental DNA analysis (blood, father's seminal fluid and mother's buccal, vaginal, and cervical cells) did not reveal the mutation. Authors pose that the apparently de novo variant was actually inherited through very low grade somatic mosaicism or maternal gonadal mosaicism.

PMID: 18792980 Kosaki et al., 2008


TP63 is associated with several AD conditions in OMIM, including Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 MIM:604292 (accessed 3rd Dec 2025).; to: PMID: 34703865 Chen, Issa and Schmidt, 2021
Report of a 31 yo African American man harbouring a 'TP63 gene copy number variant' (not specified) with a mosaic distribution (ratio not given). Putative diagnosis: ectodermal dysplasia (ED). Phenotype: patterned skin hypopigmentation (including linear hypopigmented patches following Blaschkoid lines), alopecia, and dental anomaly (one hypoplastic, conical tooth). Variant identified through an ED-associated gene panel.

PMID: 28977327 Rosa et al., 2017
3 siblings with Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, parents unaffected. Germline mosaicism hypothesised, but no DNA sequencing described.

PMID: 27351625 Enriquez et al., 2016
Report of two sibling fetuses with urogenital abnormalities, split hand and foot malformation, and bilateral cleft lip and palate. Both het for c.1051G > A; p.D351N in TP63. Both parents were unaffected. 'Parental lymphocyte DNA showed no evidence of the TP63 mutation but germline mosaicism in a parent is assumed' - only TP63 sequenced, parents are WT. Mosaicism presumed due to recurrence in the two siblings. The same missense mutation was reported de novo in other families (PMID: 21434540 Ergin et al., 2010 and PMID: 16691622 Rinne et al., 2006).

PMID: 22740388 Barbaro et al., 2012
Two sisters with Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Both sisters were heterozygous for TP63 c.1568T>C p.L523P (NM_003722.5: c.1574T>C, p.Leu525Pro) - not in gnomAD v4.1.0. Parental DNA analysis (blood, father's seminal fluid and mother's buccal, vaginal, and cervical cells) did not reveal the mutation. Authors pose that the apparently de novo variant was actually inherited through very low grade somatic mosaicism or maternal gonadal mosaicism.

PMID: 18792980 Kosaki et al., 2008
Newborn with split hand/foot malformation with whorl-like pigmentary pattern following Blaschko lines, heterozygous for c.727C>T, p.R204W (NM_003722.5: c.727C>T, p.Arg243Trp) - germline, variant not present in gnomAD v4.1.0. Mosaicism confirmed in the father (sequencing of peripheral blood and hair). Father presented with ectrodactyly of the hands a whorl-like pigmentary pattern following Blaschko lines.

TP63 is associated with several AD conditions in OMIM, including Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 MIM:604292 (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska edited their review of gene: TP63: Changed rating: GREEN; Changed publications to: 18792980, 22740388, 27351625, 28977327, 34703865; Changed phenotypes to: Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders - deep sequencing v3.9 TP63 Ida Ertmanska reviewed gene: TP63: Rating: ; Mode of pathogenicity: None; Publications: 18792980, 22740388, 27351625, 34703865; Phenotypes: ; Mode of inheritance: None
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska Tag Q4_25_NHS_review tag was added to gene: PMVK.
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska commented on gene: PMVK: Comment on list classification: There are at least 13 unrelated individuals reported in literature with germline heterozygous variants in PMVK, diagnosed with a type of porokeratosis. Porokeratosis is characterised by keratotic lesions with an atrophic center rimmed by an elevated border. Disease onset is mostly in childhood or adolescence. Based on the available evidence, PMVK should be promoted to Green for Pigmentary skin disorders.
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES. Age of onset: mostly between 5-10 yo.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man, presented with persistent non-pruritic skin lesions since childhood: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated cases (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska changed review comment from: PMID: 38360177 Polubothu et al., 2024
Patient with Inflammatory linear verrucous epidermal nevus (ILVEN) reported to carry a de novo PMVK variant c.126delG, p.R42fs (NM_006556.4: c.124del, p.Arg42Glyfs*16) - not in gnomAD v4.1.0; method: 250x WES; mosaic in blood and skin, no second variant detected in the same gene in skin.

PMID: 30942823 Atzmony et al., 2019 / PMID: 35853659 Atzmony et al., 2022
Report of 2 patients with Linear Porokeratosis. Inheritance pattern unknown.
Patient 1: 20 yo man with a germline-heterozygous PMVK c.329G>A, p.R110Q mutation in blood & affected skin. Skin showed a higher mutant allele fraction (Ref:Non-Ref read ratio was 21:15 in blood and 16:61 in tissue). Suggested somatic loss-of-heterozygosity.
Patient 2: 5 yo girl with a germline mutation PMVK c.79G>T, p.Glu27* & a somatic mutation PMVK c.379C>T, p.Gln127* (Ref:Non-Ref = 113:0 in blood, and 119:34 in tissue). Variant p.Glu27* has MAF = 0.0005930 in gnomAD v4.1.0 (Admixed American pop), no homozygotes.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87). PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 38360177 Polubothu et al., 2024
Patient with Inflammatory linear verrucous epidermal nevus (ILVEN) reported to carry a de novo PMVK variant c.126delG, p.R42fs (NM_006556.4: c.124del, p.Arg42Glyfs*16) - not in gnomAD v4.1.0; method: 250x WES; mosaic in blood and skin, no second variant detected in the same gene in skin.

PMID: 30942823 Atzmony et al., 2019 / PMID: 35853659 Atzmony et al., 2022
Report of 2 patients with Linear Porokeratosis - plaques distributed along the lines of Blaschko, suggesting cutaneous mosaicism. Inheritance pattern unknown.
Patient 1: 20 yo man with a germline-heterozygous PMVK c.329G>A, p.R110Q mutation in blood & affected skin. Skin showed a higher mutant allele fraction (Ref:Non-Ref read ratio was 21:15 in blood and 16:61 in tissue). Suggested somatic loss-of-heterozygosity.
Patient 2: 5 yo girl with a germline mutation PMVK c.79G>T, p.Glu27* & a somatic mutation PMVK c.379C>T, p.Gln127* (Ref:Non-Ref = 113:0 in blood, and 119:34 in tissue). Variant p.Glu27* has MAF = 0.0005930 in gnomAD v4.1.0 (Admixed American pop), no homozygotes.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87). PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

This gene is NOT predicted to be LoF intolerant (pLI = 0.02, LOEUF = 0.87).
PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.

PMVK is associated with AD Porokeratosis 1, multiple types MIM:175800 in OMIM (accessed 3rd Dec 2025).
Pigmentary skin disorders v4.8 PMVK Ida Ertmanska Phenotypes for gene: PMVK were changed from Porokeratosis 1, multiple types, OMIM:175800 to Porokeratosis 1, multiple types, OMIM:175800; porokeratosis, MONDO:0006602
Pigmentary skin disorders v4.7 PMVK Ida Ertmanska Publications for gene: PMVK were set to 26202976; 27052676
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska commented on gene: PMVK: Comment on list classification: There are 3 unrelated individuals diagnosed with linear porokeratosis / ILVEN with mosaic PMVK variants. 1 individual harboured a mosaic PMVK variant only (vPMID: 38360177), while two patients carried a germline PMVK mutation together with either a somatic PMVK variant, or evidence of loss of heterozygosity (PMID: 30942823). Based on the available evidence, this gene should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PMVK.
Mosaic skin disorders - deep sequencing v3.9 PMVK Ida Ertmanska Phenotypes for gene: PMVK were changed from Linear porokeratosis to inflammatory linear verrucous epidermal nevus, MONDO:0019318; Porokeratosis 1, multiple types OMIM:175800
Mosaic skin disorders - deep sequencing v3.8 PMVK Ida Ertmanska Publications for gene: PMVK were set to 30942823
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of Disseminated Superficial Porokeratosis (DSP) in 2 five-generation Chinese families with members affected by DSP. Identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families through WES.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*;c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*; c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska edited their review of gene: PMVK: Changed phenotypes to: Porokeratosis 1, multiple types, OMIM:175800, porokeratosis, MONDO:0006602
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska edited their review of gene: PMVK: Changed publications to: 26202976, 27052676, 37315547, 41296516
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska Classified gene: PMVK as Amber List (moderate evidence)
Pigmentary skin disorders v4.6 PMVK Ida Ertmanska Gene: pmvk has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v4.5 PMVK Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: PMVK.
Pigmentary skin disorders v4.5 PMVK Ida Ertmanska changed review comment from: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 cases (including related individuals) reported in Table 1. 2 variants (from a family and an individual) recorded in OMIM. These cases do NOT include DSAP/DSP cases though and instead include other subtypes of porokeratosis.

PMID: 27052676 Wang et al 2016
investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.
Sources: Literature; to: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 unrelated families (some cases sporadic some familial). PMVK variants detected: c.1A>G, p.Met1?; c.94A>T, p.Arg32*;c.205A>G, p.Lys69Glu; c.312G>A, p.Trp104*; c.412C>T, p.Arg138*; c.550del, p.Leu184*.

PMID: 27052676 Wang et al 2016
Investigated the genetic basis of DSP in 2 five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.

PMID: 37315547 Zhang et al., 2023
Identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in PMVK in a Chinese pedigree with 4 individuals affected by porokeratosis. Patients presented with keratotic lesions in childhood / adolescence. Only 4 genes were sequenced: MVK, MVD, PMVK, and FDPS.

PMID: 41296516 Narula et al., 2025 (online ahead of print)
20-year-old Indian man presented with persistent non-pruritic skin lesions: skin-coloured papules on the scrotum and pigmented annular plaques over the forearms, dorsum of the foot, elbows, knees, and buttocks. Heterozygous for NM_006556.4: c.412C>T (p.Arg138*) - same variant as reported in PMID: 27052676.
Pigmentary skin disorders v4.5 PMVK Ida Ertmanska gene: PMVK was added
gene: PMVK was added to Pigmentary skin disorders. Sources: Literature
Mode of inheritance for gene: PMVK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMVK were set to 26202976; 27052676
Phenotypes for gene: PMVK were set to Porokeratosis 1, multiple types, OMIM:175800
Review for gene: PMVK was set to GREEN
Added comment: PMID: 26202976 Zhang et al. 2015
Screened 12 isoprenoid genes in 134 Chinese probands with porokeratosis and identified PMVK mutations:
9 cases (including related individuals) reported in Table 1. 2 variants (from a family and an individual) recorded in OMIM. These cases do NOT include DSAP/DSP cases though and instead include other subtypes of porokeratosis.

PMID: 27052676 Wang et al 2016
investigated the genetic basis of DSP in two five-generation Chinese families with members diagnosed with DSP. By whole-exome sequencing, they identified a nonsense variation c.412C>T (p.Arg138*) in PMVK in both families.
Sources: Literature
Mosaic skin disorders - deep sequencing v3.7 PMVK Ida Ertmanska reviewed gene: PMVK: Rating: GREEN; Mode of pathogenicity: None; Publications: 30942823, 35853659, 38360177; Phenotypes: inflammatory linear verrucous epidermal nevus, MONDO:0019318, Porokeratosis 1, multiple types OMIM:175800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 TK2 William Macken gene: TK2 was added
gene: TK2 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: NHS GMS
Mode of inheritance for gene: TK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TK2 were set to 22345218 23303857 24198295 31092255 25948719
Phenotypes for gene: TK2 were set to mitochondrial disease; limb girdle muscular dystrophy; congenital muscular dystrophy
Penetrance for gene: TK2 were set to Complete
Review for gene: TK2 was set to GREEN
Added comment: This is already green in mitochondrial disease. It causes limb girdle muscular dystrophy and should be on this panel and the wider related panel other rare neuromuscular
Sources: NHS GMS
Congenital muscular dystrophy v6.1 TK2 William Macken changed review comment from: Sources: NHS GMS; to: Sources: NHS GMS, TK2 is on a mitochondrial panel however, it causes a muscle predominant phenotype and should be present on congenital muscular dystrophy, LGMD and as a consequence other rare neuromuscular disorders and hypotonic infant
Congenital muscular dystrophy v6.1 TK2 William Macken gene: TK2 was added
gene: TK2 was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: TK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TK2 were set to 11687801 18021809 19736010 16831967 36146520
Phenotypes for gene: TK2 were set to Congenital muscular dystrophy; mitochondrial disease; limb girdle muscular dystrophy
Penetrance for gene: TK2 were set to Complete
Mode of pathogenicity for gene: TK2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: TK2 was set to GREEN
gene: TK2 was marked as current diagnostic
Added comment: Sources: NHS GMS
Mitochondrial disorders v9.36 MT-ATP8 Zornitza Stark reviewed gene: MT-ATP8: Rating: AMBER; Mode of pathogenicity: None; Publications: 24153443, 20207608, 32858252, 33340416, 32858252, 19759059, 22919063; Phenotypes: Mitochondrial cardiomyopathy complex V (ATP synthase) deficiency; Mode of inheritance: MITOCHONDRIAL
Mosaic skin disorders - deep sequencing v3.7 GJA1 Ida Ertmanska changed review comment from: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30.5%).
The same variant but germline was reported as causative in erythrokeratodermia variabilis et progressiva (EKVP) in PMID: 25398053 Boyden et al., 2015).; to: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30%).
The same variant but germline was reported as causative in erythrokeratodermia variabilis et progressiva (EKVP) in PMID: 25398053 Boyden et al., 2015).
Mosaic skin disorders - deep sequencing v3.7 GJA1 Ida Ertmanska Phenotypes for gene: GJA1 were changed from Inflammatory Linear Verrucous Epidermal Naevi (ILVEN) to inflammatory linear verrucous epidermal nevus, MONDO:0019318
Mosaic skin disorders - deep sequencing v3.6 GJA1 Ida Ertmanska Publications for gene: GJA1 were set to PMID: 27890787
Mosaic skin disorders - deep sequencing v3.5 GJA1 Ida Ertmanska Classified gene: GJA1 as Red List (low evidence)
Mosaic skin disorders - deep sequencing v3.5 GJA1 Ida Ertmanska Added comment: Comment on list classification: As there is only one individual reported in literature with a skin disorder and a mosaic GJA1 variant, this gene should remain Red for Mosaic skin disorders - deep sequencing, until more evidence emerges.
Mosaic skin disorders - deep sequencing v3.5 GJA1 Ida Ertmanska Gene: gja1 has been classified as Red List (Low Evidence).
Mosaic skin disorders - deep sequencing v3.4 GJA1 Ida Ertmanska changed review comment from: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30.5%).; to: PMID: 27890787 Umegaki-Arao et al., 2017
14-year-old girl with inflammatory linear verrucous epidermal nevus (ILVEN); onset at 1yo, worsening over time. At age 14, she developed widespread erythematous plaques and verrucous plaques along Blaschko’s lines on the extremities and buttocks, as well as palmoplantar hyperkeratosis. Hair, teeth, and nails were not affected.
8 candidate variants detected; GJA1 c.131C>T (p.A44V) was the only candidate mutation detected in affected epidermis but not in white blood cells; detected in 22 of 72 reads (30.5%).
The same variant but germline was reported as causative in erythrokeratodermia variabilis et progressiva (EKVP) in PMID: 25398053 Boyden et al., 2015).
Mosaic skin disorders - deep sequencing v3.4 GJA1 Ida Ertmanska edited their review of gene: GJA1: Changed rating: RED
Mosaic skin disorders - deep sequencing v3.4 GJA1 Ida Ertmanska reviewed gene: GJA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27890787; Phenotypes: inflammatory linear verrucous epidermal nevus, MONDO:0019318; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.191 CYP27A1 Ida Ertmanska Mode of inheritance for gene: CYP27A1 was changed from Other - please specify in evaluation comments to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.640 CPOX Ida Ertmanska Mode of inheritance for gene: CPOX was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.190 SOX3 Sahana Chatakondu reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: Other; Publications: 25402377; Phenotypes: Dyspraxia, Growth Hormone Deficiency, Intellectual Disability, Short stature,; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Vascular skin disorders v2.4 FECH Arina Puzriakova Publications for gene: FECH were set to 7857832; 9649563
Non-acute porphyrias v1.32 FECH Arina Puzriakova Publications for gene: FECH were set to 857832; 16911284; 39969427; 32873934; 38940544; 11753383; 16385445
Mosaic skin disorders - deep sequencing v3.4 CARD14 Arina Puzriakova Publications for gene: CARD14 were set to
Mosaic skin disorders - deep sequencing v3.3 CARD14 Ida Ertmanska Phenotypes for gene: CARD14 were changed from ILVEN (submitted 2 cases) to inflammatory linear verrucous epidermal nevus, MONDO:0019318
Mosaic skin disorders - deep sequencing v3.2 CARD14 Ida Ertmanska Classified gene: CARD14 as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v3.2 CARD14 Ida Ertmanska Gene: card14 has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: CARD14.
Tag Q4_25_NHS_review tag was added to gene: CARD14.
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated individuals reported with inflammatory linear verrucous epidermal nevus and mosaic variants in CARD14. 2 more cases have been reported without clinical or variant details.; to: Comment on list classification: There are 2 unrelated individuals reported with inflammatory linear verrucous epidermal nevus and mosaic variants in CARD14. 2 more mosaic cases have been reported without clinical or variant details. There is some functional evidence in cell cultures supporting the role of CARD14 in keratinocyte proliferation. Based on available evidence, this gene should be promoted to Green for Mosaic skin disorders - deep sequencing.
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
Functional evidence - patient 2 keratinocyte culture: WST-1 proliferation assay showed a significant a proliferation rate increase; ELISA showed a significant increase in NF-κB p65 subunit activity.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).; to: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
Functional evidence: WST-1 proliferation assay showed a significant a proliferation rate increase in SVK14 cells transfected with the mutant CARD14 construct; ELISA showed a significant increase in NF-κB p65 subunit activity in patient 2 keratinocyte culture.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).; to: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
Functional evidence - patient 2 keratinocyte culture: WST-1 proliferation assay showed a significant a proliferation rate increase; ELISA showed a significant increase in NF-κB p65 subunit activity.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska edited their review of gene: CARD14: Added comment: Comment on list classification: There are 2 unrelated individuals reported with inflammatory linear verrucous epidermal nevus and mosaic variants in CARD14. 2 more cases have been reported without clinical or variant details.; Changed rating: GREEN; Changed publications to: 34116062, 35853659, 38360177
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska changed review comment from: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.
This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?; to: PMID: 34116062 Riachi et al., 2021
2 probands with heterozygous mosaic CARD14 variants, diagnosed with Inflammatory linear verrucous epidermal naevus (ILVEN).
Patient 1: c.356T > A, p.Met119Lys present in 20% of DNA. Variant not present in gnomAD v4. Same variant in a non-mosaic state caused pityriasis rubra pilaris (PMID: 28301045 Lwin et al., 2018).
Patient 2: c.277A>G, p.Lys93Glu present in 1% of DNA extracted from affected skin. Variant not in gnomAD v4.

PMID: 38360177 Polubothu et al., 2024
2 patients with ILVEN with mosaic variants in CARD14 picked up on 250x WES - patient / variant details not specified.

PMID: 35853659 Atzmony et al., 2023
Patient 2 - female patient diagnosed with ILVEN, developed psoriasis vulgaris at 13 months; het for germline variant CARD14 c. 2044C>T, p.R682W; she also carried a post-zygotic variant in KRT10: c.467G>A, p.R156H. The CARD14 variant is very common (MAF = 0.01604 in gnomAD v4 - European population, total of 30 homozygotes reported). Mosaic KRT10 more likely to be causal?

This gene is associated with AD Pityriasis rubra pilaris MIM:173200 and AD Psoriasis 2 MIM:602723 in OMIM (accessed 28th Nov 2025).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Ida Ertmanska reviewed gene: CARD14: Rating: AMBER; Mode of pathogenicity: None; Publications: 34116062, 35853659; Phenotypes: inflammatory linear verrucous epidermal nevus, MONDO:0019318; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Vascular skin disorders v2.3 FECH Ida Ertmanska reviewed gene: FECH: Rating: GREEN; Mode of pathogenicity: None; Publications: 10954661, 9649563; Phenotypes: Protoporphyria, erythropoietic,1 OMIM:177000, protoporphyria, erythropoietic, 1 MONDO:0008319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Iron metabolism disorders - NOT common HFE mutations v3.1 FECH Ida Ertmanska changed review comment from: FECH product, ferrochelatase, is an enzyme in the heme biosynthesis pathway that catalyses insertion of an iron atom into protoporphyrin IX. According to Barman-Aksoezen et al., 2017 (PMID: 28185024) Erythropoietic protoporphyria (EPP) patients 'frequently exhibit low serum iron and a microcytic hypochromic anemia'. However, as reviewed by Sharon Whatley, the iron deficiency is often mild.

PMID: 21659066 Morais et al., 2011
Portuguese male proband with compound het mutations c.1052delA, p.Glu351Glyfs*6 and IVS3-48T>C in FECH - diagnosed with EPP, presented with acute episodes of photosensitivity, microcytic anemia and mild hepatic dysfunction.

PMID: 20412370 Wahlin et al., 2011
Swedish cohort of 51 EPP patients - 44% had low ferritin levels.

PMID: 28614581 Balwani et al., 2017
US report of 226 patients, 37.4% of EPP patients were anemic.; to: FECH product, ferrochelatase, is an enzyme in the heme biosynthesis pathway that catalyses insertion of an iron atom into protoporphyrin IX. According to Barman-Aksoezen et al., 2017 (PMID: 28185024) Erythropoietic protoporphyria (EPP) patients 'frequently exhibit low serum iron and a microcytic hypochromic anemia'. However, as reviewed by Sharon Whatley, the iron deficiency is often mild (low to low-normal serum iron).

PMID: 21659066 Morais et al., 2011
Portuguese male proband with compound het mutations c.1052delA, p.Glu351Glyfs*6 and IVS3-48T>C in FECH - diagnosed with EPP, presented with acute episodes of photosensitivity, microcytic anemia and mild hepatic dysfunction.

PMID: 20412370 Wahlin et al., 2011
Swedish cohort of 51 EPP patients - 44% had low ferritin levels.

PMID: 28614581 Balwani et al., 2017
US report of 226 patients, 37.4% of EPP patients were anemic.

FECH is associated with Protoporphyria, erythropoietic,1 OMIM:177000 (OMIM accessed 26th Nov 2025).
Optic neuropathy v5.26 NDUFAF8 Neringa Jurkute gene: NDUFAF8 was added
gene: NDUFAF8 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF8 were set to PMID: 41234160
Phenotypes for gene: NDUFAF8 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF8 was set to Other
Review for gene: NDUFAF8 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFS7 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFAF4 Neringa Jurkute gene: NDUFAF4 was added
gene: NDUFAF4 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF4 were set to PMID: 41234160
Phenotypes for gene: NDUFAF4 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF4 was set to Other
Review for gene: NDUFAF4 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
2 unrelated families were carrying NDUFS7 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFAF3 Neringa Jurkute gene: NDUFAF3 was added
gene: NDUFAF3 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF3 were set to PMID: 41234160
Phenotypes for gene: NDUFAF3 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF3 was set to Other
Review for gene: NDUFAF3 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family were carrying NDUFAF3 pathogenic variants and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFAF2 Neringa Jurkute gene: NDUFAF2 was added
gene: NDUFAF2 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFAF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF2 were set to PMID: 41234160
Phenotypes for gene: NDUFAF2 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFAF2 was set to Other
Review for gene: NDUFAF2 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
2 unrelated families were carrying NDUFAF2 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFB11 Neringa Jurkute gene: NDUFB11 was added
gene: NDUFB11 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFB11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NDUFB11 were set to PMID: 41234160
Phenotypes for gene: NDUFB11 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFB11 was set to Other
Review for gene: NDUFB11 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family were carrying NDUFB11 pathogenic variant and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFA10 Neringa Jurkute gene: NDUFA10 was added
gene: NDUFA10 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFA10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA10 were set to PMID: 41234160
Phenotypes for gene: NDUFA10 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFA10 was set to Other
Review for gene: NDUFA10 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFA10 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFA1 Neringa Jurkute gene: NDUFA1 was added
gene: NDUFA1 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NDUFA1 were set to PMID: 41234160
Phenotypes for gene: NDUFA1 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFA1 was set to Other
Review for gene: NDUFA1 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
3 unrelated families were carrying NDUFA1 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFV2 Neringa Jurkute gene: NDUFV2 was added
gene: NDUFV2 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFV2 were set to PMID: 41234160
Phenotypes for gene: NDUFV2 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFV2 was set to Other
Review for gene: NDUFV2 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family was carrying NDUFV2 pathogenic variant and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFV1 Neringa Jurkute gene: NDUFV1 was added
gene: NDUFV1 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFV1 were set to PMID: 41234160
Phenotypes for gene: NDUFV1 were set to Optic neuropathy, optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFV1 was set to Other
Review for gene: NDUFV1 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
1 family was carrying NDUFV1 pathogenic variant and affected individual was diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NDUFS7 Neringa Jurkute gene: NDUFS7 was added
gene: NDUFS7 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NDUFS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFS7 were set to PMID: 41234160
Phenotypes for gene: NDUFS7 were set to Optic neuropathy; optic atrophy; LHON-like
Mode of pathogenicity for gene: NDUFS7 was set to Other
Review for gene: NDUFS7 was set to GREEN
Added comment: Recently accepted publication "Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy" reports Complex I genes, which pathogenic defects lead to optic atrophy; LHON-like phenotypes.
5 unrelated families were carrying NDUFS7 pathogenic variants and were diagnoses with optic neuropathy

Defects in core CI subunits in reported cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defect.
Sources: Literature, Research
Optic neuropathy v5.26 NSUN3 Neringa Jurkute gene: NSUN3 was added
gene: NSUN3 was added to Optic neuropathy. Sources: Literature,Research
Mode of inheritance for gene: NSUN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSUN3 were set to PMID: 38790159; PMID: 40465263
Phenotypes for gene: NSUN3 were set to optic neuropathy; optic atrophy; LHON; LHON-like
Mode of pathogenicity for gene: NSUN3 was set to Other
Review for gene: NSUN3 was set to GREEN
Added comment: PMID: 40465263
Biallelic NSUN3 variants were reported to be associated with an early onset severe mitochondrial disorder characterized by combined mitochondrial respiratory chain complex deficiency.
2 individuals from the paper presented with LHON-like phenotype;
5 with attenuated
2 syndromic
Optic atrophy was unifying feature.

PMID: 38790159
Mutations in NSUN3, a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy
Reports early onset optic neuropathy

A follow up par
Sources: Literature, Research
Severe microcephaly v8.21 KBTBD2 Arina Puzriakova Classified gene: KBTBD2 as Amber List (moderate evidence)
Severe microcephaly v8.21 KBTBD2 Arina Puzriakova Added comment: Comment on list classification: Adding to this panel as Amber as despite there being 3 unrelated cases, a specific description of the phenotype is not provided in one case (GDX6) making it challenging to make genotype-phenotype correlations. Microcephaly is reported in the other two individuals, however the severity is not specified. Based on the current evidence additional support is needed before this gene can be added to a diagnostic panel.
Severe microcephaly v8.21 KBTBD2 Arina Puzriakova Gene: kbtbd2 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.7 KBTBD2 Arina Puzriakova Classified gene: KBTBD2 as Amber List (moderate evidence)
Monogenic diabetes v3.7 KBTBD2 Arina Puzriakova Added comment: Comment on list classification: Adding to this panel as Amber as despite there being 3 unrelated cases, a specific description of the phenotype is not provided in one case (GDX6) making it challenging to make genotype-phenotype correlations.

There is only one reported case with diabetes, although it is possible that the other individuals may develop diabetes later in life. It is worth noting that this association is supported by the mouse model where insulin resistance and severe diabetes is observed. However, based on the current evidence additional support is needed before this gene can be added to a diagnostic panel.
Monogenic diabetes v3.7 KBTBD2 Arina Puzriakova Gene: kbtbd2 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.6 KBTBD2 Arina Puzriakova gene: KBTBD2 was added
gene: KBTBD2 was added to Monogenic diabetes. Sources: Literature
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: KBTBD2 was set to AMBER
Added comment: PMID: 39313616 (2024) - 3 unrelated cases with biallelic variants in this gene. Variants were LOF/missense compound het in 2 cases and homozygous LOF in the other case. Phenotypes include growth retardation (3/3), hyperglycemia and diabetes in an adolescent individual (1/3 - others thought to be too young to have developed diabetes), microcephaly (2/2), motor developmental delay. One individual had cardiomyopathy but also harboured an additional variant in MYH7 which could be contributing this phenotype.

Knock down in mice resulted in elevated expression of p85α and a phenotype involving lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes and growth retardation, which recapitulates some of the features observed in human cases.
Sources: Literature
Severe microcephaly v8.20 KBTBD2 Arina Puzriakova gene: KBTBD2 was added
gene: KBTBD2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: KBTBD2 was set to AMBER
Added comment: PMID: 39313616 (2024) - 3 unrelated cases with biallelic variants in this gene. Variants were LOF/missense compound het in 2 cases and homozygous LOF in the other case. Phenotypes include growth retardation (3/3), hyperglycemia and diabetes in an adolescent individual (1/3 - others thought to be too young to have developed diabetes), microcephaly (2/2), motor developmental delay. One individual had cardiomyopathy but also harboured an additional variant in MYH7 which could be contributing this phenotype.

Knock down in mice resulted in elevated expression of p85α and a phenotype involving lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes and growth retardation, which recapitulates some of the features observed in human cases.
Sources: Literature
Iron metabolism disorders - NOT common HFE mutations v3.1 FECH Ida Ertmanska reviewed gene: FECH: Rating: AMBER; Mode of pathogenicity: None; Publications: 20412370, 21659066, 28185024, 28614581; Phenotypes: Protoporphyria, erythropoietic,1 OMIM:177000, protoporphyria, erythropoietic, 1 MONDO:0008319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Vascular skin disorders v2.3 FECH Ida Ertmanska Publications for gene: FECH were set to 9649563
Vascular skin disorders v2.2 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from Protoporphyria, erythropoietic, 1, OMIM:177000 to Protoporphyria, erythropoietic, 1, OMIM:177000; protoporphyria, erythropoietic, 1, MONDO:0008319
Rare genetic inflammatory skin disorders v4.7 FECH Ida Ertmanska Tag curated_removed tag was added to gene: FECH.
Rare genetic inflammatory skin disorders v4.7 FECH Ida Ertmanska commented on gene: FECH
Non-acute porphyrias v1.31 FECH Ida Ertmanska Publications for gene: FECH were set to
Non-acute porphyrias v1.30 FECH Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 26th Nov 2025.
Non-acute porphyrias v1.30 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from Protoporphyria, erythropoietic,1 OMIM:177000; protoporphyria, erythropoietic, 1 MONDO:0008319 to Protoporphyria, erythropoietic,1 OMIM:177000; protoporphyria, erythropoietic, 1 MONDO:0008319
Cutaneous photosensitivity with a likely genetic cause v3.15 FECH Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 26th Nov 2025.
Cutaneous photosensitivity with a likely genetic cause v3.15 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from Erythropoietic Protoporphyria; Protoporphyria, erythropoietic, autosomal recessive, 177000 to Protoporphyria, erythropoietic, 1, OMIM:177000; protoporphyria, erythropoietic, 1, MONDO:0008319
Cutaneous photosensitivity with a likely genetic cause v3.14 FECH Ida Ertmanska Publications for gene: FECH were set to
Fetal anomalies v6.117 ITGAV Eleanor Williams Phenotypes for gene: ITGAV were changed from Syndromic disease, MONDO:0002254 to syndromic disease, MONDO:0002254
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Eleanor Williams Tag watchlist tag was added to gene: SVIL.
Arthrogryposis v9.14 SVIL Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 26th Nov 2025
Arthrogryposis v9.14 SVIL Eleanor Williams Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Congenital myopathy v6.40 SVIL Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 26th Nov 2025
Congenital myopathy v6.40 SVIL Eleanor Williams Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Arthrogryposis v9.13 SVIL Eleanor Williams Tag watchlist tag was added to gene: SVIL.
Arthrogryposis v9.13 SVIL Eleanor Williams Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Hypertrophic cardiomyopathy v5.17 SVIL Eleanor Williams Publications for gene: SVIL were set to 39966646
Hypertrophic cardiomyopathy v5.16 SVIL Eleanor Williams Added comment: Comment on publications: PMID:36778260 is a preprint of PMID:39966646
Hypertrophic cardiomyopathy v5.16 SVIL Eleanor Williams Publications for gene: SVIL were set to 39966646
Hypertrophic cardiomyopathy v5.15 SVIL Eleanor Williams Publications for gene: SVIL were set to PMID: 36778260
Retinal disorders v8.74 RNU6-9 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-9.
Tag Q3_25_promote_green tag was added to gene: RNU6-9.
Retinal disorders v8.74 RNU6-8 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-8.
Tag Q3_25_promote_green tag was added to gene: RNU6-8.
Retinal disorders v8.74 RNU4-2 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU4-2.
Tag Q3_25_promote_green tag was added to gene: RNU4-2.
Retinal disorders v8.74 RNU6-2 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-2.
Tag Q3_25_promote_green tag was added to gene: RNU6-2.
Rare genetic inflammatory skin disorders v4.7 FECH Ida Ertmanska Phenotypes for gene: FECH were changed from 177000 to Protoporphyria, erythropoietic, 1, OMIM:177000
Retinal disorders v8.74 RNU6-1 Achchuthan Shanmugasundram Tag Q4_25_promote_green was removed from gene: RNU6-1.
Tag Q3_25_promote_green tag was added to gene: RNU6-1.
Monogenic hearing loss v5.47 TBX2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TBX2.
Monogenic hearing loss v5.47 TBX2 Ida Ertmanska edited their review of gene: TBX2: Added comment: Comment on list classification: As the article by Hua et al. has now been published (PMID: 40962492, Sep 2025), there is enough evidence to promote this gene to Green for Monogenic hearing loss (2 unrelated probands with nonsense variants in TBX2 & a supportive mouse model).; Changed rating: GREEN; Changed publications to: 15459098, 20206336, 21271665, 22052739, 35508658, 40962492
Monogenic hearing loss v5.47 TBX2 Ida Ertmanska changed review comment from: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.

TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss.
Sources: Literature; to: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.

TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss.
Sources: Literature
Severe microcephaly v8.19 GPKOW Eleanor Williams changed review comment from: To date, three GPKOW variants have been associated with male-lethal microcephaly with intrauterine growth restriction (PMID: 28612833; 40221893).

Carroll et al 2017 (PMID: 28612833) report a splicing variant (NM_015698.4: c.331+5G>A) in a multigenerational family, with four female carriers, all of those who could be measured have short stature and microcephaly. Male-lethal microcephaly with intrauterine growth restriction was seen in three males within the family and two further male fetuses were terminated after ultrasound diagnosis of intrauterine growth restriction (IUGR). Analysis of patient IV-1 (terminated fetus), showed the presence of a hemizygous NM_015698.4: c.331+5G>A, which had been inherited from his carrier mother.

Two further GPKOW variants were identified by Mok, et al 2025 (PMID: 40221893), in three individuals from two families. These frameshift variants were in the last exon of GPKOW (NM_015698.5: c.1329dupG, p.(Arg441SerfsTer30) and c.1323_1324del, p.(Ser444GlufsTer28)). The male carriers of NM_015698.5: c.1329dupG had IUGR, and other features, but not microcephaly nor lethality. The male carrier of c.1323_1324del had IUGR and microcephaly and was terminated at (33/40). The mothers of these cases had short stature, microcephaly (in one case) and other phenotypic features.

Extensive support from functional studies were also presented in PMID: 28612833; 40221893.; to: To date, three GPKOW variants have been associated with male-lethal microcephaly with intrauterine growth restriction (PMID: 28612833; 40221893).

Carroll et al 2017 (PMID: 28612833) report a splicing variant (NM_015698.4: c.331+5G>A) in a multigenerational family, with four female carriers, all of those who could be measured have short stature and microcephaly. Male-lethal microcephaly with intrauterine growth restriction was seen in three males within the family and two further male fetuses were terminated after ultrasound diagnosis of intrauterine growth restriction (IUGR). Analysis of patient IV-1 (terminated fetus), showed the presence of a hemizygous NM_015698.4: c.331+5G>A, which had been inherited from his carrier mother.

Two further GPKOW variants were identified by Mok, et al 2025 (PMID: 40221893), in three individuals from two families. These frameshift variants were in the last exon of GPKOW (NM_015698.5: c.1329dupG, p.(Arg441SerfsTer30) and c.1323_1324del, p.(Ser444GlufsTer28)). The male carriers of NM_015698.5: c.1329dupG had IUGR, and other features, but not microcephaly nor lethality. The male carrier of c.1323_1324del had IUGR and microcephaly and was terminated at (33/40). The mothers of these cases had short stature, microcephaly (in one case) and other phenotypic features.

Extensive support from functional studies were also presented in PMID: 28612833; 40221893.
Fetal anomalies v6.116 GPKOW Eleanor Williams edited their review of gene: GPKOW: Changed rating: GREEN
Fetal anomalies v6.116 GPKOW Eleanor Williams edited their review of gene: GPKOW: Changed rating: AMBER
Hypertrophic cardiomyopathy v5.14 SVIL Ida Ertmanska Phenotypes for gene: SVIL were changed from HCM to hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy v5.13 SVIL Ida Ertmanska Classified gene: SVIL as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v5.13 SVIL Ida Ertmanska Gene: svil has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: Comment on list classification: The main piece of evidence for this gene-disease association is a GWAS study, with very limited co-segregation evidence (PMID: 39966646). There are no other cases reported with Hypertrophic cardiomyopathy and heterozygous variants in SVIL. Individuals homozygous for nonsense variants in SVIL have been reported, but the myopathy presentation includes very mild to no cardiac involvement (PMID: 32779703). Based on available evidence, this gene should be rated Amber for Hypertrophic cardiomyopathy, until more evidence emerges.; to: Comment on list classification: The main piece of evidence for this gene-disease association is a GWAS study, with no clinical details and limited co-segregation evidence (PMID: 39966646). There are no other cases reported with Hypertrophic cardiomyopathy and heterozygous variants in SVIL. Individuals homozygous for nonsense variants in SVIL have been reported, but the myopathy presentation includes very mild to no cardiac involvement (PMID: 32779703). Based on available evidence, this gene should be rated Amber for Hypertrophic cardiomyopathy, until more evidence emerges.
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska edited their review of gene: SVIL: Added comment: Comment on list classification: The main piece of evidence for this gene-disease association is a GWAS study, with very limited co-segregation evidence (PMID: 39966646). There are no other cases reported with Hypertrophic cardiomyopathy and heterozygous variants in SVIL. Individuals homozygous for nonsense variants in SVIL have been reported, but the myopathy presentation includes very mild to no cardiac involvement (PMID: 32779703). Based on available evidence, this gene should be rated Amber for Hypertrophic cardiomyopathy, until more evidence emerges.; Changed rating: AMBER
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization, homozygous for truncating variants in SVIL. Very mild cardiac involvement: Slightly hypertrophic left ventricular wall 2/4, slight tricuspid regurgitation 2/4; Increased basal wall thickness (30mm) in Individual 1 - noted on cardiac MRI at age 27.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).; to: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL. Numerous other rare nonsense variants in SVIL were also reported in the non-HCM control cohort (see supplementary table 19).
Limited evidence of segregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization, homozygous for truncating variants in SVIL. Very mild cardiac involvement: Slightly hypertrophic left ventricular wall 2/4, slight tricuspid regurgitation 2/4; Increased basal wall thickness (30mm) in Individual 1 - noted on cardiac MRI at age 27.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).; to: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization, homozygous for truncating variants in SVIL. Very mild cardiac involvement: Slightly hypertrophic left ventricular wall 2/4, slight tricuspid regurgitation 2/4; Increased basal wall thickness (30mm) in Individual 1 - noted on cardiac MRI at age 27.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska changed review comment from: PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myofibrillar myopathy. Muscle biopsy showed Structural myopathy with prominent lobulated type 1 fibres, myofibrillar disintegration and signs of altered proteostasis/impaired autophagy in all 4 affected individuals. All patients showed increased creatine kinase levels, but no or minor muscle weakness. Variable presentation, including muscle pain, slowly progressive stiffness, exercise intolerance, as well as distinct anomalies of neck and shoulder girdle; 3/4 patients presented with contractures. Very mild heart involvement.
Seq method: WES/ targeted exome with Sanger confirmation.
Family 1: Lebanese, 2 sibs affected, both homozygous for c.4812C>A, p.(Tyr1604*) - variant not in gnomAD v4.1.0. Symptom onset: childhood/adolescence.
Family 2: Turkish, 2 sibs affected, both homozygous for c.3578_3579del, p.(Val1193Glufs*46) - variant not in gnomAD v4.1.0; symptoms onset at birth/ in infancy.

SVIL is associated with AR Myofibrillar myopathy 10, MIM: 619040 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization. Muscle biopsy showed Structural myopathy with prominent lobulated type 1 fibres, myofibrillar disintegration and signs of altered proteostasis/impaired autophagy in all 4 affected individuals. All patients showed increased creatine kinase levels, but no or minor muscle weakness. Variable presentation, including muscle pain, slowly progressive stiffness, exercise intolerance, as well as distinct anomalies of neck and shoulder girdle; 3/4 patients presented with contractures. Very mild heart involvement.
Seq method: WES/ targeted exome with Sanger confirmation.
Family 1: Lebanese, 2 sibs affected, both homozygous for c.4812C>A, p.(Tyr1604*) - variant not in gnomAD v4.1.0. Symptom onset: childhood/adolescence.
Family 2: Turkish, 2 sibs affected, both homozygous for c.3578_3579del, p.(Val1193Glufs*46) - variant not in gnomAD v4.1.0; symptoms onset at birth/ in infancy.

SVIL is associated with AR Myofibrillar myopathy 10, MIM: 619040 (OMIM accessed 24th Nov 2025).
Sources: Literature
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska changed review comment from: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).; to: PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL.
Limited evidence of cosegregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).
Hypertrophic cardiomyopathy v5.12 SVIL Ida Ertmanska reviewed gene: SVIL: Rating: RED; Mode of pathogenicity: None; Publications: 36778260, 39966646; Phenotypes: hypertrophic cardiomyopathy, MONDO:0005045; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska changed review comment from: Comment on list classification: There are 4 individuals from 2 unrelated families reported in literature with homozygous nonsense variants in SVIL, diagnosed with myofibrillar myopathy. This gene should be rated Amber on Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies until more evidence emerges.; to: Comment on list classification: There are 4 individuals from 2 unrelated families reported in literature with homozygous nonsense variants in SVIL, diagnosed with myopathy with myofibrillar disorganization. This gene should be rated Amber on Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies until more evidence emerges.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska edited their review of gene: SVIL: Changed phenotypes to: Myofibrillar myopathy 10, OMIM:619040, myofibrillar myopathy 10, MONDO:0033620
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.22 SVIL Ida Ertmanska Phenotypes for gene: SVIL were changed from Myofibrillar myopathy 10, OMIM:619040 to Myofibrillar myopathy 10, OMIM:619040; myofibrillar myopathy 10, MONDO:0033620
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.21 SVIL Ida Ertmanska Classified gene: SVIL as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.21 SVIL Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 2 unrelated families reported in literature with homozygous nonsense variants in SVIL, diagnosed with myofibrillar myopathy. This gene should be rated Amber on Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies until more evidence emerges.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.21 SVIL Ida Ertmanska Gene: svil has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.20 SVIL Ida Ertmanska edited their review of gene: SVIL: Changed rating: AMBER; Changed publications to: 32779703
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.20 SVIL Ida Ertmanska changed review comment from: Sources: Literature; to: PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myofibrillar myopathy. Muscle biopsy showed Structural myopathy with prominent lobulated type 1 fibres, myofibrillar disintegration and signs of altered proteostasis/impaired autophagy in all 4 affected individuals. All patients showed increased creatine kinase levels, but no or minor muscle weakness. Variable presentation, including muscle pain, slowly progressive stiffness, exercise intolerance, as well as distinct anomalies of neck and shoulder girdle; 3/4 patients presented with contractures. Very mild heart involvement.
Seq method: WES/ targeted exome with Sanger confirmation.
Family 1: Lebanese, 2 sibs affected, both homozygous for c.4812C>A, p.(Tyr1604*) - variant not in gnomAD v4.1.0. Symptom onset: childhood/adolescence.
Family 2: Turkish, 2 sibs affected, both homozygous for c.3578_3579del, p.(Val1193Glufs*46) - variant not in gnomAD v4.1.0; symptoms onset at birth/ in infancy.

SVIL is associated with AR Myofibrillar myopathy 10, MIM: 619040 (OMIM accessed 24th Nov 2025).
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.20 SVIL Ida Ertmanska gene: SVIL was added
gene: SVIL was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SVIL were set to Myofibrillar myopathy 10, OMIM:619040
Review for gene: SVIL was set to GREEN
Added comment: Sources: Literature
DDG2P v6.8 CCNK Ida Ertmanska commented on gene: CCNK
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects. Variant not reported in gnomAD v4.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms. Variant not reported in gnomAD v4.
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.; to: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are also several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska commented on gene: CCNK: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate features of human disease. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska Deleted their comment
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- mouse model

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- knockdown mouse model showed deficient neural progenitor cell proliferation and enhanced apoptotic cell death.

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska commented on gene: CCNK: Comment on list classification: There are at least 3 unrelated individuals reported in literature with de novo missense variants in CCNK, diagnosed with Intellectual developmental disorder with hypertelorism and distinctive facies. There are several individuals reported with deletions affecting CCNK among other genes - these deletions are generally associated with a more severe phenotype. Functional evidence for this gene-disease association includes zebrafish and mouse knockdowns, which recapitulate the human disease phenotype. Based on the available evidence, this gene should be promoted to Green for Intellectual disability.
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new (P1 & P3) and 3 previously reported cases. Seq method: exome seq + Sanger.
Patient 1 - Chinese Female 1 y 4 mo; het for c.556T>C, p.(Trp186Arg) - de novo; Moderate DD/ID, distinctive facial features, congenital cardiac defects.
Patient 3 - Chinese Female 5 y 4 mo; het for c.772T>C, p.(Tyr258His) - de novo; Mild DD/ID (IQ 59 - WPPSI scale), facial dysmorphisms
Functional evidence: Ccnk +/- mouse model

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska changed review comment from: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.
Sources: Literature; to: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.

CCNK pLI score = 1.00 - predicted to be extremely intolerant to LoF. CCNK is putatively associated with AD Intellectual developmental disorder with hypertelorism and distinctive facies, MIM:618147 (OMIM accessed 24th Nov 2025).
Sources: Literature
Intellectual disability v9.190 CCNK Ida Ertmanska edited their review of gene: CCNK: Changed phenotypes to: ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147, intellectual developmental disorder with hypertelorism and distinctive facies, MONDO:0029143
Intellectual disability v9.190 CCNK Ida Ertmanska Phenotypes for gene: CCNK were changed from ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147 to ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147; intellectual developmental disorder with hypertelorism and distinctive facies, MONDO:0029143
Intellectual disability v9.189 CCNK Ida Ertmanska Classified gene: CCNK as Amber List (moderate evidence)
Intellectual disability v9.189 CCNK Ida Ertmanska Gene: ccnk has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.188 CCNK Ida Ertmanska gene: CCNK was added
gene: CCNK was added to Intellectual disability. Sources: Literature
Q4_25_promote_green tags were added to gene: CCNK.
Mode of inheritance for gene: CCNK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCNK were set to 30122539; 35063350; 37597256; 41101726
Phenotypes for gene: CCNK were set to ?Intellectual developmental disorder with hypertelorism and distinctive facies, OMIM:618147
Review for gene: CCNK was set to GREEN
Added comment: PMID: 30122539 Fan et al., 2018
Report of 3 unrelated Chinese individuals with de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region (with several other genes being deleted) and 1 African American individual harbouring a de novo CCNK variant c.331A>G (p.Lys111Glu) - variant not present in gnomAD v4; Revel score = 0.52. Common phenotype: developmental delay and moderate (1/4) to severe (3/4) intellectual disability (DD/ID), language defects, distinctive facial dysmorphism. 4/4 cases confirmed as de novo.
Functional evidence: Ccnk knockdown in zebrafish resulted in defective brain development, small eyes, and curly spinal cord; defects were partially rescued by WT CCNK mRNA but not by the c.331A>G mRNA variant.

PMID: 35063350 Rouxel et al., 2022
ID B5 - 1.5 yr old female, het for a missense variant in CCNK (variant not specified); phenotype: distinctive facial features matching CDK13-deficient patients, neuropsychological assessment not conducted; high methylation variant pathogenicity (MVP) score - methylation score matched individuals with pathogenic CDK13 variants; CDK13 forms a complex with cyclin K (encoded by CCNK).

PMID: 37597256 Dai et al., 2023
Report of 2 new and 3 previously reported cases

PMID: 41101726 Xiol et al., Oct 2025 - online ahead of print
Report of an 11yr old girl with a de novo CCNK missense variant c.549A>C, p.(Gln183His) - not in gnomAD v4.1.0, Revel score = 0.43; phenotype: mild intellectual disability (WISC-V at 10yrs showed IQ of 69), subtle dysmorphism (hypertelorism, depressed/broad nasal bridge), ventriculomegaly, delayed motor milestones & hypotonia.
Sources: Literature
Vici Syndrome and other autophagy disorders v1.3 Eleanor Williams List of related panels changed from to
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Multiple Epiphyseal Dysplasia v1.7 Eleanor Williams List of related panels changed from to
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Hydroa vacciniforme v1.3 Eleanor Williams List of related panels changed from to
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Early onset or syndromic epilepsy v8.76 RANBP2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.; to: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy with seizures, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.
Early onset or syndromic epilepsy v8.76 RANBP2 Ida Ertmanska Phenotypes for gene: RANBP2 were changed from {Encephalopathy, acute, infection-induced, 3, susceptibility to} 608033 to {Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033
Early onset or syndromic epilepsy v8.75 RANBP2 Ida Ertmanska Publications for gene: RANBP2 were set to
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska edited their review of gene: RANBP2: Changed publications to: 34377735, 36621064, 38050538, 40538544
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion on this panel.; to: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska commented on gene: RANBP2: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion on this panel.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025).

PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.; to: PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.

RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025). RANBP2 association with familial acute necrotizing encephalopathy has been classified as Moderate in ClinGen by the Epilepsy Expert panel (April 2024) and Limited for Leigh Syndrome (Mitochondrial Diseases Expert Panel, June 2021).
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025).

PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.

PMID: 32426208 Levine et al., 2020; to: RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025).

PMID: 40538544 Varghese et al., 2025
Case 1 - previously healthy 23-month-old female presented with lethargy and acute-onset encephalopathy, following a 2-day fever. Brain MRI consistent with Acute necrotizing encephalopathy (ANE). She presented with another episode of acute-onset encephalopathy at 4yrs 10 mo; she remains non-verbal and non-ambulatory. Family history: 2 maternal uncles, deceased at 16 & 22 months old - both with working diagnoses of Leigh-like disease. Patient was heterozygous for c.1754C>G, p.Thr585Met (maternally inherited) - rare in gnomAD v4.1.0 (2 heterozygotes), Revel score = 0.18 Benign Moderate. Seq method: rapid Trio WES.

Case 2 - A 24-month-old male, previously described in PMID: 36632547 Olubiyi et al., 2022. Patient presented with acute encephalopathy, seizures, and emesis. Positive for respiratory SARS-CoV-2; brain MRI concerning for ANE; discharged from hospital on day 7. Presented again at 30 months with acute-onset encephalopathy, delirium, and seizures. At 4.5yrs, patient is much improved - he was forming sentences and ambulated independently with a mildly ataxic gait, WPPSI-IV IQ 65 (mild ID). Heterozygous for RANBP2 c.1966A>G (p.Ile656Val) - maternally inherited; variant rare in gnomAD v4.1.0 (1 heterozygote), Revel score = 0.31 Uncertain.

PMID: 38050538 Li et al., 2023
Report of 1‐year‐old girl - presented with influenza‐associated encephalopathy after which she made a full recovery; followed by severe acute respiratory syndrome coronavirus 2 infection - the patient presented with seizures and deteriorating mental status. Brain MRI revealed necrotic lesions. WES revealed heterozygous c.1754C>T, p.Thr585Met and c.6952G>A, p.Asp2318Asn variants in RANBP2 (presumed in cis?). Variant c.6952G>A, p.Asp2318Asn is not in gnomAD v4, Revel score = 0.34 Benign Supporting.
The penetrance of RANBP2 missense variants is estimated at around 40%.

PMID: 36621064 Forest et al., 2023
Report of a 10-year-old girl with acute onset of decreased level of consciousness and fever. Brain and spinal cord MRI confirmed extensive areas of cytotoxic edema; MRI suggestive for necrosis. Diagnosed with ANE associated with Sars-CoV-2 infection. First episode noted to be at 2yo - trigerred by Influenza A. WES revealed a de novo c.1754C>T p.(Thr585Met) mutation in RANBP2.

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska edited their review of gene: RANBP2: Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska reviewed gene: RANBP2: Rating: ; Mode of pathogenicity: None; Publications: 38050538, 40538544; Phenotypes: {Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033; Mode of inheritance: None
Retinal disorders v8.74 RNU6-9 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-9.
Retinal disorders v8.74 RNU6-8 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-8.
Retinal disorders v8.74 RNU6-2 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-2.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6-1.
Retinal disorders v8.74 RNU4-2 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU4-2.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-1 specific data: n.55_56insG insertion in RNU6-1 reported in patients from 4 diverse RP families - 2 cases suspected to be de novo; n.56_57insG detected in 2 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.74 RNU6-1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: Recurrent RNU6-1 variants (n.55_56insG & n.56_57insG) were detected in patients from 6 unrelated families with retinitis pigmentosa - 2 cases suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-1 should be promoted to Green for Retinal disorders at the next GMS update.; to: Comment on list classification: Recurrent RNU6-1 variants (n.55_56insG & n.56_57insG) were detected in patients from 6 unrelated families with retinitis pigmentosa - 2 cases suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-1 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Classified gene: RNU6-1 as Amber List (moderate evidence)
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: Recurrent RNU6-1 variants (n.55_56insG & n.56_57insG) were detected in patients from 6 unrelated families with retinitis pigmentosa - 2 cases suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-1 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.74 RNU6-1 Ida Ertmanska Gene: rnu6-1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.73 RNU6-1 Ida Ertmanska gene: RNU6-1 was added
gene: RNU6-1 was added to Retinal disorders. Sources: Literature
Q4_25_promote_green tags were added to gene: RNU6-1.
Mode of inheritance for gene: RNU6-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-1 were set to 39830270
Phenotypes for gene: RNU6-1 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-1 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.72 RNU6-9 Ida Ertmanska changed review comment from: Comment on list classification: RNU6-9 variants (n.55_56insG & n.56_57insG) were detected in patients from 17 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 6 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-9 should be promoted to Green for Retinal disorders at the next GMS update.; to: Comment on list classification: Recurrent RNU6-9 variants (n.55_56insG & n.56_57insG) were detected in patients from 17 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 6 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-9 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.72 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms. Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families - 1 case de novo; incomplete penetrance was observed for nine obligate carriers, without visual symptoms. Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.72 RNU6-9 Ida Ertmanska Classified gene: RNU6-9 as Amber List (moderate evidence)
Retinal disorders v8.72 RNU6-9 Ida Ertmanska Gene: rnu6-9 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.71 RNU6-9 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.71 RNU6-9 Ida Ertmanska commented on gene: RNU6-9: Comment on list classification: RNU6-9 variants (n.55_56insG & n.56_57insG) were detected in patients from 17 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 6 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-9 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.71 RNU6-9 Ida Ertmanska gene: RNU6-9 was added
gene: RNU6-9 was added to Retinal disorders. Sources: Literature
Q4_25_promote_green tags were added to gene: RNU6-9.
Mode of inheritance for gene: RNU6-9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-9 were set to 39830270
Phenotypes for gene: RNU6-9 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-9 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-9 specific data: n.55_56insG insertion in RNU6-9 reported in numerous patients from 14 diverse RP families - 3 cases confirmed and 6 suspected to be de novo; n.56_57insG detected in 3 unrelated adRP families (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Sources: Literature
Retinal disorders v8.70 RNU6-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families - 3 cases confirmed de novo, 3 suspected to be de novo; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.70 RNU6-8 Ida Ertmanska Classified gene: RNU6-8 as Amber List (moderate evidence)
Retinal disorders v8.70 RNU6-8 Ida Ertmanska Added comment: Comment on list classification: Recurrent RNU6-8 variant n.55_56insG was detected in patients from 12 unrelated diverse families with retinitis pigmentosa - 1 case confirmed de novo, 1 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-8 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.70 RNU6-8 Ida Ertmanska Gene: rnu6-8 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.69 RNU6-2 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: RNU6-2 variants (n.55_56insG & n.56_57insG) were detected in patients from 14 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 3 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-2 should be promoted to Green for Retinal disorders at the next GMS update.; to: Comment on list classification: RNU6-2 variants (n.55_56insG & n.56_57insG) were detected in patients from 14 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 3 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-2 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.69 RNU6-8 Ida Ertmanska gene: RNU6-8 was added
gene: RNU6-8 was added to Retinal disorders. Sources: Literature
Q4_25_promote_green tags were added to gene: RNU6-8.
Mode of inheritance for gene: RNU6-8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-8 were set to 39830270
Phenotypes for gene: RNU6-8 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-8 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-8 specific data: n.55_56insG insertion in RNU6-8 reported in numerous patients from 12 diverse RP families - 1 case confirmed and 1 suspected to be de novo; n.56_57insG not detected in RNU6-8 (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.68 RNU6-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7. Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total).
Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.68 RNU6-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in individuals from 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: RNU6-2.
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Classified gene: RNU6-2 as Amber List (moderate evidence)
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: RNU6-2 variants (n.55_56insG & n.56_57insG) were detected in patients from 14 unrelated families with retinitis pigmentosa - 3 cases confirmed de novo, 3 suspected to be de novo. 78% of individuals with U4/U6 changes presented with first RP symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU6-2 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.68 RNU6-2 Ida Ertmanska Gene: rnu6-2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.67 RNU6-2 Ida Ertmanska gene: RNU6-2 was added
gene: RNU6-2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: RNU6-2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-2 were set to 39830270
Phenotypes for gene: RNU6-2 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU6-2 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

n.55_56insG insertion recurred in the RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8, and RNU6-9) - 102 individuals from 47 diverse, unrelated families. Pathogenic variants were NOT detected in RNU6-7.
Insertion at the same position, n.55_56insT, is reported in gnomAD in all 5 paralogs (181 alleles total). Insertion n.56_57insG was detected in RNU6 paralogs in 6 families.

RNU6-2 specific data: n.55_56insG insertion in RNU6-2 reported in 13 diverse RP families; n.56_57insG in RNU6-2 detected in 1 RP family (based on pre-print supplementary table 2).

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Retinal disorders v8.66 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms. Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.66 RNU4-2 Ida Ertmanska commented on gene: RNU4-2: Comment on list classification: Recurrent RNU4-2 variants (n.56T>C & n.18_19insA) were detected in 41 patients from 15 unrelated families with retinitis pigmentosa - 1 case de novo. 78% of the individuals presented with first symptoms during childhood or adolescence. Importantly, 9 obligate carriers from these families had no visual symptoms, hinting at incomplete disease penetrance. Based on the available evidence, RNU4-2 should be promoted to Green for Retinal disorders at the next GMS update.
Retinal disorders v8.66 RNU4-2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: RNU4-2.
Retinal disorders v8.66 RNU4-2 Ida Ertmanska Classified gene: RNU4-2 as Amber List (moderate evidence)
Retinal disorders v8.66 RNU4-2 Ida Ertmanska Gene: rnu4-2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.65 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), cataract/lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Details for patients with U4 and U6 changes:
Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), non-age-related cataract / lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.65 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Age of onset of RP: under 12yo = 42 patients (62%); 13-19 years = 11; 20-30 years = 8; adulthood 30+ = 7 patients.
Phenotype spectrum in addition to classical RP features: ocular edema (56%), cataract/lens opacity (24%), vitreoretinal complications (31%).
Range of ethnicities: Spanish, German, Polish, USA, Indian Jewish, Afro-carribean, Belgian.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.

Sources: Literature
Retinal disorders v8.65 RNU4-2 Ida Ertmanska changed review comment from: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature; to: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA. Method: genome sequencing.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Intellectual disability v9.187 SPAST Arina Puzriakova Publications for gene: SPAST were set to 39731306
Intellectual disability v9.186 SPAST Arina Puzriakova reviewed gene: SPAST: Rating: ; Mode of pathogenicity: None; Publications: 39457434; Phenotypes: ; Mode of inheritance: None
Retinal disorders v8.65 RNU4-2 Ida Ertmanska gene: RNU4-2 was added
gene: RNU4-2 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU4-2 were set to 39830270
Phenotypes for gene: RNU4-2 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: RNU4-2 was set to GREEN
Added comment: PMID: 39830270 Quinodoz et al., 2025
Large cohort of RP patients screened using Sanger sequencing of genes encoding U4 and U6. Reported 153 individuals across 67 families with retinitis pigmentosa, with monoallelic variants in RNU4-2 and RNU6 paralogs.

Recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families; incomplete penetrance was observed for nine obligate carriers, without visual symptoms.
Recurrent variants: n.56T>C, n.18_19insA - not reported in gnomAD v4.1.0.
Family M1-A - 7 siblings and father affected - het for RNU4-2 NR_003137.2:n.18_19insA.

Functional effect prediction: RP-related variants identified reside in a region that critical for binding of the U4/U6 duplex to the splicing factors PRPF31, PRPF3, and PRPF8 - genes previously linked to AD retinitis pigmentosa.
Sources: Literature
Hereditary ataxia with onset in adulthood v8.12 PNPT1 Lucy Jackson gene: PNPT1 was added
gene: PNPT1 was added to Hereditary ataxia with onset in adulthood. Sources: NHS GMS
Mode of inheritance for gene: PNPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: PNPT1 was set to GREEN
Added comment: Already green on childhood ataxia panel, see https://panelapp.genomicsengland.co.uk/panels/477/gene/PNPT1/
The ataxia phenotype can manifest in adulthood, therefore suggest adding to this panel also.
Sources: NHS GMS
Intellectual disability v9.186 ANKS1B Nour Elkhateeb gene: ANKS1B was added
gene: ANKS1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANKS1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKS1B were set to 31388001; 38129387
Phenotypes for gene: ANKS1B were set to Developmental delay; Intellectual disability; Autism; Speech and language delay
Review for gene: ANKS1B was set to GREEN
Added comment: Monoallelic ANKS1B microdeletion resulting in Haploinsufficiency have been reported to be associated with variable developmental delays, intellectual disability, behavioural difficulties, as well as other features such as Craniofacial dysmorphism, and MRI brain abnormalities in 4 families (PMID 31388001, 38129387).
Sources: Literature
Intellectual disability v9.186 AFF3_GGC Eleanor Williams commented on STR: AFF3_GGC: To align with other STRs within PanelApp, the STR name AFF3_GCC was changed to AFF3_GGC and the repeat sequence has been changed from GCC to GGC in March 2025.
Amelogenesis imperfecta v4.24 LTBP3 Claire Smith reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29625025; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Currarino triad v1.2 Eleanor Williams List of related panels changed from to
Classical tuberous sclerosis v1.3 Eleanor Williams List of related panels changed from to
Chondrodysplasia punctata v1.6 Eleanor Williams List of related panels changed from to
Choanal atresia v1.17 Eleanor Williams List of related panels changed from to
Cerebral folate deficiency v1.4 Eleanor Williams List of related panels changed from to
Autosomal recessive congenital ichthyosis v1.15 Eleanor Williams List of related panels changed from to
Intellectual disability v9.186 BSN Ida Ertmanska Classified gene: BSN as Amber List (moderate evidence)
Intellectual disability v9.186 BSN Ida Ertmanska Gene: bsn has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.185 BSN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BSN.
Intellectual disability v9.185 BSN Ida Ertmanska changed review comment from: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Sources: Other; to: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Intellectual disability v9.185 BSN Ida Ertmanska commented on gene: BSN: Comment on list classification: As reviewed by Helen Lord, there are numerous individuals reported in literature with a neurodevelopmental disorder with monoallelic variants in BSN. The disorder includes a range of variably penetrant features, with DD/ID and epilepsy being the most common (PMID: 40393460 Guzman et al., 2025). There are 4 individuals reported with compound heterozygous variants in BSN with early onset epilepsy. However, only 1/4 of the biallelic cases presented with developmental delay (PMID: 36600631, Ye et al., 2023). Based on the available evidence this gene should be rated Green for Intellectual disability, with MOI set to BIALLELIC, autosomal or pseudoautosomal.

BSN is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Intellectual disability v9.185 BSN Ida Ertmanska gene: BSN was added
gene: BSN was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: BSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BSN were set to 36600631; 39616287; 40393460
Phenotypes for gene: BSN were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: BSN was set to GREEN
Added comment: Literature review by Helen Lord (Oxford Medical Genetics Laboratories) copied from the Epilepsy panel:

There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Sources: Other
Early onset or syndromic epilepsy v8.74 BSN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BSN.
Tag Q4_25_NHS_review tag was added to gene: BSN.
Early onset or syndromic epilepsy v8.74 BSN Ida Ertmanska Phenotypes for gene: BSN were changed from Seizures - different types to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v8.73 BSN Ida Ertmanska Publications for gene: BSN were set to PMID: 36600631; 39616287; 40393460
Early onset or syndromic epilepsy v8.72 BSN Ida Ertmanska Mode of inheritance for gene: BSN was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.71 BSN Ida Ertmanska Classified gene: BSN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.71 BSN Ida Ertmanska Gene: bsn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.70 BSN Ida Ertmanska reviewed gene: BSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 36600631, 39616287, 40393460; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Malformations of cortical development v7.17 BAIAP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). As only 1 patient presented with lissencephaly, BAIAP2 should be rated Red for Malformations of cortical development, until more evidence emerges.; to: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). Baiap2 knockdown in mouse causes abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). As only 1 patient presented with lissencephaly, BAIAP2 should be rated Red for Malformations of cortical development, until more evidence emerges.
Malformations of cortical development v7.17 BAIAP2 Ida Ertmanska commented on gene: BAIAP2: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). As only 1 patient presented with lissencephaly, BAIAP2 should be rated Red for Malformations of cortical development, until more evidence emerges.
Malformations of cortical development v7.17 BAIAP2 Ida Ertmanska gene: BAIAP2 was added
gene: BAIAP2 was added to Malformations of cortical development. Sources: Other
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAIAP2 were set to 30696821; 38149472; 41133935
Phenotypes for gene: BAIAP2 were set to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Review for gene: BAIAP2 was set to RED
Added comment: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Sources: Other
Intellectual disability v9.184 BAIAP2 Ida Ertmanska Classified gene: BAIAP2 as Amber List (moderate evidence)
Intellectual disability v9.184 BAIAP2 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). All 7 individuals presented with global developmental delay, intellectual disability, poor motor milestone achievement, and poor / lack of speech development.
Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). Additional functional evidence from coimmunoprecipitation studies shows that missense variants around aa 340-366 in BAIAP2 are likely to disrupt binding of 14-3-3, necessary for BAIAP2 inhibition (PMID: 30696821). Based on the available evidence, BAIAP2 should be promoted to Green for Intellectual disability.
Intellectual disability v9.184 BAIAP2 Ida Ertmanska Gene: baiap2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.183 BAIAP2 Ida Ertmanska gene: BAIAP2 was added
gene: BAIAP2 was added to Intellectual disability. Sources: Other
Q4_25_promote_green tags were added to gene: BAIAP2.
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAIAP2 were set to 30696821; 38149472; 41133935
Phenotypes for gene: BAIAP2 were set to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Review for gene: BAIAP2 was set to GREEN
Added comment: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Sources: Other
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska edited their review of gene: BAIAP2: Changed publications to: 30696821, 38149472, 41133935
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BAIAP2.
Tag Q4_25_NHS_review tag was added to gene: BAIAP2.
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska Publications for gene: BAIAP2 were set to PMID: 41133935
Early onset or syndromic epilepsy v8.69 BAIAP2 Ida Ertmanska Phenotypes for gene: BAIAP2 were changed from DEE to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Early onset or syndromic epilepsy v8.68 BAIAP2 Ida Ertmanska Mode of inheritance for gene: BAIAP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v8.67 BAIAP2 Ida Ertmanska Classified gene: BAIAP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.67 BAIAP2 Ida Ertmanska Gene: baiap2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472).; to: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). All individuals presented with early onset epilepsy. Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). Additional functional evidence from coimmunoprecipitation studies shows that missense variants around aa 340-366 in BAIAP2 are likely to disrupt binding of 14-3-3, necessary for BAIAP2 inhibition (PMID: 30696821). Based on the available evidence, BAIAP2 should be promoted to Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2. 14-3-3

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).; to: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2. 14-3-3

Functional evidence: Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).; to: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2. 14-3-3

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska edited their review of gene: BAIAP2: Added comment: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472).; Changed phenotypes to: developmental and epileptic encephalopathy, MONDO:0100620, classic lissencephaly, MONDO:0015146
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska reviewed gene: BAIAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38149472, 41133935; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v5.9 TARS2 Ida Ertmanska edited their review of gene: TARS2: Changed phenotypes to: Combined oxidative phosphorylation deficiency 21, OMIM:615918, combined oxidative phosphorylation defect type 21, MONDO:0014398
Neonatal diabetes v5.9 TARS2 Ida Ertmanska Phenotypes for gene: TARS2 were changed from Neonatal diabetes; developmental delay; epilepsy to Combined oxidative phosphorylation deficiency 21, OMIM:615918; combined oxidative phosphorylation defect type 21, MONDO:0014398
Neonatal diabetes v5.8 TARS2 Ida Ertmanska Publications for gene: TARS2 were set to PMID: 39509107 and PMID: 37454282
Neonatal diabetes v5.7 TARS2 Ida Ertmanska Classified gene: TARS2 as Amber List (moderate evidence)
Neonatal diabetes v5.7 TARS2 Ida Ertmanska Gene: tars2 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.6 TARS2 Ida Ertmanska commented on gene: TARS2: Comment on list classification: Out of more than 30 individuals reported in literature with biallelic TARS2 variants and Combined oxidative phosphorylation deficiency 21, only 4 patients presented with the additional phenotype of neonatal diabetes. 4/4 of those patients were homozygous for the same missense variant p.(Arg327Gln) - 3 families had a shared haplotype (PMID:39509107, Donis et al., 2025). An additional patient with TARS2-related COXPD-21 and diabetes was reported in PMID: 37454282 Accogli et al., 2023 - age of onset unknown. Based on the available evidence, this gene should be rated Amber for Neonatal diabetes until more evidence emerges.

Importantly, ID/DD and axial hypotonia are the main features reported in COXPD-21 patients (92% and 85% of individuals respectively - PMID: 39509107). TARS2 is already rated Green / tagged for promotion on other panels in PanelApp which cover the most common symptoms, including: Intellectual disability; Childhood onset dystonia, chorea or related movement disorder; Mitochondrial disorders .
Neonatal diabetes v5.6 TARS2 Ida Ertmanska reviewed gene: TARS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24827421, 34508595, 37454282, 39394138, 39509107; Phenotypes: Combined oxidative phosphorylation deficiency 21, OMIM:615918; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v6.18 PRKCI Ida Ertmanska edited their review of gene: PRKCI: Changed phenotypes to: van der Woude syndrome, MONDO:0019508, orofacial cleft, MONDO:0000358
Clefting v6.18 PRKCI Ida Ertmanska Phenotypes for gene: PRKCI were changed from van der Woude syndrome, MONDO:0019508 to van der Woude syndrome, MONDO:0019508; orofacial cleft, MONDO:0000358
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); lower lip pits + hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska commented on gene: PRKCI: Comment on list classification: There are at least 21 individuals from unrelated families reported in literature with monoallelic variants in PRKCI. 18/21 individuals presented with orofacial clefts (as an isolated phenotype in 13 of them). Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance); 3 individuals had a syndromic presentation WITHOUT orofacial clefts. Ambiguous functional evidence and segregation studies indicate a complex genetic mechanism. There is not yet enough evidence to ascertain a disease mechanism. Based on a large number of cases reported, this gene should be promoted to Green on the Clefting panel.
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01).

Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

Functional evidence: 12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01). Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants).
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe
walking & muscle weakness (1/4), chronic
constipation (1/4).

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant!

pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant.
This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025). ; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders and metabolic disease (variable penetrance in the cohort).
Seq method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual reported in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe walking & muscle weakness (1/4), chronic constipation (1/4).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not predicted to be LoF intolerant (pLI score for this gene = 0.01).

Prkci -/- knockouts in mice result in early embryonic lethality; heterozygous Prkci -/+ mice are asymptomatic.

This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska changed review comment from: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS.

Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation.

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF.


This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Sources: Other; to: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts (OFCs) and peridermopathies + 3 individuals from clinical databases with OFC and rare de novo PRKCI variants).
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by WGS (including 9 trios).

Variants confirmed as de novo (7 probands):
c.407A>G, p.Tyr136Cys - phenotype: cleft soft palate. Not in gnomAD v.4.1.0; Revel score = 0.84.
c.1148A>G, p.Asn383Ser - found de novo in five unrelated individuals, indicating a hotspot mutation; phenotype: van der Woude syndrome (2/5), cleft palate (4/5), ID/DD (2/5); hypodontia + seizures + hypospadias + eczema (1). 1 heterozygous individual in gnomAD v.4.1.0; Revel score = 0.91.
c.1155A>C, p.Leu385Phe - phenotype: cleft palate, sygnathia, elbow/knee contractures, ankyloblepharon, atrial septal defect. Not in gnomAD v.4.1.0; Revel score = 0.48.

Variants inherited from parents (14 individuals): 12 missense variants, 1 nonsense variant (c.1684C>T, p.Gln562Ter).
c.1684C>T, p.Gln562Ter - lies in a predicted NMD escape region (PRKCI has 596 aa - Decipher).
In some instances, the PRKCI variant in the proband was inherited from the unaffected parent, while the other parent was reported as affected - ?
Phenotype summary: 10 individuals with an isolated cleft lip and/or palate (10) and 4 individuals with a complex syndromic presentation, including: IUGR (2/4); autism, DD, speech delay (2/4); congenital cardiac defects (2/4), orofacial clefts (1/4), toe
walking & muscle weakness (1/4), chronic
constipation (1/4).

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF - gene not LoF intolerant!

pLI score for this gene = 0.01 - not predicted to be loss-of-function intolerant.
This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Clefting v6.17 PRKCI Ida Ertmanska Classified gene: PRKCI as Amber List (moderate evidence)
Clefting v6.17 PRKCI Ida Ertmanska Gene: prkci has been classified as Amber List (Moderate Evidence).
Clefting v6.16 PRKCI Ida Ertmanska gene: PRKCI was added
gene: PRKCI was added to Clefting. Sources: Other
Q4_25_promote_green tags were added to gene: PRKCI.
Mode of inheritance for gene: PRKCI was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKCI were set to 40902599
Phenotypes for gene: PRKCI were set to van der Woude syndrome, MONDO:0019508
Review for gene: PRKCI was set to GREEN
Added comment: PMID: 40902599 Robinson et al., 2025
Identified 7 de novo variants and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic orofacial clefts and peridermopathies.
Additional symptoms included congenital heart disease, intellectual disabilities, neurodevelopmental disorders such as autism spectrum disorder, and metabolic disease (variable penetrance in the cohort). Method: pathogenic variants in IRF6 or GRHL3 excluded by targeted seq, followed by trio WGS.

Vairant c.1148A>G (p.Asn383Ser) was found de novo in five unrelated individuals, indicating a hotspot mutation.

12 patient alleles tested in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), confirmed as LoF.


This gene is not yet associated with a phenotype in OMIM (accessed 14th Nov 2025).
Sources: Other
Intellectual disability v9.182 UROC1 Ida Ertmanska Phenotypes for gene: UROC1 were changed from UROCANASE DEFICIENCY (UROD) to ?Urocanase deficiency , OMIM:276880; urocanic aciduria, MONDO:0010167
Intellectual disability v9.181 UROC1 Ida Ertmanska Publications for gene: UROC1 were set to 19304569
Intellectual disability v9.180 UROC1 Ida Ertmanska Tag Q4_25_demote_red tag was added to gene: UROC1.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild ID (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 - mild (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Phenotype: ataxia, ataxic gait, action tremor, dysarthric speech, slight nystagmus. Cognitive evaluation rated her IQ at 54 (Wechsler Intelligence Scale for ChildrenRevised: verbal 57 and manipulation 60).
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska commented on gene: UROC1: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability, and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia. ; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - phenotype: "Neurologic (with or without other organ systems)"; 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.
Patient 65 - Phenotype: "Neurologic (with or without other organ systems)" - 7months old female - normal metabolomic findings; homozygous for c.1054G>A, p.Ala352Thr in UROC1 - MAF 0.001684 in gnomAD v4.1.0 - Likely Benign.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025). Gene is currently rated Red for Intellectual disability in PanelApp Australia.
Intellectual disability v9.180 UROC1 Ida Ertmanska changed review comment from: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).; to: PMID: 19304569 Espinos et al., 2009
Female proband, compound het for NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys) & NM_144639.3(UROC1):c.209T>C (p.Leu70Pro). Sequenced UROC1 gene only. Cognitive evaluation rated her IQ at 54.
Disease association disputed in PMID: 30619714.

PMID: 27391121 Al-Shamsi et al., 2016
Proband homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) - rare in gnomAD v4.1.0, 10 alleles, no homozygotes. Patient phenotype: Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, elevated imidazole propionate. Seq method: WES.

PMID: 30619714 Glinton et al., 2018
Case 1 - 27yo female - urocanic aciduria detected at 8 weeks of age; developed normally, psychological assessment at 3yo using the McCarthy Scales of Children's Abilities gave a general cognitive score of 115 (83rd percentile for age).
Case 2 - 21yo male, asymptomatic brother of Case1 with urocanic aciduria (detected on biochemical testing).
Both siblings compound het for NM_144639.3(UROC1):c.356C>G (p.Pro119Arg) and NM_144639.3(UROC1):c.907G>C (p.Ala303Pro) - parents confirmed as carriers. Seq method: UROC1 only.

PMID: 32439973 Alaimo et al., 2020
Patient 75 - 5yo male homozygous for NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) with urocanic aciduria. Seq method: exome seq. Authors note that 'the biochemical phenotype is benign and not causative of the patient phenotype'.

This gene is putatively associated with Urocanase deficiency , OMIM:276880 (OMIM accessed 13th Nov 2025).
Intellectual disability v9.180 UROC1 Ida Ertmanska reviewed gene: UROC1: Rating: RED; Mode of pathogenicity: None; Publications: 19304569, 27391121, 30619714, 32439973; Phenotypes: ?Urocanase deficiency , OMIM:276880, urocanic aciduria, MONDO:0010167; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.180 SPRTN Ida Ertmanska Classified gene: SPRTN as Red List (low evidence)
Intellectual disability v9.180 SPRTN Ida Ertmanska Gene: sprtn has been classified as Red List (Low Evidence).
Intellectual disability v9.179 SPRTN Ida Ertmanska Classified gene: SPRTN as No list
Intellectual disability v9.179 SPRTN Ida Ertmanska Gene: sprtn has been removed from the panel.
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: SPRTN.
Tag Q4_25_NHS_review tag was added to gene: SPRTN.
Childhood solid tumours v5.8 SPRTN Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be rated Amber for Childhood solid tumours, until more evidence emerges.; to: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma (died before 18yo), genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be rated Amber for Childhood solid tumours, until more evidence emerges.
Childhood solid tumours v5.8 SPRTN Ida Ertmanska Classified gene: SPRTN as Amber List (moderate evidence)
Childhood solid tumours v5.8 SPRTN Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be rated Amber for Childhood solid tumours, until more evidence emerges.
Childhood solid tumours v5.8 SPRTN Ida Ertmanska Gene: sprtn has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v5.7 SPRTN Ida Ertmanska gene: SPRTN was added
gene: SPRTN was added to Childhood solid tumours. Sources: Other
Mode of inheritance for gene: SPRTN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRTN were set to 12503110; 25261934; 25501849
Phenotypes for gene: SPRTN were set to Ruijs-Aalfs syndrome, OMIM:616200; progeroid features-hepatocellular carcinoma predisposition syndrome, MONDO:0014527
Review for gene: SPRTN was set to AMBER
Added comment: PMID: 25261934 Lessel et al., 2014
Reported biallelic germline mutations in SPRTN in three patients from two unrelated families, affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. Seq method: linkage analysis + WES.

Family A: NM_032018.7:c.723del, p.Lys241Asnfs*9 homozygous
Family A originally described in PMID: 12503110 Ruijs et al., 2003 - Report of a Moroccan boy from a consanguineous family with chromosomal breakage syndrome, who died at 17yo due to hepatocellular carcinoma. Presented with short stature, bilateral cataracts, premature hair graying.

Family B: NM_032018.7:c.350A>G, p.Tyr117Cys & c.717_718+2delAGGT compound heterozygous
Family B = nonconsanguineous Australian family of European ancestry. 2 affected male sibs B-II:1 and B-II:4 presented with low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age and mild joint restrictions. Both individuals developed early onset HCC at age 16 and 14.

FUNCTIONAL EVIDENCE: PMID: 25501849: Maskey et al., 2014: Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Complete Spartan knockout causes early embryonic lethality; hypomorphic mice are viable, but growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Mouse model recapitulated human phenotype, except for the carcinoma susceptibility (no tumours detected in 1 year old Spartan-deficient mice).

SPRTN is associated with AR Ruijs-Aalfs syndrome, OMIM:616200 (OMIM accessed 13th Nov 2025).
Sources: Other
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features. Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be promoted to Green on Paediatric disorders - additional genes at the next GMS update; to: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be promoted to Green on Paediatric disorders - additional genes at the next GMS update
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska changed review comment from: PMID: 25261934 Lessel et al., 2014
Found biallelic germline mutations in SPRTN in three patients from two unrelated families, affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. Seq method: linkage analysis + WES.

Family A: NM_032018.7:c.723del, p.Lys241Asnfs*9 homozygous
Family A originally described in PMID: 12503110 Ruijs et al., 2003 - Report of a Moroccan boy from a consanguineous family with chromosomal breakage syndrome, who died at 17yo due to hepatocellular carcinoma. Presented with short stature, bilateral cataracts, premature hair graying.

Family B: NM_032018.7:c.350A>G, p.Tyr117Cys & c.717_718+2delAGGT compound heterozygous
Family B = nonconsanguineous Australian family of European ancestry. 2 affected male sibs B-II:1 and B-II:4 presented with low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age and mild joint restrictions. Both individuals developed early onset HCC at age 16 and 14.

FUNCTIONAL EVIDENCE: PMID: 25501849: Maskey et al., 2014: Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Complete Spartan knockout causes early embryonic lethality; hypomorphic mice are viable, but growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Mouse model recapitulated human phenotype, except for the carcinoma susceptibility (no tumours detected in 1 year old Spartan-deficient mice).

SPRTN is associated with AR Ruijs-Aalfs syndrome, OMIM:616200 (OMIM accessed 13th Nov 2025).; to: PMID: 25261934 Lessel et al., 2014
Reported biallelic germline mutations in SPRTN in three patients from two unrelated families, affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. Seq method: linkage analysis + WES.

Family A: NM_032018.7:c.723del, p.Lys241Asnfs*9 homozygous
Family A originally described in PMID: 12503110 Ruijs et al., 2003 - Report of a Moroccan boy from a consanguineous family with chromosomal breakage syndrome, who died at 17yo due to hepatocellular carcinoma. Presented with short stature, bilateral cataracts, premature hair graying.

Family B: NM_032018.7:c.350A>G, p.Tyr117Cys & c.717_718+2delAGGT compound heterozygous
Family B = nonconsanguineous Australian family of European ancestry. 2 affected male sibs B-II:1 and B-II:4 presented with low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age and mild joint restrictions. Both individuals developed early onset HCC at age 16 and 14.

FUNCTIONAL EVIDENCE: PMID: 25501849: Maskey et al., 2014: Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Complete Spartan knockout causes early embryonic lethality; hypomorphic mice are viable, but growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Mouse model recapitulated human phenotype, except for the carcinoma susceptibility (no tumours detected in 1 year old Spartan-deficient mice).

SPRTN is associated with AR Ruijs-Aalfs syndrome, OMIM:616200 (OMIM accessed 13th Nov 2025).
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska edited their review of gene: SPRTN: Changed phenotypes to: Ruijs-Aalfs syndrome, OMIM:616200, progeroid features-hepatocellular carcinoma predisposition syndrome, MONDO:0014527
Paediatric disorders - additional genes v7.24 SPRTN Ida Ertmanska Phenotypes for gene: SPRTN were changed from Ruijs-Aalfs syndrome, MIM# 616200 to Ruijs-Aalfs syndrome, OMIM:616200; progeroid features-hepatocellular carcinoma predisposition syndrome, MONDO:0014527
Paediatric disorders - additional genes v7.23 SPRTN Ida Ertmanska Publications for gene: SPRTN were set to 12503110; 25261934
Paediatric disorders - additional genes v7.22 SPRTN Ida Ertmanska Classified gene: SPRTN as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.22 SPRTN Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features. Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be promoted to Green on Paediatric disorders - additional genes at the next GMS update
Paediatric disorders - additional genes v7.22 SPRTN Ida Ertmanska Gene: sprtn has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.21 SPRTN Ida Ertmanska reviewed gene: SPRTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 12503110, 25261934, 25501849; Phenotypes: Ruijs-Aalfs syndrome, OMIM:616200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.151 ACTB Ida Ertmanska Mode of inheritance for gene: ACTB was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset dystonia v1.150 ARX Ida Ertmanska Mode of inheritance for gene: ARX was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Epidermolysis bullosa and congenital skin fragility v2.10 ATP2A2 Ida Ertmanska Publications for gene: ATP2A2 were set to
Epidermolysis bullosa and congenital skin fragility v2.9 ATP2A2 Ida Ertmanska Phenotypes for gene: ATP2A2 were changed from Darier-White disease, OMIM:124200 to Darier disease, OMIM:124200; Acrokeratosis verruciformis, OMIM:101900; Darier disease, MONDO:0007417; acrokeratosis verruciformis, MONDO:0007048
Epidermolysis bullosa and congenital skin fragility v2.8 ATP2A2 Ida Ertmanska Classified gene: ATP2A2 as Red List (low evidence)
Epidermolysis bullosa and congenital skin fragility v2.8 ATP2A2 Ida Ertmanska Gene: atp2a2 has been classified as Red List (Low Evidence).
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel.; to: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel and should be rated Red.
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska changed review comment from: PMID: 38536168 Atzmony et al., 2024
9 patients with Darier disease (DD) from (presumed) unrelated families with heterozygous pathogenic germline LoF variants in ATP2A2. 8/9 patients had family history of DD. 8/9 individuals had classic disease distribution with hyperkeratotic papules and plaques over seborrheic areas and v-shaped notching of the nails. One patient had comedonal DD, manifested over forehead, cheeks and trunk.
Variants detected in ATP2A2 - none of which are present in gnomAD v4.1.0.:
c.1000C>T, p.Arg334X
c.1582C>T, p.Arg528X
c.2256_2256Dup, p.(Tyr753Leufs*60)
c.1406_1415del, p.(Asn469Thrfs*7)
c.530A>C, p.Gln177Pro (recurring, 3/9 families)
c.395A>C, p.Gln132Pro; c.392G>T, p. Arg131Leu - detected in cis in patient DD5
c.1327 A>C, p.Thr443Pro
Patients with persistent lesions had additional somatic variants in ATP2A2, while individuals with a 'wax and wane' skin presentation did not.

Many other cases of ATP2A2-related Darier disease have been reported in literature:
PMID: 10080178 Sakuntabhai et al., 1999 - 8 unrelated British families and 5 sporadic cases with DD
PMID: 10441325 Jacobsen et al., 1999 - 19 unrelated DD patients with 17 mutations detected in ATP2A2 + link to neuropsychiatric phenotypes
PMID: 35283639 Hagino et al., 2022 - 34-year-old Japanese woman with familial DD, het for c.616A>C (p.Asn206His) in ATP2A2
PMID: 38791022 Frustaci et al., 2024 - 62-year-old female (DD onset at 9yo), developed cardiac symptoms at 60yo, heterozygous for ATP2A2 c.118G>A

This gene is associated with AD Darier disease, OMIM:124200 and Acrokeratosis verruciformis, OMIM:101900 (accessed 13th Nov 2025).; to: PMID: 38536168 Atzmony et al., 2024
9 patients with Darier disease (DD) from (presumed) unrelated families with heterozygous pathogenic germline LoF variants in ATP2A2. 8/9 patients had family history of DD. Age ranged from 40 to 69 years on enrollment. 8/9 individuals had classic disease distribution with hyperkeratotic papules and plaques over seborrheic areas and v-shaped notching of the nails. One patient had comedonal DD, manifested over forehead, cheeks and trunk.
Variants detected in ATP2A2 - none of which are present in gnomAD v4.1.0.:
c.1000C>T, p.Arg334X
c.1582C>T, p.Arg528X
c.2256_2256Dup, p.(Tyr753Leufs*60)
c.1406_1415del, p.(Asn469Thrfs*7)
c.530A>C, p.Gln177Pro (recurring, 3/9 families)
c.395A>C, p.Gln132Pro; c.392G>T, p. Arg131Leu - detected in cis in patient DD5
c.1327 A>C, p.Thr443Pro
Patients with persistent lesions had additional somatic variants in ATP2A2, while individuals with a 'wax and wane' skin presentation did not.

Many other cases of ATP2A2-related Darier disease have been reported in literature:
PMID: 10080178 Sakuntabhai et al., 1999 - 8 unrelated British families and 5 sporadic cases with DD
PMID: 10441325 Jacobsen et al., 1999 - 19 unrelated DD patients with 17 mutations detected in ATP2A2 + link to neuropsychiatric phenotypes
PMID: 35283639 Hagino et al., 2022 - 34-year-old Japanese woman with familial DD, het for c.616A>C (p.Asn206His) in ATP2A2
PMID: 38791022 Frustaci et al., 2024 - 62-year-old female (DD onset at 9yo), developed cardiac symptoms at 60yo, heterozygous for ATP2A2 c.118G>A

This gene is associated with AD Darier disease, OMIM:124200 and Acrokeratosis verruciformis, OMIM:101900 (accessed 13th Nov 2025).
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska edited their review of gene: ATP2A2: Added comment: Comment on list classification: There are numerous patients reported in literature with monoallelic LoF germline variants in ATP2A2 causing Darier disease. Darier disease is characterized by warty papules and plaques in seborrheic areas, palmoplantar pits, and distinctive nail abnormalities (PMID: 10080178). The age of onset is usually in childhood/adolescence. Due to the age of onset, this gene does not fit into the scope of this panel.; Changed rating: RED; Changed publications to: 10080178, 10441325, 35283639, 38791022, 38536168
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Ida Ertmanska reviewed gene: ATP2A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38536168; Phenotypes: Darier disease, OMIM:124200, Acrokeratosis verruciformis, OMIM:101900, Darier disease, MONDO:0007417, acrokeratosis verruciformis, MONDO:0007048; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v4.24 CLDN16 Achchuthan Shanmugasundram Publications for gene: CLDN16 were set to 26426912
Amelogenesis imperfecta v4.23 CLDN16 Achchuthan Shanmugasundram Phenotypes for gene: CLDN16 were changed from Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis (FHHNC) to familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, MONDO:0017624; amelogenesis imperfecta, MONDO:0019507
Congenital myaesthenic syndrome v5.4 UNC13A Achchuthan Shanmugasundram Tag Q4_25_NHS_review tag was added to gene: UNC13A.
Familial non syndromic congenital heart disease v1.89 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as No list
Familial non syndromic congenital heart disease v1.89 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been removed from the panel.
Familial non syndromic congenital heart disease v1.88 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Familial non syndromic congenital heart disease v1.88 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore has been removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Familial non syndromic congenital heart disease v1.88 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Familial non syndromic congenital heart disease v1.87 ISCA-37433-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37433-Loss.
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.178 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-37433-Loss.
Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Intellectual disability v9.177 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Early onset or syndromic epilepsy v8.65 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Clefting v6.15 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Clefting v6.14 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_promote_green tag was added to Region: ISCA-37433-Loss.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.75 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.75 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Loss)

Checked and approved by the Genomics England Clinical team.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.75 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.74 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Classified Region: ISCA-37433-Gain as Green List (high evidence)
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37446 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37446-Gain)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.177 ISCA-37433-Gain Arina Puzriakova Region: isca-37433-gain has been classified as Green List (High Evidence).
Intellectual disability v9.176 ISCA-37433-Gain Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Gain.
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37404-Loss.
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore has been removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Congenital hypothyroidism v3.2 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Hereditary ataxia with onset in adulthood v8.12 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Hereditary ataxia with onset in adulthood v8.12 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Hereditary ataxia with onset in adulthood v8.12 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Hereditary ataxia with onset in adulthood v8.11 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.176 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Intellectual disability v9.175 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Early onset or syndromic epilepsy v8.64 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Paediatric motor neuronopathies v3.11 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Paediatric motor neuronopathies v3.11 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Paediatric motor neuronopathies v3.11 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Paediatric motor neuronopathies v3.10 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Ataxia and cerebellar anomalies - narrow panel v8.31 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Ataxia and cerebellar anomalies - narrow panel v8.31 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)

Checked and approved by the Genomics England Clinical team.
Ataxia and cerebellar anomalies - narrow panel v8.31 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.30 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova changed review comment from: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).; to: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Classified Region: ISCA-37404-Gain as Green List (high evidence)
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Gain).

Checked and approved by the Genomics England Clinical team.
Intellectual disability v9.175 ISCA-37404-Gain Arina Puzriakova Region: isca-37404-gain has been classified as Green List (High Evidence).
Intellectual disability v9.174 ISCA-37404-Gain Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Gain.
Intellectual disability v9.174 ISCA-37498-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review (Last Evaluated:06/25/2025): Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen
Intellectual disability v9.174 ISCA-37448-Loss Arina Puzriakova Phenotypes for Region: ISCA-37448-Loss were changed from to Developmental delay/intellectual disability, epilepsy, autism spectrum disorder, schizophrenia, congenital heart disease, and variable dysmorphic features
Early onset or syndromic epilepsy v8.64 ISCA-37448-Loss Arina Puzriakova Phenotypes for Region: ISCA-37448-Loss were changed from to Developmental delay/intellectual disability, epilepsy, autism spectrum disorder, schizophrenia, congenital heart disease, and variable dysmorphic features
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Amber List (moderate evidence)
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.173 ISCA-37448-Loss Arina Puzriakova Region: isca-37448-loss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Region: isca-37448-loss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.62 ISCA-37448-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review (Last Evaluated:04/12/2021): Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.172 ISCA-37448-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review (Last Evaluated:04/12/2021): Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Early onset or syndromic epilepsy v8.62 ISCA-37448-Loss Arina Puzriakova Region: ISCA-37448-Loss was added
Region: ISCA-37448-Loss was added to Early onset or syndromic epilepsy. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37448-Loss.
Mode of inheritance for Region: ISCA-37448-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37448-Loss were set to 31451536; 24352232; 30767844; 31665216
Review for Region: ISCA-37448-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.172 ISCA-37448-Loss Arina Puzriakova Region: ISCA-37448-Loss was added
Region: ISCA-37448-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37448-Loss.
Mode of inheritance for Region: ISCA-37448-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37448-Loss were set to 31451536; 24352232; 30767844; 31665216
Review for Region: ISCA-37448-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review: Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Classified Region: ISCA-46296-Loss as Amber List (moderate evidence)
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.171 ISCA-46296-Loss Arina Puzriakova Region: isca-46296-loss has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.170 ISCA-46296-Loss Arina Puzriakova Region: ISCA-46296-Loss was added
Region: ISCA-46296-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46296-Loss.
Mode of inheritance for Region: ISCA-46296-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46296-Loss were set to 22180641; 19921647
Phenotypes for Region: ISCA-46296-Loss were set to Developmental delays, intellectual disability, brain anomalies, non-specific craniofacial abnormalities, hypotonia, ocular abnormalities, hearing loss, and other variable clinical features
Review for Region: ISCA-46296-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46296

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 LCR A-C recurrent region has been reported in at least 5 patients. The reported clinical findings include developmental delays (speech and motor), intellectual disability, brain anomalies, non-specific craniofacial abnormalities, hypotonia, ocular abnormalities, hearing loss, and other variable clinical features. In all cases where parental studies have been performed, deletions were found to be de novo. Case-control comparison studies have provided evidence for enrichment of this deletion in the clinical population, although overall numbers are somewhat limited.
Sources: ClinGen
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Amber List (moderate evidence)
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.169 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.16 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Amber List (moderate evidence)
Malformations of cortical development v7.16 ISCA-46300-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Malformations of cortical development v7.16 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.19 ISCA-46300-Loss Arina Puzriakova Classified Region: ISCA-46300-Loss as Amber List (moderate evidence)
Severe microcephaly v8.19 ISCA-46300-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen, however, microcephaly reported in patients is often now within the severity range relevant to this panel (OFC reported in 27399968; 22180641: 10-15th, 0.6-2nd, 3rd, 10th percentile) so will include as Amber based on this evidence.
Severe microcephaly v8.19 ISCA-46300-Loss Arina Puzriakova Region: isca-46300-loss has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-46300-Loss.
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova edited their review of Region: ISCA-46300-Loss: Changed rating: AMBER
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Malformations of cortical development v7.15 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.168 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Malformations of cortical development v7.15 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Malformations of cortical development. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Severe microcephaly. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.168 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Sources: ClinGen
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Classified Region: ISCA-37498-Loss as Amber List (moderate evidence)
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Intellectual disability v9.167 ISCA-37498-Loss Arina Puzriakova Region: isca-37498-loss has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.166 ISCA-37498-Loss Arina Puzriakova Region: ISCA-37498-Loss was added
Region: ISCA-37498-Loss was added to Intellectual disability. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-37498-Loss.
Mode of inheritance for Region: ISCA-37498-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37498-Loss were set to 28211979; 21373257; 37152320
Phenotypes for Region: ISCA-37498-Loss were set to Developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features
Review for Region: ISCA-37498-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37498

ClinGen review: Reported in at least 2 individuals with developmental delay/intellectual disability, dysmorphic features, dental anomalies, long slender fingers with 5th finger clinodactyly, and additional clinical features. Another patient (PMID: 28018436) was reported to have an overlapping 11q13 deletion that involves most of the recurrent region with a similar clinical phenotype. All reported deletions of the recurrent 11q13.2q13.4 region with informative parental testing have been shown to be de novo. Case-control data are currently uninformative due to the rarity of this deletion. Additionally, this deletion encompasses two curated dosage sensitive genes, KMT5B and SHANK2.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.
Sources: ClinGen
Bilateral congenital or childhood onset cataracts v7.5 PTBP1 Ida Ertmanska commented on gene: PTBP1: Comment on list classification: While there are several individuals reported with monoallelic PTBP1 variants with an ocular phenotype as part of a syndromic presentation, only 1/27 reported patients presented with cataracts. Hence, PTBP1 should be rated Red for Bilateral congenital or childhood onset cataracts.
Bilateral congenital or childhood onset cataracts v7.5 PTBP1 Ida Ertmanska gene: PTBP1 was added
gene: PTBP1 was added to Bilateral congenital or childhood onset cataracts. Sources: Other
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PTBP1 were set to 40965981
Review for gene: PTBP1 was set to RED
Added comment: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).
Sources: Other
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37404-Loss.
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: Removing this region as it has been deprecated by ClinGen and has been subsumed into ISCA-37478 which is green on multiple GMS panels (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss)
Hereditary ataxia v1.343 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Retinal disorders v8.64 PTBP1 Ida Ertmanska changed review comment from: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).
Sources: Other; to: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).
Retinal disorders v8.64 PTBP1 Ida Ertmanska commented on gene: PTBP1: Comment on list classification: While there are several individuals reported with monoallelic PTBP1 variants with an ocular phenotype as part of a syndromic presentation, the symptoms do not fit into the scope of the Retinal disorders panel. Hence, PTBP1 should be rated Red for Retinal disorders.
Retinal disorders v8.64 PTBP1 Ida Ertmanska gene: PTBP1 was added
gene: PTBP1 was added to Retinal disorders. Sources: Other
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PTBP1 were set to 40965981
Review for gene: PTBP1 was set to RED
Added comment: PMID: 40965981 Masson et al., 2025
27 individuals with heterozygous variants in PTBP1 diagnosed with syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. 12/27 individuals noted to have a variable 'ophthalmological' phenotype: microphthalmos (1), myopia (6), strabismus (1), glaucoma (4), papilledema (1), astigmatism (4), cataract (1), septo-optic dysplasia (1), nystagmus (1), amblyopia (1).
Sources: Other
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova changed review comment from: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).; to: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels including this panel (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova changed review comment from: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss) which is green on multiple GMS panels.; to: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 which is green on multiple GMS panels (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss).
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss: This region has been deprecated by ClinGen and therefore should be removed from the panel.

This region has been subsumed into ISCA-37478 (https://panelapp.genomicsengland.co.uk/panels/entities/ISCA-37478-Loss) which is green on multiple GMS panels.
Severe early-onset obesity v5.18 ISCA-37404-Loss Arina Puzriakova Tag Q4_25_demote_red tag was added to Region: ISCA-37404-Loss.
Congenital myaesthenic syndrome v5.4 UNC13A Ida Ertmanska Phenotypes for gene: UNC13A were changed from to congenital myasthenic syndrome, MONDO:0018940
Congenital myaesthenic syndrome v5.3 UNC13A Ida Ertmanska Publications for gene: UNC13A were set to 27648472
Congenital myaesthenic syndrome v5.2 UNC13A Ida Ertmanska Classified gene: UNC13A as Amber List (moderate evidence)
Congenital myaesthenic syndrome v5.2 UNC13A Ida Ertmanska Gene: unc13a has been classified as Amber List (Moderate Evidence).
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: UNC13A.
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska commented on gene: UNC13A: Comment on list classification: There are 2 unrelated individuals with biallelic putative LoF variants in UNC13A who presented with congenital hypotonia and sever muscle weakness. Additionally, knockout mouse models show that Unc13A deficiency interferes with the synaptic maturation process. In contrast, 4 unrelated individuals with heterozygous missense variants in UNC13A presented with intellectual disability and seizures. Hence, there are two distinct disease entities, with different MOIs, associated with this gene. Based on the available evidence, UNC13A should be promoted to Green for Congenital myaesthenic syndrome at the next GMS update.
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska changed review comment from: BIALLELIC CASES:
PMID: 27648472 Engel et al., 2016
Report of a native American girl, born prematurely at 32 weeks - hypotonic at birth, needed ventilatory support, developed aspiration pneumonia; died at age 50 months due to respiratory failure; EMG studies revealed abnormally low-amplitude CMAPs at rest; histochemical studies of the anconeus muscle revealed marked type 2 fiber atrophy and type 1 fiber hypertrophy; homozygous for NM_001080421.2; c.304C>T, p.(Gln102*) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

PMID: 36447687 Mullins et al., 2022
Case report of a female infant with congenital encephalopathy and a severe neuromuscular phenotype - delivered at 40 weeks due to abnormal heart rate and reduced fetal movement; she had mildly dysmorphic features, alternating hypertonia and hypotonia, extreme generalized muscle weakness, severe kyphoscoliosis and hernias. She died at 8 months due to bronchopneumonia. Homozygous for c.1188delC p.(Asp397Thrfs*107) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

MONOALLELIC: 4 heterozygous cases harbouring missense variants in UNC13A have been detailed previously by Tom Hodgkinson (see below) - individuals presented with seizures and intellectual disability, NOT myaesthenic syndrome.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).; to: BIALLELIC CASES:
PMID: 27648472 Engel et al., 2016
Report of a native American girl, born prematurely at 32 weeks - hypotonic at birth, needed ventilatory support, developed aspiration pneumonia; died at age 50 months due to respiratory failure; EMG studies revealed abnormally low-amplitude CMAPs at rest; histochemical studies of the anconeus muscle revealed marked type 2 fiber atrophy and type 1 fiber hypertrophy; homozygous for NM_001080421.2; c.304C>T, p.(Gln102*) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

PMID: 36447687 Mullins et al., 2022
Case report of a female infant with congenital encephalopathy and a severe neuromuscular phenotype - delivered at 40 weeks due to abnormal heart rate and reduced fetal movement; she had mildly dysmorphic features, alternating hypertonia and hypotonia, extreme generalized muscle weakness, severe kyphoscoliosis and hernias. She died at 8 months due to bronchopneumonia. Homozygous for c.1188delC p.(Asp397Thrfs*107) in UNC13A - variant extremely rare in gnomAD v4.1.0., no homozygotes; method: WES.

MONOALLELIC: 4 heterozygous cases harbouring missense variants in UNC13A have been detailed previously by Tom Hodgkinson (see below) - individuals presented with seizures and intellectual disability, NOT myaesthenic syndrome.

FUNCTIONAL EVIDENCE:
PMID: 10440375 Augustin et al., 1999: In glutamatergic hippocampal neurons from Unc13A -/- mice the synaptic-vesicle cycle is arrested at the maturation step, stopping transmitter release from the synapses.
PMID: 15988013 Frédérique Varoqueaux et al., 2005: Triple knockout of Unc13A/B/C in the mouse results in paralysis and death; double knockout Unc13B/C mice were viable and fertile - thus, Unc13A was highlighted as crucial for CNS development and function.

This gene is not yet associated with a phenotype in OMIM (accessed 12th Nov 2025).
Congenital myaesthenic syndrome v5.1 UNC13A Ida Ertmanska reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27648472, 28192369, 39634123; Phenotypes: congenital myasthenic syndrome, MONDO:0018940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v6.39 CASQ1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 12th Nov 2025.
Congenital myopathy v6.39 CASQ1 Ida Ertmanska Phenotypes for gene: CASQ1 were changed from Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231 to Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231; myopathy due to calsequestrin and SERCA1 protein overload, MONDO:0014546
Congenital myopathy v6.38 CASQ1 Ida Ertmanska reviewed gene: CASQ1: Rating: RED; Mode of pathogenicity: None; Publications: 30258016; Phenotypes: Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 unrelated families with biallelic variants in LRRC45. 2/5 individuals were noted to have an ophthalmological phenotype: isolated cone-rod dystrophy, and nystagmus as part of a syndromic presentation (PMIDs: 34716235; 39638757). Another individual was diagnosed with Bardet-Biedl syndrome-like multi-systemic ciliopathy - often associated with ocular findings, though not specified in the report (PMID: 34716235).; to: Comment on list classification: There are 5 individuals from 4 unrelated families with biallelic variants in LRRC45. 2/5 individuals were noted to have an ophthalmological phenotype: isolated cone-rod dystrophy, and nystagmus as part of a syndromic presentation (PMIDs: 34716235; 39638757). Another individual was diagnosed with Bardet-Biedl syndrome-like multi-systemic ciliopathy - often associated with ocular findings, though not specified in the report (PMID: 34716235). Based on the available evidence, this gene should be rated Amber for Ophthalmological ciliopathies until more evidence emerges.
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska commented on gene: LRRC45: Comment on list classification: There are 5 individuals from 4 unrelated families with biallelic variants in LRRC45. 2/5 individuals were noted to have an ophthalmological phenotype: isolated cone-rod dystrophy, and nystagmus as part of a syndromic presentation (PMIDs: 34716235; 39638757). Another individual was diagnosed with Bardet-Biedl syndrome-like multi-systemic ciliopathy - often associated with ocular findings, though not specified in the report (PMID: 34716235).
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska Classified gene: LRRC45 as Amber List (moderate evidence)
Ophthalmological ciliopathies v5.9 LRRC45 Ida Ertmanska Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v5.8 LRRC45 Ida Ertmanska gene: LRRC45 was added
gene: LRRC45 was added to Ophthalmological ciliopathies. Sources: Literature
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 30131441; 34716235; 39638757
Phenotypes for gene: LRRC45 were set to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443; neurodevelopmental disorder, MONDO:0700092
Review for gene: LRRC45 was set to AMBER
Added comment: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal; patient died at 3 months old. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Intellectual disability v9.165 LRRC45 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: LRRC45.
Intellectual disability v9.165 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Added comment: Comment on list classification: There are 5 individuals form 4 unrelated families reported in literature with biallelic variants in LRRC45. 2/5 patients did not live beyond 3 months of age. In remaining 3 cases, 3/3 presented with severe developmental delay, delayed milestone attainment, and intellectual disability (severity not stated). Based on available evidence, this gene should be promoted to Green for Intellectual disability at the next GMS update.; Changed rating: GREEN
Intellectual disability v9.165 LRRC45 Ida Ertmanska Classified gene: LRRC45 as Amber List (moderate evidence)
Intellectual disability v9.165 LRRC45 Ida Ertmanska Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.164 LRRC45 Ida Ertmanska gene: LRRC45 was added
gene: LRRC45 was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 30131441; 34716235; 39638757
Phenotypes for gene: LRRC45 were set to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443; neurodevelopmental disorder, MONDO:0700092
Review for gene: LRRC45 was set to AMBER
Added comment: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal; patient died at 3 months old. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Other
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Changed publications to: 30131441, 34716235, 39638757
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska changed review comment from: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature; to: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal; patient died at 3 months old. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska changed review comment from: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature; to: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

Functional evidence:
PMID: 30131441 Kurtulmus et al., 2018 - LRRC45 shown to be associated with the basal body of primary and motile cilia in both differentiated and stem cells - broad function in ciliogenesis.

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: LRRC45.
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska commented on gene: LRRC45: Comment on list classification: There are 5 individuals from 4 unrelated families reported in literature with biallelic variants in LRRC45. The individuals presented with a range of symptoms from the ciliopathy spectrum: severe neurodevelopmental delay, seizures, cone-rod dystrophy, respiratory insufficiency, muscular hypotonia. The c.1402-2A>G variant was shown to result in a significant reduction of primary cilia frequency and length in patient fibroblasts. In addition, LRRC45 is known to have a role in ciliogenesis. Based on the available evidence, LRRC45 should be promoted to Green for Neurological ciliopathies at the next GMS update.
Neurological ciliopathies v6.11 LRRC45 Ida Ertmanska Phenotypes for gene: LRRC45 were changed from ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443 to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443; neurodevelopmental disorder, MONDO:0700092
Neurological ciliopathies v6.10 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Changed phenotypes to: ciliopathy, MONDO:0005308, Abnormal brain morphology, HP:0012443, neurodevelopmental disorder, MONDO:0700092
Neurological ciliopathies v6.10 LRRC45 Ida Ertmanska edited their review of gene: LRRC45: Changed phenotypes to: ciliopathy, MONDO:0005308, Abnormal brain morphology, HP:0012443
Neurological ciliopathies v6.10 LRRC45 Ida Ertmanska Phenotypes for gene: LRRC45 were changed from ciliopathy, MONDO:0005308 to ciliopathy, MONDO:0005308; Abnormal brain morphology, HP:0012443
Neurological ciliopathies v6.9 LRRC45 Ida Ertmanska Classified gene: LRRC45 as Amber List (moderate evidence)
Neurological ciliopathies v6.9 LRRC45 Ida Ertmanska Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.8 LRRC45 Ida Ertmanska gene: LRRC45 was added
gene: LRRC45 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 34716235; 39638757
Phenotypes for gene: LRRC45 were set to ciliopathy, MONDO:0005308
Review for gene: LRRC45 was set to GREEN
Added comment: PMID: 34716235 Best et al., 2022
2 unrelated individuals with LP biallelic variants in LRRC45.
Proband 1 (CMC Patient 48): Bardet-Biedl syndrome-like multi-systemic ciliopathy - homozygous for NM_144999.4: c.1074_1075insTG, p.(Leu359CysfsTer19), also homozygous for CFAP45 (CCDC19) NM_012337.3: c.433C>T, p.(Arg145Ter).
Sibling with developmental delay and ID was homozygous for the LRRC45 variant, did not harbour the CFAP45 mutation (proposed to account for the ciliopathy phenotype); parents confirmed as het for each.
Proband 2: presented with cone-rod dystrophy (possible ciliopathy basis) - compound het: NM_144999.4: c.1A>T, p.Met1? & NM_144999.4: c.1126–1G>A. Singleton case.

PMID: 39638757 Radhakrishnan et al., 2025
Report of 3 individuals from 2 unrelated families with severe central nervous system anomalies, harbouring biallelic variants in LRRC45: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Method: Exome seq.
P1 - female, onset at 1yr 8months, Indian origin, presented with febrile seizures and developmental delay, severe brain anomalies. At 3yr 7 mo: titubation, nystagmus, axial and peripheral hypotonia, normal deep tendon reflexes and pes planus.
P2 & 3 - born to Turkish consanguineous parents; P2 - female, presented with severe muscular hypotonia, respiratory insufficiency, and apnea bradycardia syndrome; ophthalmological exam was normal. P3 - male fetus, pregnancy terminated.
Functional evidence - P1 fibroblasts - variant c.1402-2A>G shown to result in a transcript lacking exon 14 (total 17 exons); LRRC45 mRNA and protein levels significantly reduced; significant reduction of primary cilia frequency and length.
c.1402-2A>G - splice acceptor - MAF 0.0001647 (South Asian population, 14 heterozygotes - gnomAD v4.1).
c.1262G>C (p.Arg421Thr) - MAF 8.475e-7 (1 het in European pop - gnomAD v4.1); Revel score =
Uncertain (0.31).

This gene is not yet associated with a disease in OMIM (accessed 11th Nov 2025).
Sources: Literature
Optic neuropathy v5.26 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. ; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.
Amelogenesis imperfecta v4.22 SMARCD2 Ida Ertmanska Phenotypes for gene: SMARCD2 were changed from Specific granule deficiency 2, 617475 to Specific granule deficiency 2, OMIM:617475
Amelogenesis imperfecta v4.21 SMARCD2 Ida Ertmanska Publications for gene: SMARCD2 were set to 28369036
Amelogenesis imperfecta v4.20 SMARCD2 Ida Ertmanska Classified gene: SMARCD2 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.20 SMARCD2 Ida Ertmanska Gene: smarcd2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.19 SMARCD2 Ida Ertmanska reviewed gene: SMARCD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28369036, 33025377, 33279574, 36135322; Phenotypes: Specific granule deficiency 2, OMIM:617475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.17 TUFT1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TUFT1.
Ectodermal dysplasia v4.17 TUFT1 Ida Ertmanska Phenotypes for gene: TUFT1 were changed from ectodermal dysplasia syndrome, MONDO:0019287 to Woolly hair-skin fragility syndrome, OMIM:620415
Ectodermal dysplasia v4.16 TUFT1 Ida Ertmanska Publications for gene: TUFT1 were set to 36689522
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska changed review comment from: Comment on list classification: As there are now 11 individuals from 4 unrelated families reported in literature (including 2 families with the same founder variant), there is enough evidence to promote TUFT1 to Green for Ectodermal dysplasia at the next GMS update. This association is supported by a knockout mouse model that recapitulates the human phenotype.; to: Comment on list classification: As there are now 11 individuals from 4 unrelated families reported in literature (including 2 families with the same founder variant), there is enough evidence to promote TUFT1 to Green for Ectodermal dysplasia at the next GMS update. This association is supported by a knockout mouse model that recapitulates the human phenotype (PMID: 37716648).
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska commented on gene: TUFT1: Comment on list classification: As there are now 11 individuals from 4 unrelated families reported in literature (including 2 families with the same founder variant), there is enough evidence to promote TUFT1 to Green for Ectodermal dysplasia at the next GMS update. This association is supported by a knockout mouse model that recapitulates the human phenotype.
Amelogenesis imperfecta v4.19 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted. WES identified a homozygous splice acceptor site variant in intron 8, c.724-2A>G in TUFT1.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted. WES identified a homozygous splice acceptor site variant in intron 8, c.724-2A>G in TUFT1.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.19 TUFT1 Ida Ertmanska Phenotypes for gene: TUFT1 were changed from amelogenesis imperfecta to Woolly hair-skin fragility syndrome, OMIM:620415
Amelogenesis imperfecta v4.18 TUFT1 Ida Ertmanska Publications for gene: TUFT1 were set to 7919663
Amelogenesis imperfecta v4.17 TUFT1 Ida Ertmanska Mode of inheritance for gene: TUFT1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska edited their review of gene: TUFT1: Changed rating: GREEN; Changed publications to: 36689522, 37716648; Changed phenotypes to: Woolly hair-skin fragility syndrome, OMIM:620415; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.15 TUFT1 Ida Ertmanska commented on gene: TUFT1
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska edited their review of gene: TUFT1: Added comment: Comment on list classification: As reviewed by Claire Smith, variants in TUFT1 are not associates with dental abnormalities. Instead, 11 individuals from 4 families with biallelic variants in TUFT1 presented with woolly hair and skin fragility. Based on the available evidence, TUFT1 should remain Red for Amelogenesis imperfecta.; Changed phenotypes to: Woolly hair-skin fragility syndrome, OMIM:620415
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska changed review comment from: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. A Tuft1-knockout mouse model mimicked the patients' phenotypes. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).; to: PMID: 36689522 Jackson et al., 2023
Report of 9 individuals from 3 families with woolly hair and skin fragility, homozygous for either c.60+1G>A (Irish founder variant) or p.Gln189Asnfs*49. No dental abnormalities.

PMID: 37716648 Verkerk et al., 2024
Report of two Dutch siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma. Both sibs harboured a homozygous splice-site variant in the TUFT1 gene. The teeth were all present and had a normal appearance, though susceptibility to caries was noted.
A Tuft1-knockout mouse model mimicked the patients' phenotypes: KO mice showed abnormal fur with a wavy appearance mimicking the woolly hair phenotype; 40% of KO mice developed spontaneous skin erosions.

This gene is associated with AR Woolly hair-skin fragility syndrome, OMIM:620415 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.16 TUFT1 Ida Ertmanska reviewed gene: TUFT1: Rating: ; Mode of pathogenicity: None; Publications: 25531160, 36689522, 37716648; Phenotypes: ; Mode of inheritance: None
Amelogenesis imperfecta v4.16 TP63 Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.; to: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). The association is supported by a knockout mouse model, showing absence of hair follicles, teeth and mammary glands (PMID: 10227293). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.
Amelogenesis imperfecta v4.16 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, MONDO:0011428
Amelogenesis imperfecta v4.15 TP63 Ida Ertmanska Phenotypes for gene: TP63 were changed from Split hand-split foot-ectodermal dysplasia and amelogenesis imperfecta to Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292
Amelogenesis imperfecta v4.14 TP63 Ida Ertmanska Publications for gene: TP63 were set to
Amelogenesis imperfecta v4.13 TP63 Ida Ertmanska Classified gene: TP63 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.13 TP63 Ida Ertmanska Gene: tp63 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: TP63.
Tag Q4_25_expert_review tag was added to gene: TP63.
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska edited their review of gene: TP63: Added comment: Comment on list classification: Monoallelic variants may cause Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (OMIM:604292). At least 5 patients heterozygous for TP63 variants presented with dental abnormalities, as part of a syndromic presentation: missing teeth (3/5), enamel defects (3/5), taurodontia, peg-shaped teeth. However, the presentation in variable, and 2/5 variants showed incomplete penetrance (healthy heterozygous parents). Based on the available evidence, this gene is recommended for Green rating for Amelogenesis imperfecta, with an additional request of Expert Review.; Changed rating: GREEN
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska changed review comment from: PMID: 22065540 Kantaputra et al., 2012
Mother and son affected with split hand-split foot (formerly described as ectrodactyly), ectodermal dysplasia, hyperpigmentation of skin, and dystrophic nails. Heterozygous c.588-2A > C variant detected in TP63 in both mother and son. Only the son was affected with Amelogenesis Imperfecta (hypocalcification, hypoplasia, and hypomaturation), in the primary and permanent dentition. Mother had no dental abnormalities - incomplete penetrance?

PMID: 33126320 Otsuki et al., 2020
Case report: 13-year-old Japanese boy with ectrodactyly in the right hand and left foot and syndactyly in the left and right foot; skin abnormalities including dry skin and café au lait spots; teeth with peg-shaped appearance. Het for a maternally transmitted c.956G>A, p.(R319H) variant in TP63 - however, the mother was healthy.

PMID: 31050217 Zheng et al., 2021
Proband 1 - 6yo Chinese girl - Phenotype: nail dysplasia of the second toe; her hair was yellow when she was a baby; cutaneous syndactyly; missing distal phalanx of the second toe of the left foot; congenital lack of deciduous and permanent teeth, and taurodontia; remaining deciduous teeth in the mouth could be seen with enamel hypoplasia and caries. WES and Sanger results revealed a heterozygous TP63 mutation c.728G>A (p.R243Q). Father of the proband was similarly affected, and carried the same TP63 variant.
Proband 2 - 18‐year‐old Chinese boy - phenotype: sparse and curly hair, missing teeth; ectrodactyly on both hands and feet with dysplastic nails; heterozygous for a de novo c.955C>T (p.R319C) variant in TP63.
Proband 3 - 12‐year‐old Chinese boy - severe ectodermal phenotypes: lack of hair, sparse eyebrows, no eyelashes, underactive sweat glands, nail dysplasia, and missing teeth; short stature noted; Oral examination showed multiple congenitally missing permanent teeth. The remaining teeth displayed enamel hypoplasia and dentin exposure. Proband was heterozygous for c.1769C>T (p.P590L) in TP63 - de novo.

Functional evidence: complete deletion of mouse TP63 results in epidermal defects and epithelial abnormalities - including absence of hair follicles, teeth and mammary glands (PMID: 10227293 Mills et al., 1999).

This gene is associated with multiple autosomal dominant conditions in OMIM, including AD Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 (accessed 7th Nov 2025).; to: PMID: 22065540 Kantaputra et al., 2012
Mother and son affected with split hand-split foot (formerly described as ectrodactyly), ectodermal dysplasia, hyperpigmentation of skin, and dystrophic nails. Heterozygous c.588-2A > C variant detected in TP63 in both mother and son. Only the son was affected with Amelogenesis Imperfecta (hypocalcification, hypoplasia, and hypomaturation), in the primary and permanent dentition. Mother had no dental abnormalities - incomplete penetrance?

PMID: 33126320 Otsuki et al., 2020
Case report: 13-year-old Japanese boy with ectrodactyly in the right hand and left foot and syndactyly in the left and right foot; skin abnormalities including dry skin and café au lait spots; teeth with peg-shaped appearance. Het for a maternally transmitted c.956G>A, p.(R319H) variant in TP63 - however, the mother was healthy.

PMID: 31050217 Zheng et al., 2021
Seq method: WES in probands and Sanger in family members.
Proband 1 - 6yo Chinese girl - Phenotype: nail dysplasia of the second toe; her hair was yellow when she was a baby; cutaneous syndactyly; missing distal phalanx of the second toe of the left foot; congenital lack of deciduous and permanent teeth, and taurodontia; remaining deciduous teeth in the mouth could be seen with enamel hypoplasia and caries. WES and Sanger results revealed a heterozygous TP63 mutation c.728G>A (p.R243Q). Father of the proband was similarly affected, and carried the same TP63 variant.
Proband 2 - 18‐year‐old Chinese boy - phenotype: sparse and curly hair, missing teeth; ectrodactyly on both hands and feet with dysplastic nails; heterozygous for a de novo c.955C>T (p.R319C) variant in TP63.
Proband 3 - 12‐year‐old Chinese boy - severe ectodermal phenotypes: lack of hair, sparse eyebrows, no eyelashes, underactive sweat glands, nail dysplasia, and missing teeth; short stature noted; Oral examination showed multiple congenitally missing permanent teeth. The remaining teeth displayed enamel hypoplasia and dentin exposure. Proband was heterozygous for c.1769C>T (p.P590L) in TP63 - de novo.

Functional evidence: complete deletion of mouse TP63 results in epidermal defects and epithelial abnormalities - including absence of hair follicles, teeth and mammary glands (PMID: 10227293 Mills et al., 1999).

This gene is associated with multiple autosomal dominant conditions in OMIM, including AD Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292 (accessed 7th Nov 2025).
Amelogenesis imperfecta v4.12 TP63 Ida Ertmanska reviewed gene: TP63: Rating: AMBER; Mode of pathogenicity: None; Publications: 10227293, 22065540, 31050217, 33126320; Phenotypes: Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska changed review comment from: Comment on list classification: there are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Ectodermal dysplasia v4.15 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573 to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573; ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565
Ectodermal dysplasia v4.14 NECTIN4 Ida Ertmanska Publications for gene: NECTIN4 were set to
Ectodermal dysplasia v4.13 NECTIN4 Ida Ertmanska reviewed gene: NECTIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 20691405, 21346770, 34067522, 37183149, 37829154; Phenotypes: Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573, ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v4.8 NECTIN4 Ida Ertmanska commented on gene: NECTIN4: Comment on list classification: Ectodermal dysplasia-syndactyly syndrome 1 has a variable presentation, mostly commonly including hair and dental abnormalities, as well as cutaneous syndactyly. There are at least 26 individuals from 3 unrelated families described in literature with biallelic NECTIN4 variants and palmoplantar keratoderma (PMIDs: 21346770, 34067522, 37183149). Based on the available evidence, NECTIN4 should be rated Green for Palmoplantar keratodermas.
Palmoplantar keratodermas v4.8 NECTIN4 Ida Ertmanska Classified gene: NECTIN4 as Amber List (moderate evidence)
Palmoplantar keratodermas v4.8 NECTIN4 Ida Ertmanska Gene: nectin4 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v4.7 NECTIN4 Ida Ertmanska gene: NECTIN4 was added
gene: NECTIN4 was added to Palmoplantar keratodermas. Sources: Other
Q4_25_promote_green tags were added to gene: NECTIN4.
Mode of inheritance for gene: NECTIN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NECTIN4 were set to 20691405; 21346770; 34067522; 37183149; 37829154
Phenotypes for gene: NECTIN4 were set to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573; ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565
Review for gene: NECTIN4 was set to GREEN
Added comment: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.

NECTIN4, previously known as PVRL4, is linked to Ectodermal dysplasia-syndactyly syndrome 1, 613573 (OMIM, accessed 7th Nov 2025).
Sources: Other
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: NECTIN4.
Amelogenesis imperfecta v4.12 NECTIN4 Ida Ertmanska Publications for gene: NECTIN4 were set to PMID: 34067522; 37183149
Amelogenesis imperfecta v4.11 NECTIN4 Ida Ertmanska edited their review of gene: NECTIN4: Changed publications to: 20691405, 21346770, 34067522, 37183149, 37829154
Amelogenesis imperfecta v4.11 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from syndactyly of the toes and fingers; hair abnormalities; variable dental genesis; enamel hypoplasia (amelogenesis imperfecta?); variable nail dystrophy; variable palmoplantar keratoderma, hyperkeratosis, reduced sweating to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573; ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565; amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.10 NECTIN4 Ida Ertmanska Classified gene: NECTIN4 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.10 NECTIN4 Ida Ertmanska Gene: nectin4 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska commented on gene: NECTIN4: Comment on list classification: there are at least 6 unrelated individuals with biallelic NECTIN4 variants and Ectodermal dysplasia-syndactyly syndrome 1. All affected individuals presented with dental abnormalities, including enamel hypoplasia, tooth agenesis, and peg-shaped, widely-spaced teeth. Based on available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska changed review comment from: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.
;
PMID: 40586252 Abu Assab et al. 2025; to: PMID: 20691405 Brancati et al. 2010
Family A - 4 affected siblings, Algerian origins, first-cousin parents; c.851G>A (p.Arg284Gln), homozygous; phenotype: progressive alopecia, pili torti, widely-spaced peg-shaped teeth, syndactyly fingers 2-3/3-4, toes 2-3/4-5. Study shows that the variants results in exon 4 skipping, leading to a p.(Phe244CysfsX22) change (premature stop codon).
Family B - 2 sibs born to nonconsanguineous Italian parents; phenotype: alopecia, pili torti, abnormal teeth, cutaneous syndactyly. Compound heterozygous c.554C>T (p.Thr185Met) + c.906delT (p.Pro304HisfsX2). 50% reduced mRNA expression in cultured epidermal keratinocytes of patient II:1 (family B).

PMID: 21346770, Jelani et al. 2011
10 affected individuals across a consanguineous Pakistani pedigree. Used microsatellite markers to assign disease locus. Affected individuals homozygous for c.635C>G; p.Pro212Arg - LOD score 5.05. Phenotype: sparse hair, conical teeth with enamel hypoplasia, nail dystrophy, palmoplantar keratoderma, bilateral syndactyly fingers 3-4 and toes 2-3.

PMID: 34067522 Rotunno et al., 2021
Reports 5yo female patient; c.1150delC (p.Gln384ArgfsTer7), homozygous; phenotype: Brittle hair, sparse eyebrows/eyelashes, toenail dystrophy, mild palmoplantar keratoderma. Her teeth were widely spaced and conical, with small crowns and enamel hypoplasia + agenesis of 4 wisdom teeth.

PMID: 37829154 Ali et al., 2023
Consanguineous Kashmiri Family. All 4 affected individuals harboured a homozygous nonsense variant NM 030916: c.181C > T, p.(Gln61Ter). Method: WES. Hypotrichosis, syndactyly fingers 3-4 and toes 2-3, discolored nails, upper lip cleft; conical teeth, with enamel ridges, and pits, widely spaced.

PMID: 37183149 Hajra et al., 2023
Large consanguineous Pakistani family. Only NECTIN4 coding region sequenced. All 15 affected individuals were homozygous for c.163C>T; p.(Arg55*). Phenotype: sparse hair; hypoplastic nails with thick flat discoloured nail plates; peg-shaped, conical, and widely spaced teeth with enamel hypoplasia; proximal cutaneous syndactyly of fingers and toes; skin was dry and scaly with hyperkeratosis and palmoplantar keratoderma.

NECTIN4, previously known as PVRL4, is linked to Ectodermal dysplasia-syndactyly syndrome 1, 613573 (OMIM, accessed 7th Nov 2025).
Amelogenesis imperfecta v4.9 NECTIN4 Ida Ertmanska reviewed gene: NECTIN4: Rating: GREEN; Mode of pathogenicity: None; Publications: 34067522, 37183149; Phenotypes: Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573, ectodermal dysplasia-syndactyly syndrome 1, MONDO:0024565, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia without a known gene mutation v1.29 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from Ectodermal dysplasia-syndactyly syndrome 1 613573 to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573
Ectodermal dysplasia v4.13 NECTIN4 Ida Ertmanska Phenotypes for gene: NECTIN4 were changed from Ectodermal dysplasia-syndactyly syndrome 1 613573 to Ectodermal dysplasia-syndactyly syndrome 1, OMIM:613573
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: CLDN16.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska changed review comment from: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The dental defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska changed review comment from: Comment on list classification: There are at 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.; to: Comment on list classification: There are 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska commented on gene: CLDN16: Comment on list classification: There are at 6 unrelated individuals reported in literature with biallelic variants in CLDN16 with amelogenesis imperfecta. The enamel defects are part of a syndromic presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The association is supported by a Cldn16−/− mouse model, showing enamel fractures and coronal dentin exposition on molars, caused by ameloblast defects and low extracellular pH. Based on the available evidence, this gene should be promoted to Green for Amelogenesis imperfecta at the next GMS update.
Likely inborn error of metabolism v8.83 CLDN16 Ida Ertmanska Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal 248250 to Hypomagnesemia 3, renal, OMIM:248250
Undiagnosed metabolic disorders v1.638 CLDN16 Ida Ertmanska Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal 248250 to Hypomagnesemia 3, renal, OMIM:248250
Nephrocalcinosis or nephrolithiasis v5.2 CLDN16 Ida Ertmanska Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal to Hypomagnesemia 3, renal, OMIM:248250
Amelogenesis imperfecta v4.9 CLDN16 Ida Ertmanska reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: None; Publications: 26426912, 32710267; Phenotypes: familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, MONDO:0017624, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.61 BAIAP2 Alexander Symon-Allen gene: BAIAP2 was added
gene: BAIAP2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAIAP2 were set to PMID: 41133935
Phenotypes for gene: BAIAP2 were set to DEE
Penetrance for gene: BAIAP2 were set to unknown
Mode of pathogenicity for gene: BAIAP2 was set to Other
Review for gene: BAIAP2 was set to AMBER
Added comment: De novo missense variants detected in 6 unrelated individuals with DEE. One of which has also been seen on DECIPHER and deposited as a research variant (also de novo).
Seizure type is highly variable.
ID ranges from mild to profound.
Animal models (zebrafish) provide some evidence of pathogenicity through abnormal neurite growth (lack or absence of filopodia) and increased neuronal excitability (reduced rheobase & increased AP firing patterns in whole cell recordings). Ion channels within membrane remain unaffected - no significant difference between WT and mutants in specific AP characteristics such as amplitude, voltage threshold, afterhyperpolarisation, and half-width values.
The above evidence led the authors hypothesis that GoF is the mechanism of disease for the variants in this study, however, they propose that LoF variants may also be pathogenic (no evidence to confirm this).
Further studies needed to verify findings and confirm this proposed biphasic disease mechanism model (LoF & GoF variants cause disease).
Currently only evidence for GoF in for a very specific repertoire of residues that are clustered within the phosphorylation site region that is critical to 14-3-3 binding for autoinhibited conformation: T340, Pro342, Arg363 and one variant within the I-BAR domain which is crucial for maintaining the overall positive charge of the dimer: Glu189Val.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.74 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia, 240300; Chronic mucocutaneous candidiasis (CMC); Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED); Autoimmune hypoparathyroidism chronic candidiasis Addison disease syndrome; Hypoparathyroidism Addison disease mucocutaneous candidiasis syndrome; Multiple endocrine deficiency Addison disease candidiasis syndrome; Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia; Diseases of Immune Dysregulation to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Intellectual disability v9.163 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Intellectual disability v9.162 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without,reversible metaphyseal dysplasia, 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: Both mono and bi allelic variants have been reported to cause Autoimmune polyendocrinopathy syndrome, type I (APS-1) - primarily characterised by hypoparathyroidism, enamel hypoplasia, adrenal insufficiency, and recurrent candidiasis. There are at least 3 indiviuals reported with monoallelic AIRE variants, and numerous cases with biallelic variants. Monoallelic variants in AIRE result in an incompletely penetrant, milder phenotype. Based on the available evidence, the MOI should remain as BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 (age range: 19 months–44 years).
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. No immunodeficiency noted.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia & Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Retinal disorders v8.63 AIRE Ida Ertmanska changed review comment from: MONOALLELIC:
PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested. No ocular phenotype reported in the cohort.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All
patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC:
PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested. No ocular phenotype reported in the cohort.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: Comment on list classification: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, as well as enamel hypoplasia. Out of more than 90 families reported in literature, only 2 individuals harbouring monoallelic variants in AIRE were diagnosed with immunodeficiency. Based on the available evidence, AIRE should be downgraded to Amber for the Primary immunodeficiency or monogenic inflammatory bowel disease panel.; to: Comment on list classification: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, as well as enamel hypoplasia. Out of more than 90 families reported in literature, only 2 individuals harbouring monoallelic variants in AIRE were diagnosed with immunodeficiency. Based on the available evidence, AIRE should be downgraded to Amber for the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska commented on gene: AIRE: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed rating: GREEN; Changed publications to: 11600535, 19393987, 27253668, 29129473, 31905445, 35521792, 37993717, 37235056
Retinal disorders v8.63 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Retinal disorders v8.62 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Retinal disorders v8.61 AIRE Ida Ertmanska Tag Q4_25_MOI tag was added to gene: AIRE.
Retinal disorders v8.61 AIRE Ida Ertmanska changed review comment from: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list mode of inheritance: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, and enamel hypoplasia. There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as an additional APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.
Retinal disorders v8.61 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed publications to: 25926518, 34122451, 37711606, 37235056
Retinal disorders v8.61 AIRE Ida Ertmanska changed review comment from: PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All
patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC:
PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested. No ocular phenotype reported in the cohort.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years). All
patients showed fundus changes ranging from isolated patchy atrophy of the RPE to an RP-like fundus and attenuated vasculature.
P1: female, P539L/P539L - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Alopecia, Growth retardation.
P2: male, R257X/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyroidism, Acne
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections
P4: male, R256X/c.967_c.979del13 - systemic findings: Oesophageal candidiasis/stricture, Hypoparathyroidism, Hypogonadism, Nails dystrophy, Alopecia
P5: female, c.463G>A/p.G155S/p.G155S - systemic findings: Autoimmune hepatitis, Mucocutaneous candidiasis, Hypoparathyroidism, Addison disease

PMID: 34122451 Sakaguchi et al. 2021
2-year-old Japanese girl homozygous for c.415C>T, (p.Arg139Ter), with bilateral autoimmune retinopathy, anti-recoverin antibodies, and steroid-responsive acute liver failure.

PMID: 37711606 Wang et al., 2023
3-year-old Chinese boy - F1-II2 - homozygous for c.769C>T, (p.Arg257Ter) - widespread tapetoretinal degeneration without bone-spicule pigmentation. rod and cone responses were non-recordable on ERG recordings. No other systemic symptoms.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Retinal disorders v8.61 AIRE Ida Ertmanska changed review comment from: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.
Retinal disorders v8.61 AIRE Ida Ertmanska edited their review of gene: AIRE: Added comment: Comment on list mode of inheritance: There are at least 7 unrelated individuals with biallelic variants in AIRE, reported to have retinopathy as part of the APS-1 disease presentation. Monoallelic variants in AIRE have not been linked to retinopathy. Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.61 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 25926518, 34122451, 37711606; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: None
Autoimmune Polyendocrine Syndrome v1.3 AIRE Ida Ertmanska Tag Q4_25_MOI tag was added to gene: AIRE.
Autoimmune Polyendocrine Syndrome v1.3 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Autoimmune Polyendocrine Syndrome v1.2 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Autoimmune Polyendocrine Syndrome v1.1 AIRE Ida Ertmanska commented on gene: AIRE: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are only 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism; the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Autoimmune Polyendocrine Syndrome v1.1 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no adrenal insufficiency noted. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and hypoparathyroidism at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no adrenal insufficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance suggested.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and hypoparathyroidism at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Autoimmune Polyendocrine Syndrome v1.1 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 11600535, 19393987, 27253668, 29129473, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska commented on gene: AIRE: Comment on list classification: Autoimmune polyendocrinopathy syndrome type I (APS-1) is characterised primarily by the presence of hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, as well as enamel hypoplasia. Out of more than 90 families reported in literature, only 2 individuals harbouring monoallelic variants in AIRE were diagnosed with immunodeficiency. Based on the available evidence, AIRE should be downgraded to Amber for the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed rating: AMBER
Familial hypoparathyroidism v3.4 AIRE Ida Ertmanska Publications for gene: AIRE were set to 19393987; 27253668; 31905445; 35521792; 37993717; 37235056
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska edited their review of gene: AIRE: Changed publications to: 11600535, 19393987, 27253668, 29129473, 31905445, 35521792, 37993717, 37235056
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and hypoparathyroidism at age 5, and CMC at age 11.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 35521792 Cranston et al., 2022
Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases:
Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism.
Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative.; to: PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 5 patients reported in literature with biallelic variants in AIRE, diagnosed with APS-1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with APS-1, they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Familial hypoparathyroidism v3.3 AIRE Ida Ertmanska Publications for gene: AIRE were set to
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska Tag Q4_25_MOI tag was added to gene: AIRE.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. In addition, AIRE knock-out mice showed defective enamel formation (PMID: 37993717). Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations.
Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected.
The other 10 probands reported did not present with hypoparathyroidism.

PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska commented on gene: AIRE: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with APS-1, they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 19393987, 27253668, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v4.6 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Ectodermal dysplasia v4.12 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Ectodermal dysplasia v4.11 AIRE Ida Ertmanska Mode of inheritance for gene: AIRE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v4.6 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Ideopathic Primary Adrenal Failure; Congenital Adrenal Hypoplasia to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Familial hypoparathyroidism v3.2 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska changed review comment from: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only 1 APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only one APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: AIRE.
Amelogenesis imperfecta v4.9 AIRE Ida Ertmanska Phenotypes for gene: AIRE were changed from Addison disease; hypoparathyroidism; chronic mucocutaneous candidiasis to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411; amelogenesis imperfecta, MONDO:0019507
Amelogenesis imperfecta v4.8 AIRE Ida Ertmanska Publications for gene: AIRE were set to PMID: 37993717; 19393987; 27253668
Amelogenesis imperfecta v4.7 AIRE Ida Ertmanska Mode of inheritance for gene: AIRE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.6 AIRE Ida Ertmanska Classified gene: AIRE as Amber List (moderate evidence)
Amelogenesis imperfecta v4.6 AIRE Ida Ertmanska Gene: aire has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska commented on gene: AIRE: Comment on list classification: There are at least 23 patients reported in literature with biallelic variants in AIRE, diagnosed with APS 1 and presenting with marked enamel hypoplasia (onset mostly in childhood / adolescence). Only 1 APS-1 patient heterozygous for an AIRE variant presented with enamel hypoplasia. Based on the available evidence, this gene should be rated Green for Amelogenesis imperfecta, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska changed review comment from: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.; to: PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: R257X/T16M. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity.

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.

Functional evidence:
PMID: 37993717 Gruper et al., 2023
Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation.
AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay).

Only 1 patient reported with a heterozygous variant in AIRE with enamel hypoplasia:
PMID: 37235056 Oftedal et al., 2023
Family X (II-I) - Female, USA - c.1102C>G, p.Pro368Ala - heterozygous variant, present in 14 individuals in gnomAD v4 (het only); Revel score = 0.27 Benign Supporting. Presented with migraines, chronic constipation, poor appetite, recurrent fever, proteinuria, hypoparathyroidism, enamel hypoplasia; positive for autoantibodies against IL-17A. Seq method: WES.
10 other patients with heterozygous variants in AIRE and APS1 did not present with enamel hypoplasia. Authors highlight incomplete penetrance of the dominant-negative mutations reported.
Amelogenesis imperfecta v4.5 AIRE Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 19393987, 27253668, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411, amelogenesis imperfecta, MONDO:0019507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.61 BSN Helen Lord gene: BSN was added
gene: BSN was added to Early onset or syndromic epilepsy. Sources: Other
Mode of inheritance for gene: BSN was set to Unknown
Publications for gene: BSN were set to PMID: 36600631; 39616287; 40393460
Phenotypes for gene: BSN were set to Seizures - different types
Penetrance for gene: BSN were set to unknown
Review for gene: BSN was set to AMBER
Added comment: There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

PMID:36600631 - Ye et al, 2023:
BSN gene encodes the Bsssoon protein which is highly expressed in the mammalian brain especially the cerebral cortex and the hippocampus.
WES in 313 trios with epilepsies of unknown causes novel BSN variants identifed in 5 cases and 3 additional variants identified in 3 cases from different centres:
Cases 1-4 compound het - variants shown to be inherited in trans
Cases 5-8 - het variants idenitied in case 5 & 6 inherited from affected parent (febrile seizure in these parents) and in cases 7 & 8 - arise de novo.
The 9 variants present in low or no allele freq in all populations or East Asian populations - no hom in gnomAD. No other pathogenic/likely pathogenic variants in other epilepsy genes identiifed.
Fig 3:
B:The 2 nonsense variants in exon 5 thought to result in the truncation of the basson protein and trigger NMD. Both de novo. They state LOF and haploinsuffucency of BSN are potentially pathogenic.
C: 6/9 missense variants led to hydrogen bond alterations - mostly creation of hydrogen bonds which were not predicted orignally. 5/9 missense variants clustered in the C-terminus. Among the 4 pairs of compound het variants at least 1 variant in each pair had hydrogen bond alterations.
In the discussion they state LOF of Bassoon is potentially the underlying mechanism of pathogenicity of BSN variants, which is consistent with the pathogenisi of other genes encoding CAZ proteins such as UNC13A and UNC13B; however, the functional effects of BSN variants warrants further investigation.
In het BSN knockout mice - no phenotype; however, hom knockout mice null led to spontaneous seizures and partial preamture lethality. Clinically the patients with monoallelic BSN missense variants achieved seizure free status without treatment or under monotherapy; whereas, the majority of patients with biallelic missense variants required combination therapy, possible correlation between genotype and phenotype severity.

PMID 39616287: Yacoub et al, 2025: WES in 10 JME (juvenille myoclonic epilepsy) patients - P4 found to have a het BSN missense variant - c.2534G>A p.(Arg845Gln), also identified in her affected brother who has GTCs, but also detected in an unaffected brother. Presumably also inherited from an unaffected pedogree (pedigree included - no mention of parental testing).

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Undiagnosed metabolic disorders v1.637 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Undiagnosed metabolic disorders v1.637 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.29 CPOX Ida Ertmanska Tag Q3_25_MOI tag was added to gene: CPOX.
Tag Q3_25_expert_review tag was added to gene: CPOX.
Hereditary neuropathy or pain disorder v7.29 CPOX Ida Ertmanska edited their review of gene: CPOX: Added comment: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.82 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Likely inborn error of metabolism v8.82 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Rare anaemia v3.13 CPOX Ida Ertmanska Tag Q3_25_expert_review was removed from gene: CPOX.
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-acute porphyrias v1.29 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Non-acute porphyrias v1.29 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.82 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare anaemia v3.13 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Non-acute porphyrias v1.29 CPOX Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: CPOX.
Non-acute porphyrias v1.29 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the appropriate MOI is 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'. However, due to low clinical penetrance of monoallelic variants (<1%), this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Non-acute porphyrias v1.29 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the appropriate MOI is 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'. However, due to low clinical penetrance of monoallelic variants (<1%), this gene is tagged for MOI Expert Review.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Retinal disorders v8.61 PAX6 Achchuthan Shanmugasundram Mode of inheritance for gene: PAX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram commented on gene: FRMD7: This gene is proposed for green rating based on sufficient evidence for the association of FRMD7 variants with foveal hypoplasia. However, expert review is sought from NHS Genomic Laboratory Hubs on the relevance of this phenotype to the scope of retinal disorders panel.
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: FRMD7.
Tag Q3_25_expert_review tag was added to gene: FRMD7.
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM accessed on 04 November 2025.
Retinal disorders v8.60 FRMD7 Achchuthan Shanmugasundram Phenotypes for gene: FRMD7 were changed from Nystagmus 1, congenital, X-linked, OMIM:310700; Nystagmus, infantile periodic alternating, X-linked, OMIM:310700; foveal hypoplasia, MONDO:0044203 to Nystagmus 1, congenital, X-linked, OMIM:310700; Nystagmus, infantile periodic alternating, X-linked, OMIM:310700; foveal hypoplasia, MONDO:0044203
Neonatal diabetes v5.6 TARS2 Anna-Marie Johnson gene: TARS2 was added
gene: TARS2 was added to Neonatal diabetes. Sources: Literature
Mode of inheritance for gene: TARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS2 were set to PMID: 39509107 and PMID: 37454282
Phenotypes for gene: TARS2 were set to Neonatal diabetes; developmental delay; epilepsy
Penetrance for gene: TARS2 were set to Complete
Mode of pathogenicity for gene: TARS2 was set to Other
Review for gene: TARS2 was set to GREEN
Added comment: Donis et al 2024 (PMID: 39509107) performed WGS on 27 neonatal diabetes patients who also had epilepsy and/or developmental delay. 3 individuals were found to be homozygous for a TARS2 missense variant, c.980G>A, p.(Arg327Gln). A replication cohort identified 1 additional individual who is also homozygous for this variant. An additional patient with diabetes (age of diagnosis not provided) and COXPD-21 related features has been reported with compound heterozygous TARS2 variants (Accogli et al 2023, PMID: 37454282). Biallelic TARS2 variants cause Combined Oxidative Phosphorylation Deficiency-21(COXPD-21, 21;OMIM: 615918) and neonatal diabetes is a reported feature of this disorder. Evidence shows that the p.(Arg327Gln) variant disrupts TARS2's regulation of the mTORC1 pathway which is essential for pancreatic beta-cells.
Sources: Literature
Retinal disorders v8.59 PAX6 Achchuthan Shanmugasundram Classified gene: PAX6 as Amber List (moderate evidence)
Retinal disorders v8.59 PAX6 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are multiple families reported with foveal hypoplasia and with monoallelic PAX6 variants. However, expert opinion is sought from the NHS Genomic Laboratory Hubs on whether the foveal hypoplasia phenotype fits within the scope of the retinal disorders panel.
Retinal disorders v8.59 PAX6 Achchuthan Shanmugasundram Gene: pax6 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.58 PAX6 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PAX6.
Tag Q3_25_expert_review tag was added to gene: PAX6.
Retinal disorders v8.58 PAX6 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 04 November 2025.
Retinal disorders v8.58 PAX6 Achchuthan Shanmugasundram Phenotypes for gene: PAX6 were changed from Foveal hypoplasia 1, OMIM:136520; Microphthalmia/coloboma 12, OMIM:120200; ?Coloboma of optic nerve, OMIM:120430; Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229 to Foveal hypoplasia 1, OMIM:136520; Microphthalmia/coloboma 12, OMIM:120200; ?Coloboma of optic nerve, OMIM:120430; ?Morning glory disc anomaly, OMIM:120430; Aniridia, OMIM:106210; Cataract with late-onset corneal dystrophy, OMIM:106210; Keratitis, OMIM:148190; Optic nerve hypoplasia, OMIM:165550; Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229
Retinal disorders v8.57 PAX6 Achchuthan Shanmugasundram edited their review of gene: PAX6: Changed phenotypes to: Foveal hypoplasia 1, OMIM:136520, Microphthalmia/coloboma 12, OMIM:120200, ?Coloboma of optic nerve, OMIM:120430, ?Morning glory disc anomaly, OMIM:120430, Aniridia, OMIM:106210, Cataract with late-onset corneal dystrophy, OMIM:106210, Keratitis, OMIM:148190, Optic nerve hypoplasia, OMIM:165550, Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229
Retinal disorders v8.57 PAX6 Achchuthan Shanmugasundram Phenotypes for gene: PAX6 were changed from Foveal Hypoplasia and Presenile Cataract Syndrome; Developmental macular and foveal dystrophy (foveal hypoplasia in the context of aniridia) to Foveal hypoplasia 1, OMIM:136520; Microphthalmia/coloboma 12, OMIM:120200; ?Coloboma of optic nerve, OMIM:120430; Anterior segment dysgenesis 5, multiple subtypes, OMIM:604229
Intellectual disability v9.161 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Intellectual disability v9.161 KIF26A Ida Ertmanska Added comment: Comment on list classification: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). 6/8 individuals assessed presented with developmental delay and/or intellectual disability: 3 cases with mild cognitive impairment, 2 with moderate ID, 1 with 'growth retardation and developmental delay' - severity not specified. As only 2 cases meet the panel criteria of moderate/severe impairment, this gene should be rated Amber for Intellectual disability until more evidence emerges.
Intellectual disability v9.161 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.92 MT-ND5 Achchuthan Shanmugasundram changed review comment from: After consultation with the clinical team, this gene is tagged for expert review by the Genomic Laboratory Hubs on the inclusion of this gene with green rating to this panel.; to: After consultation with the clinical team, this gene is tagged for expert review by the Genomic Laboratory Hubs on the inclusion of this gene with green rating on this panel.
Paediatric or syndromic cardiomyopathy v7.92 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

Expert review is being sought from the Genomic Medicine Service on whether this gene can be promoted to the next major version.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

Expert opinion is sought from the Genomic Medicine Service on the inclusion of this gene on this panel with green raring in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.92 MT-TV Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: MT-TV.
Paediatric or syndromic cardiomyopathy v7.92 MT-TV Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in at least three unrelated patients with variants in MT-TV gene. This gene can therefore be promoted to green rating on the next GMS update.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in at least three unrelated patients with variants in MT-TV gene.

Expert opinion is sought from the Genomic Medicine Service on the inclusion of this gene on this panel with green raring in the next GMS update.
Intellectual disability v9.160 KIF26A Ida Ertmanska gene: KIF26A was added
gene: KIF26A was added to Intellectual disability. Sources: Other
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36228617; 36564622; 39305096
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Review for gene: KIF26A was set to AMBER
Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Sources: Other
Hydrocephalus v5.3 KIF26A Ida Ertmanska changed review comment from: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Sources: Other; to: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Hydrocephalus v5.3 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Hydrocephalus v5.3 KIF26A Ida Ertmanska Added comment: Comment on list classification: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). 12/12 cases with brain MRI available showed congenital brain malformations - in particular ventriculomegaly/hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases.
KIF26A is associated with AR 'Cortical dysplasia, complex, with other brain malformations 11, 620156' in OMIM (accessed 31st Oct 2025). The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024). Based on the available evidence, this gene should be promoted to Green on the Hydrocephalus panel.
Hydrocephalus v5.3 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Hydrocephalus v5.2 KIF26A Ida Ertmanska gene: KIF26A was added
gene: KIF26A was added to Hydrocephalus. Sources: Other
Q4_25_promote_green tags were added to gene: KIF26A.
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36228617; 36564622; 39305096
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Review for gene: KIF26A was set to GREEN
Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.

Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Sources: Other
Limb disorders v7.13 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Limb disorders v7.13 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome, 605039 to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Intellectual disability v9.159 ASXL1 Ida Ertmanska Publications for gene: ASXL1 were set to
Intellectual disability v9.158 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Intellectual disability v9.158 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome, 605039Myelodysplastic syndrome, somatic, 614286; BOHRING-OPITZ SYNDROME to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Paediatric or syndromic cardiomyopathy v7.92 MT-TL1 Achchuthan Shanmugasundram Tag Q2_25_expert_review tag was added to gene: MT-TL1.
Paediatric or syndromic cardiomyopathy v7.92 MT-TL1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

This gene can therefore be promoted to green rating on the next GMS update.; to: Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with m.3243A>G variant.

Expert review is being sought from the Genomic Medicine Service on whether this gene can be promoted to the next major version.
Clefting v6.14 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Clefting v6.14 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from BOHRING-OPITZ SYNDROME; BOPS to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.2 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.2 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome, 605039; Metopic synostosis frequently associated with Bohring-Opitz syndrome to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Fetal anomalies v6.116 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Fetal anomalies v6.116 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from BOHRING-OPITZ SYNDROME to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Skeletal dysplasia v8.21 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed 3rd Nov 2025.
Skeletal dysplasia v8.21 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome 605039 to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Arthrogryposis v9.12 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes accessed on 3rd Nov 2025.
Arthrogryposis v9.12 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from Bohring-Opitz syndrome 605039 to Bohring-Opitz syndrome, OMIM:605039; Bohring-Opitz syndrome, MONDO:0011510
Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from chronic viral infections; v Bohring-Opitz syndrome, OMIM:605039; Myelodysplastic syndrome, somatic, OMIM: 614286iral-associated malignancies; combined immune deficiency to combined immunodeficiency, MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Boaz Palterer, there is a single case reported in literature with biallelic variants in ASXL1 and features of primary immunodeficiency. This gene should be rated Red for Primary immunodeficiency or monogenic inflammatory bowel disease until more evidence emerges.; to: Comment on list classification: As reviewed by Boaz Palterer, there is a single case reported in literature with biallelic variants in ASXL1 and features of primary immunodeficiency. This gene should be rated Red for Primary immunodeficiency or monogenic inflammatory bowel disease until more evidence emerges.
ASXL1 is associated with AD Bohring-Opitz syndrome, OMIM:605039 and Myelodysplastic syndrome, somatic, OMIM: 614286 (OMIM accessed 3rd Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska changed review comment from: Comment on phenotypes: ASXL1 is associated with AD Bohring-Opitz syndrome, OMIM:605039 and Myelodysplastic syndrome, somatic, OMIM: 614286 (OMIM accessed 3rd Nov 2025).; to: Comment on phenotypes:
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska edited their review of gene: ASXL1: Changed phenotypes to: combined immunodeficiency MONDO:0015131
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska Added comment: Comment on phenotypes: ASXL1 is associated with AD Bohring-Opitz syndrome, OMIM:605039 and Myelodysplastic syndrome, somatic, OMIM: 614286 (OMIM accessed 3rd Nov 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.72 ASXL1 Ida Ertmanska Phenotypes for gene: ASXL1 were changed from chronic viral infections; viral-associated malignancies; combined immune deficiency to chronic viral infections; v Bohring-Opitz syndrome, OMIM:605039; Myelodysplastic syndrome, somatic, OMIM: 614286iral-associated malignancies; combined immune deficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 ASXL1 Ida Ertmanska reviewed gene: ASXL1: Rating: RED; Mode of pathogenicity: None; Publications: 40742536; Phenotypes: Bohring-Opitz syndrome, OMIM:605039, Myelodysplastic syndrome, somatic, OMIM: 614286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v4.2 BTK Achchuthan Shanmugasundram Phenotypes for gene: BTK were changed from Isolated growth hormone deficiency, type III, with agammaglobulinemia (307200) to Isolated growth hormone deficiency, type III, with agammaglobulinemia, OMIM:307200
Mosaic skin disorders - deep sequencing v3.1 GJA1 Veronica Kinsler gene: GJA1 was added
gene: GJA1 was added to Mosaic skin disorders - deep sequencing. Sources: Expert Review
Mode of inheritance for gene: GJA1 was set to Other
Publications for gene: GJA1 were set to PMID: 27890787
Phenotypes for gene: GJA1 were set to Inflammatory Linear Verrucous Epidermal Naevi (ILVEN)
Review for gene: GJA1 was set to GREEN
Added comment: Mosaic, potential for germline transmission
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 TNFSF9 Ida Ertmanska reviewed gene: TNFSF9: Rating: RED; Mode of pathogenicity: None; Publications: 35657354; Phenotypes: EBV lymphoproliferation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 TNFSF9 Ida Ertmanska Classified gene: TNFSF9 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.71 TNFSF9 Ida Ertmanska Gene: tnfsf9 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.70 GCC2 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Boaz Palterer, there are 2 unrelated individuals reported in literature with biallelic variants in GCC2 and recurrent viral infections (PMID:39813120). Hence, this gene should be rated Amber for Primary immunodeficiency or monogenic inflammatory bowel disease, until more evidence emerges.
This gene is not yet associated with a phenotype in OMIM (accessed 31st Oct 2025).; to: Comment on list classification: As reviewed by Boaz Palterer, there are 2 unrelated individuals reported in literature with biallelic variants in GCC2 and recurrent viral infections, with demonstrated reduced natural killer cell function (PMID:39813120). Hence, this gene should be rated Amber for Primary immunodeficiency or monogenic inflammatory bowel disease, until more evidence emerges.
This gene is not yet associated with a phenotype in OMIM (accessed 31st Oct 2025).
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska Tag Q4_25_NHS_review tag was added to gene: KIF26A.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.70 GCC2 Ida Ertmanska Classified gene: GCC2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.70 GCC2 Ida Ertmanska Gene: gcc2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.69 GCC2 Ida Ertmanska reviewed gene: GCC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 39813120; Phenotypes: NK cell deficiency, recurrent viral infections, immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mosaic skin disorders - deep sequencing v3.1 TSC1 Veronica Kinsler edited their review of gene: TSC1: Changed rating: GREEN
Mosaic skin disorders - deep sequencing v3.1 TSC2 Veronica Kinsler edited their review of gene: TSC2: Changed phenotypes to: Cutaneous pigmentary abnormalities, and/or other aspects of germline TSC disease
Mosaic skin disorders - deep sequencing v3.1 TSC2 Veronica Kinsler gene: TSC2 was added
gene: TSC2 was added to Mosaic skin disorders - deep sequencing. Sources: Expert Review
Mode of inheritance for gene: TSC2 was set to Other
Publications for gene: TSC2 were set to PMID: 37356622
Review for gene: TSC2 was set to GREEN
Added comment: Mosaic, potential for transmission to offspring in germline
Sources: Expert Review
Mosaic skin disorders - deep sequencing v3.1 TSC1 Veronica Kinsler gene: TSC1 was added
gene: TSC1 was added to Mosaic skin disorders - deep sequencing. Sources: Expert Review
Mode of inheritance for gene: TSC1 was set to Other
Publications for gene: TSC1 were set to PMID: 37356622
Phenotypes for gene: TSC1 were set to Cutaneous pigmentary abnormalities, and/or other aspects of germline TSC disease
Added comment: Mosaic, potential for germline transmission to offspring
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v8.69 ASXL1 Ida Ertmanska Classified gene: ASXL1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.69 ASXL1 Ida Ertmanska Gene: asxl1 has been classified as Red List (Low Evidence).
Mosaic skin disorders - deep sequencing v3.1 CARD14 Veronica Kinsler reviewed gene: CARD14: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34116062, PMID: 38360177, PMID: 35853659; Phenotypes: Inflammatory Linear Verrucous Epidermal Naevi (ILVEN); Mode of inheritance: Other
Mosaic skin disorders - deep sequencing v3.1 TP63 Veronica Kinsler reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34703865, PMID: 27351625, PMID: 22740388; Phenotypes: Blaschkolinear hypopigmentation, with or without features of germline TP63 diseases; Mode of inheritance: None
Mosaic skin disorders - deep sequencing v3.1 PMVK Veronica Kinsler reviewed gene: PMVK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38360177, PMID: 35853659; Phenotypes: Inflammatory Linear Verrucous Epidermal Naevi (ILVEN); Mode of inheritance: Other
Mosaic skin disorders - deep sequencing v3.1 KITLG Veronica Kinsler reviewed gene: KITLG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28257793; Phenotypes: Blaschkolinear hyperpigmentation; Mode of inheritance: Other
Epidermolysis bullosa and congenital skin fragility v2.7 ATP2A2 Veronica Kinsler reviewed gene: ATP2A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 10080178; Phenotypes: Darier disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska changed review comment from: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.; to: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations - reported in all individuals. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska changed review comment from: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.; to: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska changed review comment from: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. These symptoms are likely caused by congenital cortical malformations. As reviewedpreviously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.; to: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, and vomiting. These symptoms are likely caused by congenital cortical malformations. As reviewed previously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities. Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska commented on gene: KIF26A: Comment on list classification: 8/13 patients reported in literature with biallelic KIF26A variants had gastrointestinal issues, including paediatric intestinal pseudo‐obstruction, megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. These symptoms are likely caused by congenital cortical malformations. As reviewedpreviously by Achchuthan Shanmugasundram, mouse Kif26a knockouts developed megacolon, enteric nerve hyperplasia in the colon and functional bowel abnormalities Based on the available evidence, this gene should be promoted to Green for Paediatric pseudo-obstruction syndrome at the next GMS update.
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: KIF26A.
Malformations of cortical development v7.14 KIF26A Ida Ertmanska changed review comment from: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).
The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
Sources: Other; to: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).
The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024).
Malformations of cortical development v7.14 KIF26A Ida Ertmanska commented on gene: KIF26A: Comment on list classification: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096). 12/12 cases with brain MRI available showed congenital brain malformations, in particular ventriculomegaly/hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases.
KIF26A is associated with AR 'Cortical dysplasia, complex, with other brain malformations 11, 620156' in OMIM (accessed 31st Oct 2025). The association of KIF26A and 'complex cortical dysplasia with other brain malformations' is classified as Strong in ClinGen (March 2024). Based on the available evidence, this gene should be promoted to Green for Malformations of cortical development
Malformations of cortical development v7.14 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Malformations of cortical development v7.14 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.13 KIF26A Ida Ertmanska gene: KIF26A was added
gene: KIF26A was added to Malformations of cortical development. Sources: Other
Q4_25_promote_green tags were added to gene: KIF26A.
Mode of inheritance for gene: KIF26A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF26A were set to 36228617; 36564622; 39305096
Phenotypes for gene: KIF26A were set to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Review for gene: KIF26A was set to GREEN
Added comment: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).
The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction. Note: several individuals died before certain clinical features could be assessed.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/12 patients and corpus callosum agenesis / hypoplasia in 7/12 cases; unavailable in 1 case. Other malformations noted on MRI: Hypogenesis of septum pellucidum, Brainstem patterning disorder, Long midbrain, Small pons, Brain atrophy, Reduced white matter, Bilateral schizencephaly, Absent hippocampal commissure.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
Sources: Other
Paediatric pseudo-obstruction syndrome v2.4 KIF26A Ida Ertmanska Phenotypes for gene: KIF26A were changed from GDNF-Ret in ENS development to Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156; cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332
Paediatric pseudo-obstruction syndrome v2.3 KIF26A Ida Ertmanska Publications for gene: KIF26A were set to 19914172; 33542431
Paediatric pseudo-obstruction syndrome v2.2 KIF26A Ida Ertmanska Classified gene: KIF26A as Amber List (moderate evidence)
Paediatric pseudo-obstruction syndrome v2.2 KIF26A Ida Ertmanska Gene: kif26a has been classified as Amber List (Moderate Evidence).
Paediatric pseudo-obstruction syndrome v2.1 KIF26A Ida Ertmanska changed review comment from: 13 patients from have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 39305096

The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/13, mild to moderate), cardiac defects (6/13), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 3 others had other gastrointestinal issues: megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/13 patients and corpus callosum agenesis / hypoplasia in 7/13 cases.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Post‐surgery, he had decreased stool frequency managed with macrogol; histopathological examination revealed features consistent with PIPO diagnosis. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137)

36228617 Q

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).; to: At least 13 patients from 10 families have been described in literature with biallelic variants in KIF26A and KIF26A‐related disorder (PMIDs: 36228617; 36564622; 39305096).

Note: several individuals died before certain clinical features could be assessed. The heterogenous syndromic presentation may include developmental delay / intellectual disability (6/8, mild to moderate), cardiac defects (6/7), neurological features e.g. hypotonia (2), spasticity (2), paediatric intestinal pseudo‐obstruction (PIPO) (3/13). While only 3/13 patients were diagnosed with PIPO, 8/13 patients had gastrointestinal issues, including megacolon, ischemic small bowels, severe ascites, abdominal distension, vomiting, and intestinal obstruction.
Brain MRI showed Ventriculomegaly/Hydrocephalus in 12/13 patients and corpus callosum agenesis / hypoplasia in 7/13 cases.

PMID: 39305096 Nosrati et al., 2025
Seq method: Trio exome.
Case #1 - 8yo Italian male; at birth: axial hypotonia, poor suction, failed to pass meconium, leading to surgery for Hirschsprung's disease. Post‐surgery, he had decreased stool frequency managed with macrogol; histopathological examination revealed features consistent with PIPO diagnosis. Compound het c.4378C > T, p.(Arg1460Trp); c.5238C > G, p.(Phe1746Leu).
Case #2 - 6mo Syrian female; presented with abdominal distension and intestinal obstruction symptoms; imaging revealed dilated bowels without mechanical obstruction; biopsies of small and large intestine showed hypoganglionosis. Homozygous for c.4085dup, p.(Ala1363Glyfs*47).
Case #3 - female born to consanguineous parents (Palestinian / Jordanian) - very different presentation: severe spastic quadriplegic cerebral palsy (CP) with epilepsy, hearing problems and cognitive impairments. Homozygous for c.3996C > A, p.(Cys1332*).

PMID: 36564622 Almannai et al., 2023
Seq method: clinical WES.
Report of 2 families with KIF26A‐related disorder.
Family 1: 4 affected individuals, homozygous for c.792dupC, p.(Val265Argfs*5), all presented with persistent abdominal distension and vomiting after birth. 3 individuals died between 2-11 months, 1 patient alive at 3.5 years.
Family 2: proband presented at 3 months with symptoms indicating intestinal obstruction and marked abdominal distension. Symptoms persist at 7yo. Homozygous for c.3330delC, p.(Ser1111Alafs*137).

36228617 Qian et al., 2022
Seq method: WES.
5 unrelated subjects with congenital brain malformations who had inherited biallelic mutations in KIF26A
A01 - consanguineous Turkish family, microcephaly (−3.45SD) and an MRI suggesting a component of cerebral atrophy, as well as dysmorphic features and ileus with megacolon. Homozygous for c.3440dupC, p.Ala1148Cysfs*20.
B01 - diagnosed prenatally with bilateral schizencephaly at 21 weeks; pregnancy terminated; compound heterozygous c.2161C>T, p.Arg721Cys, and c.4676C>T, p.Ala1559Val
C01 - male, non-consanguineous parents, presented with mild developmental delay and learning disability. Brain MRI at 18 years demonstrated agenesis of the corpus callosum; compound het KIF26A: c.4676C>T, p.Arg1624Cys, and c.4870C>T, p.Ala1559Val
D01 - was diagnosed with polymicrogyria and hydrocephalus, with inherited compound heterozygous variants in KIF26A: c.2845C>T, p.Pro949Ser, and c.4676C>T, p.Ala1559Val
E01 - male born to consanguineous parents with growth retardation and developmental delay. Brain MRI performed at 18 months revealed a thin CC, ventriculomegaly and polymicrogyria; homozygous for c.4804C>T; p.Arg1602Trp.

KIF26A is associated with Cortical dysplasia, complex, with other brain malformations 11, 620156 in OMIM (accessed 31st Oct 2025).
Paediatric pseudo-obstruction syndrome v2.1 KIF26A Ida Ertmanska reviewed gene: KIF26A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36228617, 36564622, 39305096; Phenotypes: Cortical dysplasia, complex, with other brain malformations 11, OMIM:620156, cortical dysplasia, complex, with other brain malformations 11 MONDO:0859332; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v4.4 FLNA Ida Ertmanska Classified gene: FLNA as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v4.4 FLNA Ida Ertmanska Gene: flna has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v4.3 FLNA Ida Ertmanska Publications for gene: FLNA were set to 28306229
Ehlers Danlos syndrome with a likely monogenic cause v4.2 FLNA Ida Ertmanska changed review comment from: PMID: 34863227 Billon et al., 2021
Summary report of 3 patient cohorts: 10 French female index cases from the Rare Vascular Diseases Centre, aged 14-66, 23 cases from the filaminopathies diagnostic lab, and a literature review of 59 cases - total of 92 cases with monoallelic variants in FLNA and periventricular nodular heterotopia type 1 (X-linked dominant).
50% of patients did not have neurological symptoms. Most patients presented with combined cardiovascular (CV) and connective tissue disorder (CTD) features. CV anomalies, e.g. aortic aneurysm and/or dilation, were present in 75% of patients. CTD features were present in 75% of patients - e.g. joints hyperlaxity and skin hyperelasticity.

Studies analysed in the literature review: PMIDs:11532987;15249610;15459826;15668422;15994863;15994863;16303888;16684786;19917821;20014127;20730588;20888935;21194575;21960593;22238415;22366253;23032111;24906659;26059841;27091362;27144976;27739212;28177866;28457522;29334594;29449050;30089473;30547349

PMID: 15668422 Sheen et al., 2005 - first report
2 families and 9 sporadic cases with periventricular nodular heterotopia associated with joint hyperlaxity, skin hyperelasticity, and aortic aneurysm/dissection. The authors suggested calling this condition Ehlers–Danlos variant of periventricular heterotopia.

FLNA is putatively linked to FG syndrome 2, 300321, and associated with 9 X-linked conditions: Cardiac valvular dysplasia, X-linked, 314400; Congenital short bowel syndrome, 300048; Frontometaphyseal dysplasia 1, 305620; Heterotopia, periventricular, 1, 300049; Intestinal pseudoobstruction, neuronal, 300048; Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I, 311300; Otopalatodigital syndrome, type II, 304120; Terminal osseous dysplasia, 300244 in OMIM (accessed 31st Oct 2025).; to: PMID: 34863227 Billon et al., 2021
Summary report of 3 patient cohorts: 10 French female index cases from the Rare Vascular Diseases Centre, aged 14-66, 23 cases from the filaminopathies diagnostic lab, and a literature review of 59 cases - total of 92 cases with monoallelic variants in FLNA and periventricular nodular heterotopia type 1 (X-linked dominant).
50% of patients did not have neurological symptoms. Most patients presented with combined cardiovascular (CV) and connective tissue disorder (CTD) features. CV anomalies, e.g. aortic aneurysm and/or dilation, were present in 75% of patients. CTD features were present in 75% of patients - e.g. joints hyperlaxity and skin hyperelasticity.

Studies analysed in the literature review: PMIDs:11532987;15249610;15459826;15668422;15994863;15994863;16303888;16684786;19917821;20014127;20730588;20888935;21194575;21960593;22238415;22366253;23032111;24906659;26059841;27091362;27144976;27739212;28177866;28457522;29334594;29449050;30089473;30547349

PMID: 15668422 Sheen et al., 2005 - first report
2 families and 9 sporadic cases with periventricular nodular heterotopia associated with joint hyperlaxity, skin hyperelasticity, and aortic aneurysm/dissection. The authors suggested calling this condition Ehlers–Danlos variant of periventricular heterotopia.

FLNA is putatively linked to FG syndrome 2, 300321, and associated with 9 X-linked conditions: Cardiac valvular dysplasia, X-linked, 314400; Congenital short bowel syndrome, 300048; Frontometaphyseal dysplasia 1, 305620; Heterotopia, periventricular, 1, 300049; Intestinal pseudoobstruction, neuronal, 300048; Melnick-Needles syndrome, 309350; Otopalatodigital syndrome, type I, 311300; Otopalatodigital syndrome, type II, 304120; Terminal osseous dysplasia, 300244 in OMIM (accessed 31st Oct 2025).
Ehlers Danlos syndrome with a likely monogenic cause v4.2 FLNA Ida Ertmanska edited their review of gene: FLNA: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ehlers Danlos syndrome with a likely monogenic cause v4.2 FLNA Ida Ertmanska reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 11532987, 15249610, 15459826, 15668422, 15994863, 15994863, 16303888, 16684786, 19917821, 20014127, 20730588, 20888935, 21194575, 21960593, 22238415, 22366253, 23032111, 24906659, 26059841, 27091362, 27144976, 27739212, 28177866, 28457522, 29334594, 29449050, 30089473, 30547349, 34863227; Phenotypes: Heterotopia, periventricular, 1, OMIM:300049; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.19 HNRNPA1 Ida Ertmanska commented on gene: HNRNPA1: Comment on list classification: There are at least 7 unrelated individuals reported in literature with monoallelic variants in HNRNPA1 that presented with distal myopathy. Disease onset is either juvenile or in early adulthood. The affected individuals harboured stop-loss, missense, and frameshift variants, either de novo or shown to segregated with disease in an autosomal dominant manner. Other variants in this gene have been reported as causal for juvenile-onset ALS, multisystem proteinopathy, and distal hereditary motor neuropathy. There is currently little to no correlation between the location of the causative variant and the corresponding phenotype, and no precise understanding of the different disease mechanisms. Nonetheless, there is sufficient evidence for this gene-disease relationship. HNRNPA1 should be promoted to Green for Distal myopathies at the next GMS update.
Respiratory ciliopathies including non-CF bronchiectasis v4.48 DNAJB13 Achchuthan Shanmugasundram changed review comment from: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.; to: The ClinGen Motile Ciliopathy expert panel has classified the association of DNAJB13 gene to primary ciliary dyskinesia 34 (MONDO:0014909) as 'Moderate'. More information can be found in https://search.clinicalgenome.org/CCID:008877.

This gene is associated with 'Ciliary dyskinesia, primary, 34' phenotype in OMIM (MIM #617091) - OMIM accessed on 7 July 2025.

There is an additional published case reported in PMID: 35166991. A novel homozygous frameshift variant (c.335_336del [p.Glu112Valfs*3]) variant was identified in a primary infertile male patient. The patient had abnormal sperm morphology, with recurrent respiratory infections and chronic cough.
Respiratory ciliopathies including non-CF bronchiectasis v4.48 DNAJB13 Ida Ertmanska Publications for gene: DNAJB13 were set to 27486783; 35166991
Congenital myopathy v6.38 PNPLA2 Ida Ertmanska changed review comment from: Biallelic mutations in PNPLA2 are associated with Neutral lipid-storage disease with myopathy, OMIM:610717 (NLSDM) - phenotype accessed 30th Oct 2025).

PMID: 37620213 Fu et al., 2023 - literature review
11 childhood-onset and 82 adult-onset patients; only 6/11 childhood onset patients presented with muscle weakness. NLSDM is often diagnosed by presence of Jordan's anomaly on a peripheral blood smear and elevated CK - some cases asymptomatic until later life. Age of disease onset in the childhood cases ranged from shortly after birth to 11yo. However, the onset of myopathy occurred several years after the initial symptoms in all individuals (between 3-33 years after initial symptoms).; to: Biallelic mutations in PNPLA2 are associated with Neutral lipid-storage disease with myopathy, OMIM:610717 (NLSDM) - phenotype accessed 30th Oct 2025).

PMID: 37620213 Fu et al., 2023 - literature review
11 childhood-onset and 82 adult-onset patients; only 6/11 childhood onset patients presented with muscle weakness. NLSDM is often diagnosed by presence of Jordan's anomaly on a peripheral blood smear and elevated CK - some cases asymptomatic until later life. Age of disease onset in the childhood cases ranged from shortly after birth to 11yo. However, the onset of myopathy occurred several years after the initial symptoms in all individuals (between 3-33 years after initial symptoms).

PNPLA2 is already Green on the Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies panel.
Congenital myopathy v6.38 PNPLA2 Ida Ertmanska commented on gene: PNPLA2: Comment on list classification: The average age of onset for Neutral lipid-storage disease with myopathy is around 30 years old. Among childhood-onset patients, many do not initially present with myopathy. Based on the available evidence, this gene is not in scope of the Congenital myopathy panel and should remain Red.
Congenital myopathy v6.38 PNPLA2 Ida Ertmanska reviewed gene: PNPLA2: Rating: RED; Mode of pathogenicity: None; Publications: 21544567, 37620213, 40919432; Phenotypes: Neutral lipid-storage disease with myopathy, OMIM:610717; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.21 SPRTN Ronnie Wright gene: SPRTN was added
gene: SPRTN was added to Paediatric disorders - additional genes. Sources: Literature,NHS GMS
Mode of inheritance for gene: SPRTN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRTN were set to 12503110; 25261934
Phenotypes for gene: SPRTN were set to Ruijs-Aalfs syndrome, MIM# 616200
Penetrance for gene: SPRTN were set to Complete
Review for gene: SPRTN was set to GREEN
Added comment: 2 families in literature with progeroid phenotype and susceptibility to hepatocellular carcinoma.
DNA repair defects (chromosome breakage observed) in affected patients - PMID:25261934

1 family in NWGLH - IUGR & IGF abnormalities referral. Subsequently reported with hepatocellular carcinoma and described as progeroid - remarkably consistent phenotype with families in literature. Chromosome breakage studies being arranged.
(100KGP - https://cva.genomicsengland.nhs.uk/case/25972-1 - homozygous final exon nonsense/truncating variant)

3rd family = sufficient for green rating?
Sources: Literature, NHS GMS
Congenital myopathy v6.38 HNRNPA1 Ida Ertmanska reviewed gene: HNRNPA1: Rating: RED; Mode of pathogenicity: None; Publications: 34291734, 34722876, 35550112, 39072769; Phenotypes: Myopathy, distal, 3 , OMIM:610099, distal myopathy, MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.115 SCN4A Arina Puzriakova Tag Q2_25_expert_review was removed from gene: SCN4A.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.19 HNRNPA1 Ida Ertmanska Publications for gene: HNRNPA1 were set to 34291734; 34722876; 39072769
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.18 HNRNPA1 Ida Ertmanska Classified gene: HNRNPA1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.18 HNRNPA1 Ida Ertmanska Gene: hnrnpa1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.17 HNRNPA1 Ida Ertmanska edited their review of gene: HNRNPA1: Changed publications to: 34291734, 34722876, 35550112, 39072769
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.17 HNRNPA1 Ida Ertmanska changed review comment from: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Sources: Other; to: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Sources: Other
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska edited their review of gene: HNRNPA1: Changed publications to: 34291734, 34722876, 35550112, 39072769
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.17 HNRNPA1 Ida Ertmanska gene: HNRNPA1 was added
gene: HNRNPA1 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Other
Q4_25_promote_green tags were added to gene: HNRNPA1.
Mode of inheritance for gene: HNRNPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPA1 were set to 34291734; 34722876; 39072769
Phenotypes for gene: HNRNPA1 were set to Myopathy, distal, 3 , OMIM:610099; distal myopathy, MONDO:0018949
Review for gene: HNRNPA1 was set to GREEN
Added comment: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Sources: Other
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska changed review comment from: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.
; to: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska commented on gene: HNRNPA1: Comment on list classification: There are at least 7 unrelated individuals reported in literature with monoallelic variants in HNRNPA1 that presented with distal myopathy. Disease onset is either juvenile or in early adulthood. The affected individuals harboured stop-loss, missense, and frameshift variants, either de novo or shown to segregated with disease in an autosomal dominant manner. Other variants in this gene have been reported as causal for juvenile-onset ALS, multisystem proteinopathy, and distal hereditary motor neuropathy. There is currently little to no correlation between the location of the causative variant and the corresponding phenotype, and no precise understanding of the different disease mechanisms. Nonetheless, there is sufficient evidence for this gene-disease relationship. HNRNPA1 should be promoted to Green for Distal myopathies at the next GMS update.
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska changed review comment from: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.
Sources: Other; to: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska Classified gene: HNRNPA1 as Amber List (moderate evidence)
Distal myopathies v6.13 HNRNPA1 Ida Ertmanska Gene: hnrnpa1 has been classified as Amber List (Moderate Evidence).
Distal myopathies v6.12 HNRNPA1 Ida Ertmanska gene: HNRNPA1 was added
gene: HNRNPA1 was added to Distal myopathies. Sources: Other
Q4_25_promote_green tags were added to gene: HNRNPA1.
Mode of inheritance for gene: HNRNPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPA1 were set to 34291734; 34722876; 39072769
Phenotypes for gene: HNRNPA1 were set to Myopathy, distal, 3 , OMIM:610099; distal myopathy, MONDO:0018949
Review for gene: HNRNPA1 was set to GREEN
Added comment: PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.
Sources: Other
Haematological malignancies cancer susceptibility v4.36 TCF3 Arina Puzriakova Phenotypes for gene: TCF3 were changed from B-cell acute lymphoblastic leukemia to B-cell acute lymphoblastic leukemia, MONDO:0004947
Haematological malignancies cancer susceptibility v4.35 TCF3 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI to monoallelic - PMID: 36576946 states that 'The allele fraction of each variant in each sample was confirmed to be ∼50%, consistent with a heterozygous genotype.'
Haematological malignancies cancer susceptibility v4.35 TCF3 Arina Puzriakova Mode of inheritance for gene: TCF3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Breast cancer pertinent cancer susceptibility v2.15 PTEN Arina Puzriakova Classified gene: PTEN as Amber List (moderate evidence)
Breast cancer pertinent cancer susceptibility v2.15 PTEN Arina Puzriakova Gene: pten has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.4 DLG5 Arina Puzriakova Tag Q2_25_expert_review was removed from gene: DLG5.
Cytopenia - NOT Fanconi anaemia v4.28 SRP72 Arina Puzriakova Phenotypes for gene: SRP72 were changed from Inherited Bone Marrow Failure Syndromes - Aplastic Anaemia; Bone marrow failure, familial, 614675; Familial MDS (Myelodysplastic syndromes); Bone Marrow Failure, Familial; 614675 Bone marrow failure syndrome 1; Familial Bone Marrow Failure to Bone marrow failure syndrome 1, OMIM:614675; autosomal dominant aplasia and myelodysplasia, MONDO:0013851
Cytopenia - NOT Fanconi anaemia v4.27 SRP72 Arina Puzriakova Publications for gene: SRP72 were set to 22541560; 29146883
Cytopenia - NOT Fanconi anaemia v4.26 SRP72 Arina Puzriakova Classified gene: SRP72 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.26 SRP72 Arina Puzriakova Added comment: Comment on list classification: Several lines of conflicting evidence, including lack of relevant phenotype in mouse model, unaffected carriers and variants in other genes that could explain patient phenotypes - this means strongly corroborating evidence is required before this gene can be added to a diagnostic panel.
Cytopenia - NOT Fanconi anaemia v4.26 SRP72 Arina Puzriakova Gene: srp72 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.25 SRP72 Arina Puzriakova reviewed gene: SRP72: Rating: AMBER; Mode of pathogenicity: None; Publications: 22541560, 29146883, 32098966, 31254415, 40922878; Phenotypes: Bone marrow failure syndrome 1, OMIM:614675, autosomal dominant aplasia and myelodysplasia, MONDO:0013851; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v8.68 SRP72 Arina Puzriakova Publications for gene: SRP72 were set to 22541560; 29146883; 32098966
Primary immunodeficiency or monogenic inflammatory bowel disease v8.67 SRP72 Arina Puzriakova Classified gene: SRP72 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.67 SRP72 Arina Puzriakova Added comment: Comment on list classification: Several lines of conflicting evidence, including lack of relevant phenotype in mouse model, unaffected carriers and variants in other genes that could explain patient phenotypes - this means strongly corroborating evidence is required before this gene can be added to a diagnostic panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.67 SRP72 Arina Puzriakova Gene: srp72 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.66 SRP72 Arina Puzriakova edited their review of gene: SRP72: Changed rating: AMBER
Primary immunodeficiency or monogenic inflammatory bowel disease v8.66 SRP72 Arina Puzriakova commented on gene: SRP72
Primary immunodeficiency or monogenic inflammatory bowel disease v8.66 SRP72 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SRP72.
Tag Q2_25_expert_review was removed from gene: SRP72.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.66 ELF4 Arina Puzriakova Tag Q2_25_expert_review was removed from gene: ELF4.
Intellectual disability v9.157 NAV3 Arina Puzriakova Tag Q1_25_ expert_review was removed from gene: NAV3.
Hereditary ataxia with onset in adulthood v8.11 EXOSC8 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: EXOSC8.
Retinal disorders v8.56 UNC119 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: UNC119.
Intellectual disability v9.157 EMX2 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: EMX2.
Intellectual disability v9.157 TSPAN7 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: TSPAN7.
Adult solid tumours cancer susceptibility v2.34 MUTYH Ida Ertmanska Tag Q4_25_expert_review tag was added to gene: MUTYH.
Adult solid tumours cancer susceptibility v2.34 MUTYH Ida Ertmanska Tag disputed tag was added to gene: MUTYH.
Tag Q4_25_demote_red tag was added to gene: MUTYH.
Adult solid tumours cancer susceptibility v2.34 MUTYH Ida Ertmanska commented on gene: MUTYH: Comment on list classification: The gene-disease association between MUTYH and hereditary cancers has been disputed by the ClinGen Hereditary Cancer GCEP - classified as Disputed for familial ovarian cancer (AR & AD), Disputed for AR hereditary breast carcinoma and Refuted for AD hereditary breast carcinoma, and Disputed for colorectal cancer. MUTYH is linked to familial adenomatous polyposis 2 and classified as Definitive in ClinGen. More information: https://search.clinicalgenome.org/kb/genes/HGNC:7527
Based on the available evidence, MUTYH should be demoted to Red for Adult solid tumours cancer susceptibility at the next GMS panel update.
Adult solid tumours cancer susceptibility v2.34 MUTYH Ida Ertmanska reviewed gene: MUTYH: Rating: RED; Mode of pathogenicity: None; Publications: 21063410, 24444654, 23946381, 29478780, 33309985, 33471991, 35172496; Phenotypes: Gastric cancer, somatic, OMIM:613659, Adenomas, multiple colorectal, OMIM:608456; Mode of inheritance: None
Brugada syndrome and cardiac sodium channel disease v3.13 CACNA1C Ida Ertmanska Tag disputed tag was added to gene: CACNA1C.
Pituitary hormone deficiency v4.1 BTK Ida Ertmanska Tag disputed tag was added to gene: BTK.
Pituitary hormone deficiency v4.1 BTK Ida Ertmanska Tag Q4_25_demote_red tag was added to gene: BTK.
Pituitary hormone deficiency v4.1 BTK Ida Ertmanska edited their review of gene: BTK: Changed publications to: 7849697, 8013627, 1880652; Changed phenotypes to: Isolated growth hormone deficiency, type III, with agammaglobulinemia, OMIM:307200
Monogenic short stature v1.24 BTK Ida Ertmanska Classified gene: BTK as Red List (low evidence)
Monogenic short stature v1.24 BTK Ida Ertmanska Gene: btk has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v4.1 BTK Ida Ertmanska commented on gene: BTK: Comment on list classification: There has been no experimental evidence and no further cases reported in literature linking BTK to Pituitary hormone deficiency since 1994. The association has been disputed by the ClinGen Antibody Deficiencies GCEP. Thus, this gene should be demoted to Red on the Pituitary hormone deficiency panel at the next GMS update.
Pituitary hormone deficiency v4.1 BTK Ida Ertmanska reviewed gene: BTK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Monogenic short stature v1.23 BTK Ida Ertmanska Tag disputed tag was added to gene: BTK.
Monogenic short stature v1.23 BTK Ida Ertmanska reviewed gene: BTK: Rating: RED; Mode of pathogenicity: None; Publications: 7849697, 8013627, 1880652; Phenotypes: Isolated growth hormone deficiency, type III, with agammaglobulinemia, OMIM:307200; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Tubulointerstitial kidney disease v3.10 JAG1 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: JAG1.
Tag Q4_25_NHS_review tag was added to gene: JAG1.
Tubulointerstitial kidney disease v3.10 JAG1 Ida Ertmanska Phenotypes for gene: JAG1 were changed from tubulointersitial kidney disease; kidney failure to Autosomal dominant tubulointerstitial kidney disease
Tubulointerstitial kidney disease v3.9 JAG1 Ida Ertmanska Publications for gene: JAG1 were set to PMID: 41061854
Tubulointerstitial kidney disease v3.8 JAG1 Ida Ertmanska Mode of pathogenicity for gene: JAG1 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Tubulointerstitial kidney disease v3.7 JAG1 Ida Ertmanska Classified gene: JAG1 as Amber List (moderate evidence)
Tubulointerstitial kidney disease v3.7 JAG1 Ida Ertmanska Gene: jag1 has been classified as Amber List (Moderate Evidence).
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 unrelated individuals with monoallelic variants in JAG1 and isolated tubulointerstitial kidney disease. Based on the available evidence, this gene should be rated Green for Tubulointerstitial kidney disease.; to: Comment on list classification: There are at least 3 unrelated individuals with monoallelic variants in JAG1 and isolated tubulointerstitial kidney disease. Based on the available evidence, this gene should be rated Green for Tubulointerstitial kidney disease.
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska commented on gene: JAG1: Comment on list classification: There are at least 3 unrelated individuals with monoallelic variants in JAG1 and isolated tubulointerstitial kidney disease. Based on the available evidence, this gene should be rated Green for Tubulointerstitial kidney disease.
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska edited their review of gene: JAG1: Changed rating: GREEN
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska changed review comment from: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies & ER stress analysis suggests that the tubulointerstitial renal disease was due to haploinsufficiency and loss of function. JAG1 is predicted to be dosage sensitive with pLI = 1.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025). ; to: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong. Confirmed exon skipping, abnormal transcripts constituted 44% in patient cells.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies & ER stress analysis in Families 2 & 3 suggests that the tubulointerstitial renal disease was due to haploinsufficiency and loss of function. While mRNA levels were comparable to WT, protein levels were reduced. JAG1 is predicted to be dosage sensitive with pLI = 1.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025).
Hereditary neuropathy or pain disorder v7.29 HMBS Arina Puzriakova Tag Q2_25_expert_review was removed from gene: HMBS.
Likely inborn error of metabolism v8.82 HMBS Arina Puzriakova Tag Q2_25_expert_review was removed from gene: HMBS.
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska changed review comment from: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies as well ER stress analysis suggests that the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025). ; to: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies & ER stress analysis suggests that the tubulointerstitial renal disease was due to haploinsufficiency and loss of function. JAG1 is predicted to be dosage sensitive with pLI = 1.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025).
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska changed review comment from: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & unsolved kidney disease cases from the 100,000 Genomes project.
Variant in JAG1 was identified in three large families with unsolved ADTKD, and additional rare variants were identified in sporadic cases.
None of the 23 adult patients affected with isolated kidney failure (and tubulointerstitial nephritis in individuals with available kidney biopsy) had overt sign of liver, bile duct, heart, eye, or skeletal defect. JAG1 expression studies as well ER stress analysis suggests that the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function.; to: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies as well ER stress analysis suggests that the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025).
Intellectual disability v9.157 SPAST Arina Puzriakova Mode of inheritance for gene: SPAST was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.156 SPAST Arina Puzriakova Tag Q1_25_ MOI was removed from gene: SPAST.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.66 C2 Arina Puzriakova Phenotypes for gene: C2 were changed from Complement Component C2 Deficiency; C2 deficiency, 217000; Immunodeficiency due to C1, C4, or C2 component complement deficiency; Lupus; SLE, infections with encapsulated organisms, atherosclerosis; Complement Deficiencies to C2 deficiency, OMIM:217000; complement component 2 deficiency, MONDO:0009006
Primary immunodeficiency or monogenic inflammatory bowel disease v8.65 C2 Arina Puzriakova Tag Q2_25_expert_review was removed from gene: C2.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.65 SLCO2A1 Arina Puzriakova Tag Q2_25_expert_review was removed from gene: SLCO2A1.
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska reviewed gene: JAG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 41061854; Phenotypes: Autosomal dominant tubulointerstitial kidney disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary lymphoedema v4.18 MDFIC Ida Ertmanska Tag Q4_25_NHS_review tag was added to gene: MDFIC.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.65 SLC39A4 Arina Puzriakova Classified gene: SLC39A4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.65 SLC39A4 Arina Puzriakova Added comment: Comment on list classification: Added to this panel per suggestion of the Genomics England Clinical Team as features of acrodermatitis enteropathica overlap with immunodeficiency. This gene is already green on several GMS panels and therefore can be promoted to green on this panel at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.65 SLC39A4 Arina Puzriakova Gene: slc39a4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.64 SLC39A4 Arina Puzriakova Phenotypes for gene: SLC39A4 were changed from Acrodermatitis enteropathica (Disorder of zinc metabolism); Acrodermatitis enteropathica 201100 (Disorder of zinc metabolism) to Acrodermatitis enteropathica, OMIM:201100; Disorder of zinc metabolism
Laterality disorders and isomerism v4.6 MNS1 Ida Ertmanska Publications for gene: MNS1 were set to 30148830; 31534215; 38920647
Laterality disorders and isomerism v4.5 MNS1 Ida Ertmanska edited their review of gene: MNS1: Changed publications to: 22396656, 30148830, 31534215, 38920647
Laterality disorders and isomerism v4.5 MNS1 Ida Ertmanska changed review comment from: PMID: 38920647 Hjejj et al., 2024
Report of four affected individuals and a fetus with motile ciliopathy and biallelic variants in MNS1 (four families from Afghanistan, Egypt, and Kosovo). 2 families were confirmed to be consanguineous. 4/4 affected individuals presented with laterality defects, including one male individual with heterotaxia and complex congenital heart defects. One patient displayed a pronounced respiratory phenotype. Heterozygous family members were unaffected.
Identified variants:
c.724C>T, p.(Arg242*) - Highest MAF = 0.001176 (South Asian population, includes 1 homozygote, gnomAD v4) - likely too high to cause recessive disease.
c.1084G>T, p.(Glu362*) - Highest MAF = 0.00003295 (South Asian population, no homozygotes, gnomAD v4).
c.678_680del, p.(Glu226del) - Highest MAF = 0.00005104 (Admixed American, no homozygotes, gnomAD v4).
Sequencing method: trio exome for 1 family; panel including 'all published PCD and motile ciliopathy-related genes' applied for 3 families.

PMID: 31534215 Leslie et al., 2019
Situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family - identified a biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)] - rare, MAF in gnomAD v4 = 0.000002545.
WT and heterozygous family members were unaffected, while in homozygous individuals disease presented with incomplete penetrance (4/6 exhibited situs inversus and 2/6 - situs solitus, normal organ position).
Seq method: genome-wide SNP mapping and WES.

PMID: 30148830 Ta-Shma et al., 2018
Identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families:
1) homozygous nonsense mutation c.724T>C, p.(Arg242*) in four males with laterality defects and infertility - Turkish and Israeli origins; MAF as above, relatively common in general population
2) a homozygous nonsense mutation c.607C>T, p.(Gln203*) in MNS1 in one Israeli female with laterality defects and recurrent respiratory infections. Variant c.607C>T is rare (MAF = 0.000005937, gnomAD v4, no homoz). Patient additionally carried a homozygous mutation in DNAH5 - a known PCD gene; family members homozygous for the DNAH5 mutations but not the MNS1 variant also had PCD. The contribution of each gene cannot be decoupled.
Sequencing method: linkage analysis & WES.

This gene is associated with AR Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM:618948 in OMIM (accessed 29th Oct 2025). Association between MNS1 and primary ciliary dyskinesia was classified as Disputed by ClinGen (Motile Ciliopathy GCEP, Sept 2022).; to: PMID: 38920647 Hjejj et al., 2024
Report of four affected individuals and a fetus with motile ciliopathy and biallelic variants in MNS1 (four families from Afghanistan, Egypt, and Kosovo). 2 families were confirmed to be consanguineous. 4/4 affected individuals presented with laterality defects, including one male individual with heterotaxia and complex congenital heart defects. One patient displayed a pronounced respiratory phenotype. Heterozygous family members were unaffected.
Identified variants:
c.724C>T, p.(Arg242*) - Highest MAF = 0.001176 (South Asian population, includes 1 homozygote, gnomAD v4) - likely too high to cause recessive disease.
c.1084G>T, p.(Glu362*) - Highest MAF = 0.00003295 (South Asian population, no homozygotes, gnomAD v4).
c.678_680del, p.(Glu226del) - Highest MAF = 0.00005104 (Admixed American, no homozygotes, gnomAD v4).
Sequencing method: trio exome for 1 family; panel including 'all published PCD and motile ciliopathy-related genes' applied for 3 families.

PMID: 31534215 Leslie et al., 2019
Situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family - identified a biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)] - rare, MAF in gnomAD v4 = 0.000002545.
WT and heterozygous family members were unaffected, while in homozygous individuals disease presented with incomplete penetrance (4/6 exhibited situs inversus and 2/6 - situs solitus, normal organ position).
Seq method: genome-wide SNP mapping and WES.

PMID: 30148830 Ta-Shma et al., 2018
Identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families:
1) homozygous nonsense mutation c.724T>C, p.(Arg242*) in four males with laterality defects and infertility - Turkish and Israeli origins; MAF as above, relatively common in general population
2) a homozygous nonsense mutation c.607C>T, p.(Gln203*) in MNS1 in one Israeli female with laterality defects and recurrent respiratory infections. Variant c.607C>T is rare (MAF = 0.000005937, gnomAD v4, no homoz). Patient additionally carried a homozygous mutation in DNAH5 - a known PCD gene; family members homozygous for the DNAH5 mutations but not the MNS1 variant also had PCD. The contribution of each gene cannot be decoupled.
Sequencing method: linkage analysis & WES.

Functional evidence:
PMID: 22396656 Zhou et al., 2012
Mns1-deficient mice; phenotype: situs inversus in 8/36, left isomerism (heterotaxy) in 6/36 and situs solitus in 22/36 - supports incomplete penetrance of the laterality defect phenotype in humans.

This gene is associated with AR Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM:618948 in OMIM (accessed 29th Oct 2025). Association between MNS1 and primary ciliary dyskinesia was classified as Disputed by ClinGen (Motile Ciliopathy GCEP, Sept 2022).
Laterality disorders and isomerism v4.5 MNS1 Ida Ertmanska changed review comment from: PMID: 38920647 Hjejj et al., 2024
Report of four affected individuals and a fetus with motile ciliopathy and biallelic variants in MNS1 (four families from Afghanistan, Egypt, and Kosovo). 2 families were confirmed to be consanguineous. 4/4 affected individuals presented with laterality defects, including one male individual with heterotaxia and complex congenital heart defects. One patient displayed a pronounced respiratory phenotype. Heterozygous family members were unaffected.
Identified variants:
c.724C>T, p.(Arg242*) - Highest MAF = 0.001176 (South Asian population, includes 1 homozygote, gnomAD v4) - likely too high to cause recessive disease.
c.1084G>T, p.(Glu362*) - Highest MAF = 0.00003295 (South Asian population, no homozygotes, gnomAD v4).
c.678_680del, p.(Glu226del) - Highest MAF = 0.00005104 (Admixed American, no homozygotes, gnomAD v4).
Sequencing method: trio exome for 1 family; panel including 'all published PCD and motile ciliopathy-related genes' applied for 3 families.

PMID: 31534215 Leslie et al., 2019
Situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family - identified a biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)] - rare, MAF in gnomAD v4 = 0.000002545.
WT and heterozygous family members were unaffected, while in homozygous individuals disease presented with incomplete penetrance (4/6 exhibited situs inversus and 2/6 - situs solitus, normal organ position).
Seq method: genome-wide SNP mapping and WES.

PMID: 30148830 Ta-Shma et al., 2018
Identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families:
1) homozygous nonsense mutation c.724T>C, p.(Arg242*) in four males with laterality defects and infertility - Turkish and Israeli origins; MAF as above, relatively common in general population
2) a homozygous nonsense mutation c.607C>T, p.(Gln203*) in MNS1 in one Israeli female with laterality defects and recurrent respiratory infections. Variant c.607C>T is rare (MAF = 0.000005937, gnomAD v4, no homoz). Patient additionally carried a homozygous mutation in DNAH5 - a known PCD gene; family members homozygous for the DNAH5 mutations but not the MNS1 variant also had PCD. The contribution of each gene cannot be decoupled.
Sequencing method: linkage analysis & WES.

This gene is associated with AR Ciliary dyskinesia, primary, 3, with or without situs inversus, 608644 in OMIM (accessed 29th Oct 2025). Association between MNS1 and primary ciliary dyskinesia was classified as Disputed by ClinGen (Motile Ciliopathy GCEP, Sept 2022).; to: PMID: 38920647 Hjejj et al., 2024
Report of four affected individuals and a fetus with motile ciliopathy and biallelic variants in MNS1 (four families from Afghanistan, Egypt, and Kosovo). 2 families were confirmed to be consanguineous. 4/4 affected individuals presented with laterality defects, including one male individual with heterotaxia and complex congenital heart defects. One patient displayed a pronounced respiratory phenotype. Heterozygous family members were unaffected.
Identified variants:
c.724C>T, p.(Arg242*) - Highest MAF = 0.001176 (South Asian population, includes 1 homozygote, gnomAD v4) - likely too high to cause recessive disease.
c.1084G>T, p.(Glu362*) - Highest MAF = 0.00003295 (South Asian population, no homozygotes, gnomAD v4).
c.678_680del, p.(Glu226del) - Highest MAF = 0.00005104 (Admixed American, no homozygotes, gnomAD v4).
Sequencing method: trio exome for 1 family; panel including 'all published PCD and motile ciliopathy-related genes' applied for 3 families.

PMID: 31534215 Leslie et al., 2019
Situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family - identified a biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)] - rare, MAF in gnomAD v4 = 0.000002545.
WT and heterozygous family members were unaffected, while in homozygous individuals disease presented with incomplete penetrance (4/6 exhibited situs inversus and 2/6 - situs solitus, normal organ position).
Seq method: genome-wide SNP mapping and WES.

PMID: 30148830 Ta-Shma et al., 2018
Identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families:
1) homozygous nonsense mutation c.724T>C, p.(Arg242*) in four males with laterality defects and infertility - Turkish and Israeli origins; MAF as above, relatively common in general population
2) a homozygous nonsense mutation c.607C>T, p.(Gln203*) in MNS1 in one Israeli female with laterality defects and recurrent respiratory infections. Variant c.607C>T is rare (MAF = 0.000005937, gnomAD v4, no homoz). Patient additionally carried a homozygous mutation in DNAH5 - a known PCD gene; family members homozygous for the DNAH5 mutations but not the MNS1 variant also had PCD. The contribution of each gene cannot be decoupled.
Sequencing method: linkage analysis & WES.

This gene is associated with AR Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM:618948 in OMIM (accessed 29th Oct 2025). Association between MNS1 and primary ciliary dyskinesia was classified as Disputed by ClinGen (Motile Ciliopathy GCEP, Sept 2022).
Laterality disorders and isomerism v4.5 MNS1 Ida Ertmanska Phenotypes for gene: MNS1 were changed from Heterotaxy, visceral, 9, autosomal, with male infertility, 618948 to Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM: 618948; situs inversus, MONDO:0010029
Laterality disorders and isomerism v4.4 MNS1 Ida Ertmanska edited their review of gene: MNS1: Changed phenotypes to: Heterotaxy, visceral, 9, autosomal, with male infertility, OMIM: 618948, situs inversus, MONDO:0010029
Laterality disorders and isomerism v4.4 MNS1 Ida Ertmanska Publications for gene: MNS1 were set to 31534215; 30148830; 22396656
Laterality disorders and isomerism v4.3 MNS1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. However, there is a number of confounding factors to highlight here. 7/9 families were reported to be consanguineous. 3 families were genotyped using a PCD gene panel only. The most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. The laterality defect presented with incomplete penetrance, although a mouse model supports this finding.
Due to some conflicting evidence present in literature, this gene can only be rated Amber for Laterality disorders and isomerism.; to: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. However, there is a number of confounding factors to highlight here. 7/9 families were reported to be consanguineous. 3 families were genotyped using a PCD gene panel only. The most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. The laterality defect presented with incomplete penetrance, although a mouse model supports this finding. Additionally, association of this gene with primary ciliary dyskinesia (PCD) - a primary finding for most cases described here - is Disputed in ClinGen.
Due to some conflicting evidence present in literature, this gene can only be rated Amber for Laterality disorders and isomerism.
Laterality disorders and isomerism v4.3 MNS1 Ida Ertmanska edited their review of gene: MNS1: Added comment: Comment on list classification: There are at least 16 individuals from 9 families reported in literature with biallelic MNS1 variants and laterality defects. However, there is a number of confounding factors to highlight here. 7/9 families were reported to be consanguineous. 3 families were genotyped using a PCD gene panel only. The most commonly recurring variant in MNS1 has a relatively high allele frequency in the general population, including 1 homozygote in gnomAD. The laterality defect presented with incomplete penetrance, although a mouse model supports this finding.
Due to some conflicting evidence present in literature, this gene can only be rated Amber for Laterality disorders and isomerism.; Changed publications to: 30148830, 31534215, 38920647; Changed phenotypes to: situs inversus, MONDO:0010029
Laterality disorders and isomerism v4.3 MNS1 Ida Ertmanska reviewed gene: MNS1: Rating: AMBER; Mode of pathogenicity: None; Publications: 38920647; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v4.7 ITGB1 Ida Ertmanska edited their review of gene: ITGB1: Changed mode of inheritance: Unknown
Cerebral vascular malformations v4.7 ITGB1 Ida Ertmanska edited their review of gene: ITGB1: Added comment: Comment on list classification: There are two patients reported in literature with Vein of Galen aneurysmal malformation and LoF variants in ITGB1 (presumed monoallelic but not specified). This gene should be rated Amber for Cerebral vascular malformations until more evidence is reported.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v8.63 SLC39A4 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SLC39A4.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.63 SLC39A4 Arina Puzriakova Classified gene: SLC39A4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.63 SLC39A4 Arina Puzriakova Gene: slc39a4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.62 SLC39A4 Arina Puzriakova Entity copied from Likely inborn error of metabolism v8.82
Primary immunodeficiency or monogenic inflammatory bowel disease v8.62 SLC39A4 Arina Puzriakova gene: SLC39A4 was added
gene: SLC39A4 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: London North GLH,Expert Review Green,NHS GMS
Mode of inheritance for gene: SLC39A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A4 were set to 27604308
Phenotypes for gene: SLC39A4 were set to Acrodermatitis enteropathica (Disorder of zinc metabolism); Acrodermatitis enteropathica 201100 (Disorder of zinc metabolism)
Cerebral vascular malformations v4.7 ITGB1 Ida Ertmanska Phenotypes for gene: ITGB1 were changed from Vein of Galen Malformation to Vein of Galen aneurysmal malformation, HP:0030713
Cerebral vascular malformations v4.6 ITGB1 Ida Ertmanska Classified gene: ITGB1 as Amber List (moderate evidence)
Cerebral vascular malformations v4.6 ITGB1 Ida Ertmanska Gene: itgb1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.61 SLC30A2 Arina Puzriakova Classified gene: SLC30A2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.61 SLC30A2 Arina Puzriakova Added comment: Comment on list classification: Clinical features of transient neonatal zinc deficiency, particularly more severe cases associated with biallelic variants in this gene, overlap with acrodermatitis enteropathica which would prompt genetic testing. This will be flagged for GMS expert review to determine whether this condition should be included on the panel to allow differential diagnosis.

The MOI should also be reviewed to determine whether monoallelic, as well as biallelic, variants should be included or if only more severe recessive cases are likely to be relevant.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.61 SLC30A2 Arina Puzriakova Gene: slc30a2 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v4.5 ITGB1 Ida Ertmanska reviewed gene: ITGB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37978175; Phenotypes: Vein of Galen aneurysmal malformation, HP:0030713; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v8.60 SLC30A2 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: SLC30A2.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.60 SLC30A2 Arina Puzriakova gene: SLC30A2 was added
gene: SLC30A2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: ClinGen,Literature
Q3_25_promote_green, Q3_25_expert_review tags were added to gene: SLC30A2.
Mode of inheritance for gene: SLC30A2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SLC30A2 were set to 17065149; 36967740; 22733820; 24194756; 24456035; 27304099; 28111782; 37082517; 23741301; 32278324
Phenotypes for gene: SLC30A2 were set to Zinc deficiency, transient neonatal, OMIM:608118; zinc deficiency, transient neonatal, MONDO:0011973
Review for gene: SLC30A2 was set to AMBER
Added comment: SLC30A2 is associated with Zinc deficiency, transient neonatal, OMIM:608118 in OMIM (accessed 29-10-2025), and has a DEFINITIVE gene disease association with zinc deficiency, transient neonatal, MONDO:0011973 in ClinGen (curation entry from 24-01-2025).

This condition occurs in breast-fed infants as a consequence of low milk zinc concentration in maternal breast milk, caused by maternal heterozygous variants in the SLC30A2 gene. Zinc deficiency can lead to dermatitis, alopecia, decreased growth, and impaired immune function. More severe forms of SLC30A2-related zinc deficiency may resemble the more severe disorder acrodermatitis enteropathica which would lead to consideration of genetic investigations.

The ClinGen summary states that eleven unique variants, including missense, nonsense, and frameshift mutations, documented in 13 unrelated mothers whose infants affected with TNZD across 10 publications (PMIDs: 17065149, 36967740, 22733820, 24194756, 24456035, 27304099, 28111782, 37082517, 23741301, 32278324).

Though most cases follow a dominant pattern of inheritance, distinct biallelic variants have been reported in two unrelated families with severe zinc deficiency (PMID: 23741301; 32278324), which is more likely to resemble acrodermatitis enteropathica in a clinical setting.
Sources: ClinGen, Literature
Structural eye disease v4.34 KIAA0556 Arina Puzriakova Tag new-gene-name tag was added to gene: KIAA0556.
Renal ciliopathies v4.4 KIAA0556 Arina Puzriakova Phenotypes for gene: KIAA0556 were changed from ?Joubert syndrome 26 to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Rare multisystem ciliopathy disorders v1.176 KIAA0556 Arina Puzriakova Phenotypes for gene: KIAA0556 were changed from ?Joubert syndrome 26 to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Fetal anomalies v6.115 KIAA0556 Arina Puzriakova Classified gene: KIAA0556 as Amber List (moderate evidence)
Fetal anomalies v6.115 KIAA0556 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber and tagging for additional GMS expert review to determine whether there is sufficient evidence to indicate that the phenotype is prenatally relevant.

The main finding that may plausibly be detected prenatally is cerebellar hypoplasia / molar tooth sign. Other possible fetal scan findings include: PMIDs 26714646 and 32164589 each reference one case with cleft lip and palate (although the latter had dual molecular findings) and PMID 40428346 had post-axial polydactyly. Although molar-tooth sign was present in a number of cases, there is no indication that prenatal abnormalities were detected in published cases.
Fetal anomalies v6.115 KIAA0556 Arina Puzriakova Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.114 KIAA0556 Arina Puzriakova Phenotypes for gene: KIAA0556 were changed from Joubert syndrome 26, OMIM:616784 to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Fetal anomalies v6.113 KIAA0556 Arina Puzriakova Publications for gene: KIAA0556 were set to 27245168; 26714646
Fetal anomalies v6.112 KIAA0556 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: KIAA0556.
Tag Q3_25_expert_review tag was added to gene: KIAA0556.
Fetal anomalies v6.112 KIAA0556 Arina Puzriakova reviewed gene: KIAA0556: Rating: AMBER; Mode of pathogenicity: None; Publications: 26714646, 27245168, 31197031, 31197031, 36580738, 40725402, 40428346, 32164589, 30982090; Phenotypes: Joubert syndrome 26, OMIM:616784, Joubert syndrome 26, MONDO:0014771; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ophthalmological ciliopathies v5.7 KIAA0556 Arina Puzriakova Phenotypes for gene: KIAA0556 were changed from ?Joubert syndrome 26 to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Ophthalmological ciliopathies v5.6 KIAA0556 Arina Puzriakova Publications for gene: KIAA0556 were set to
Ophthalmological ciliopathies v5.5 KIAA0556 Arina Puzriakova Classified gene: KIAA0556 as Amber List (moderate evidence)
Ophthalmological ciliopathies v5.5 KIAA0556 Arina Puzriakova Added comment: Comment on list classification: Following consultation with the Genomics England Clinical Team, it has been decided that there is sufficient evidence to make this gene Green on this panel -ocular presentations, although varied, are consistent with the range seen in ciliopathies.
Ophthalmological ciliopathies v5.5 KIAA0556 Arina Puzriakova Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v5.4 KIAA0556 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: KIAA0556.
Ophthalmological ciliopathies v5.4 KIAA0556 Arina Puzriakova reviewed gene: KIAA0556: Rating: GREEN; Mode of pathogenicity: None; Publications: 26714646, 27245168, 31197031, 31197031, 36580738, 40725402, 40428346, 32164589, 30982090; Phenotypes: Joubert syndrome 26, OMIM:616784, Joubert syndrome 26, MONDO:0014771; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.156 KIAA0556 Arina Puzriakova Classified gene: KIAA0556 as Amber List (moderate evidence)
Intellectual disability v9.156 KIAA0556 Arina Puzriakova Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.155 KIAA0556 Arina Puzriakova Publications for gene: KIAA0556 were set to
Intellectual disability v9.155 KIAA0556 Arina Puzriakova Classified gene: KIAA0556 as Amber List (moderate evidence)
Intellectual disability v9.155 KIAA0556 Arina Puzriakova Added comment: Comment on list classification: This gene was added to this panel following consultation with the Genomics England Clinical Team. Although the ID phenotype is less clear than some other features, there are two families with severe ID and another two where extent of ID is unclear or milder. There are also sufficient cases of hypotonia which is tested via the Hypotonic infant super panel, as well as short stature/hypopituitarism/growth hormone deficiency which are more likely to be picked up via the Paediatric disorders super panel. Inclusion on the ID panel would also ensure inclusion on these two super panels, where ID is a component panel.

Overall the evidence supports promotion of this gene to Green at the next GMS panel update.
Intellectual disability v9.155 KIAA0556 Arina Puzriakova Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.94 MDFIC Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 probands reported with biallelic variants in MDFIC, who presented with central conducting lymphatic anomaly - including fetal hydrops (detected at 19-22 weeks). Based on the available evidence, this gene should be promoted to Green for Fetal hydrops at the next GMS update.; to: Comment on list classification: There are at least 3 probands reported with biallelic variants in MDFIC, who presented with central conducting lymphatic anomaly - including fetal hydrops (detected at 19-22 weeks). Based on the available evidence, this gene should be rated Green for Fetal hydrops.
Fetal hydrops v1.94 MDFIC Ida Ertmanska Classified gene: MDFIC as Green List (high evidence)
Fetal hydrops v1.94 MDFIC Ida Ertmanska Gene: mdfic has been classified as Green List (High Evidence).
Fetal hydrops v1.93 MDFIC Ida Ertmanska Tag Q4_25_promote_green was removed from gene: MDFIC.
Intellectual disability v9.154 KIAA0556 Arina Puzriakova edited their review of gene: KIAA0556: Changed publications to: 26714646, 27245168, 31197031, 31197031, 36580738, 40725402, 40428346, 32164589, 30982090
Intellectual disability v9.154 KIAA0556 Arina Puzriakova gene: KIAA0556 was added
gene: KIAA0556 was added to Intellectual disability. Sources: ClinGen,Literature
new-gene-name, Q3_25_promote_green tags were added to gene: KIAA0556.
Mode of inheritance for gene: KIAA0556 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KIAA0556 were set to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Review for gene: KIAA0556 was set to GREEN
Added comment: KIAA0556 (also known as KATNIP) is now associated with Joubert syndrome 26, OMIM:616784 (AR) in OMIM (accessed 21st Oct 2025), and has a DEFINITIVE gene disease association with autosomal recessive ciliopathy-KATNIP (MONDO:0005308) in ClinGen (curation entry from 07/10/2023).

The ClinGen summary states that there are eight variants (nonsense, frameshift, splice-site) reported in 6 probands in 6 publications (PMIDs: 26714646, 27245168, 31197031, 36580738, 32164589, 30982090). There have been 2 additional reports since their review (PMIDs: 40725402, 40428346)

In total there are now 13 individuals from 8 families. In 2 of the families additional variants were found in other genes. These families are listed last in this review. Main phenotypes observed in the cases with only KIAA0556 variants:

- Brain abnormalities (including molar tooth sign) were seen in 9 individuals (5 families, 1 of these mild).
- Hypotonia was observed in 6 individuals (4 families).
- Short stature/Growth hormone deficiency/pituitary abnormalities were seen in 4 individuals (3 families)
- Developmental delay/intellectual disability was reported as severe in 4 individuals( 2 families), mild/unknown severity in an additional 3 individuals (2 families).
- An eye phenotype was observed in 4 individuals (3 families)
- A renal phenotype was only observed in 1 family (PMID: 40725402).

Evidence:

PMID:26714646 (Sanders et al 2015) - 3 children in a consanguineous Saudi Arabian family with global developmental delay and suspected Jouberts syndrome based on neuroimaging studies. Variable features between the children included recurrent infections (2), hypotonia( 2), cleft palate (1), small penis (1), short stature (1), hypopituitarism (2). No renal involvement. In patient fibroblasts there were a significant reduction in cilia compared to controls, and cilia that were present were abnormally long. Kiaa0556 knockout mice showed brain-specific defects resulting in hydrocephalus. In human cells KIAA0556 was found to locate a the ciliary base, axoneme and tip.

PMID:27245168 (Roosing et al 2016) - WES in consanguineous family from India identified a KIAA0556 homozygous single base pair deletion mutation in 2 siblings. Both showed nystagmus and oculomotor apraxia, bilaterial ptosis, hypotonia, characteristic ‘molar tooth’ sign on brain imaging and developmental delay (severity not noted). Cone dystrophy was identified, but gross visual function was not impaired. No renal or liver phenotype. A zebrafish model with kiaa0556 knocked down showed curly tails, smaller head size and perithoracic and abdominal edema which is like other ciliopathy morphants.

PMID:31197031 (Fujita et al 2019) - blood and/or hypothalamic hamartoma (HH, congenital brain malformation associated with drug-resistant epilepsy) tissue samples from 38 undiagnosed patients were analysed using WES. Germline, compound heterozygous variants in KIAA0556 were found in one 5 yo female patient (individual 12698), c.2373del (p.Asp791Glufs*206),c.4551+1G>A. Brain anomalies in this patient included agenesis of the corpus callosum, pituitary hypoplasia, the molar tooth sign, and HH. Other clinical features reported include hypotonia, oculomotor apraxia and developmental delay.

PMID:36580738 (Aksu Uzunhan et al 2023) - 2-year-old male with compound heterozygous variants KATNIP gene. He had growth hormone deficiency and central hypothyroidism, with some minor dysmorphic features. His neurodevelopment seemed normal, but cranial MRI abnormalities without a classical molar tooth sign, ectopic neurohypophysis and combined pituitary hormone deficiency. No renal, liver or eye phenotype.

PMID: 40725402 (Kulyamzin et al 2025) - 24 yo female from a non-consanguineous family of mixed Jewish origin who presented with type 2 glomerulonephritis at age 7 and underwent 2 kidney transplantations. She later developed SNHL, which was attributed to antibiotic toxicity, high intracranial pressure, and a differential diagnosis of cone rod dystrophy vs macular dystrophy with peripheral involvement. WES revealed two rare heterozygous variants in the KATNIP (KIAA0556) gene (NM_015202.4): c.49C>T; p.(Arg17*) and c.4711A>G; p.(Ser1571Gly). The proband was also heterozygous for a likely-pathogenic variant in POLG. Heterozygous variants in POLG have been linked to progressive external ophthalmoplegia (weakness of eye muscles), but the proband did not present with this.

PMID: 40428346 (Tedesco et al 2025) 5-year-old male from a consanguineous family of Roma ethnic background. Clinical features include severe developmental delay, hypotonia, and post-axial polydactyly. He had a normal cerebral MRI without the molar tooth sign, but showed severe anemia and esophageal atresia. WES identified a homozygous novel frameshift variant c.808del, p.Ser270ValfsTer28 in KATNIP. A good summary of all cases to date is provided.

Patients with variants in KIAA0556/KATNIP and another gene:

PMID:32164589 (Niceta et al 2020) - 7 year old with homozygosity for mutations in KIF7 and KIAA0556 identified by WES. The patient displayed Joubert syndrome complicated by iris and retinochoroidal coloboma, hypogonadism pituitary malformation, and growth hormone deficiency. Severe intellectual disability was reported.

PMID:30982090 (Cauley et al 2019) - Sudanese family in 3 siblings with homozygous truncating variants in both KIAA0556 and ADGRG1/GPR56 and a severe brain malformation (bilateral frontal polymicrogyra, mild molar tooth sign), severe psychomotor delay, intellectual disability and seizures.
Sources: ClinGen, Literature
Primary lymphoedema v4.18 MDFIC Ida Ertmanska Tag Q3_25_promote_green was removed from gene: MDFIC.
Tag Q4_25_promote_green tag was added to gene: MDFIC.
Fetal hydrops v1.93 MDFIC Ida Ertmanska Tag Q3_25_promote_green was removed from gene: MDFIC.
Tag Q4_25_promote_green tag was added to gene: MDFIC.
Fetal hydrops v1.93 MDFIC Ida Ertmanska Tag Q3_25_promote_green tag was added to gene: MDFIC.
Fetal hydrops v1.93 MDFIC Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
4 of the probands presented with hydrops - 3 of them fetal (19-22 weeks) and 1 at birth.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Sources: Other; to: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families. 2/3 presented with hydrops.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous. Presented with hydrops at birth.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Fetal hydrops v1.93 MDFIC Ida Ertmanska edited their review of gene: MDFIC: Added comment: Comment on list classification: There are at least 3 probands reported with biallelic variants in MDFIC, who presented with central conducting lymphatic anomaly - including fetal hydrops (detected at 19-22 weeks). Based on the available evidence, this gene should be promoted to Green for Fetal hydrops at the next GMS update.; Changed publications to: 35235341
Fetal hydrops v1.93 MDFIC Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
4 of the probands presented with hydrops - 3 of them fetal (19-22 weeks) and 1 at birth.

PMID: 39386015 Weidner et al., 2024
13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Sources: Other; to: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
4 of the probands presented with hydrops - 3 of them fetal (19-22 weeks) and 1 at birth.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Sources: Other
Fetal hydrops v1.93 MDFIC Ida Ertmanska Classified gene: MDFIC as Amber List (moderate evidence)
Fetal hydrops v1.93 MDFIC Ida Ertmanska Gene: mdfic has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.92 MDFIC Ida Ertmanska gene: MDFIC was added
gene: MDFIC was added to Fetal hydrops. Sources: Other
Mode of inheritance for gene: MDFIC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDFIC were set to 35235341; 39386015
Phenotypes for gene: MDFIC were set to Nonimmune hydrops fetalis, HP:0001790; Lymphatic malformation 12, OMIM:620014; lymphatic malformation 12, MONDO:0031043
Review for gene: MDFIC was set to GREEN
Added comment: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
4 of the probands presented with hydrops - 3 of them fetal (19-22 weeks) and 1 at birth.

PMID: 39386015 Weidner et al., 2024
13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Sources: Other
Primary lymphoedema v4.18 MDFIC Ida Ertmanska Tag Q3_25_promote_green tag was added to gene: MDFIC.
Primary lymphoedema v4.18 MDFIC Ida Ertmanska Phenotypes for gene: MDFIC were changed from primary lymphoedema; central conducting lymphatic anomaly to Lymphatic malformation 12, OMIM:620014; lymphatic malformation 12, MONDO:0031043
Primary lymphoedema v4.17 MDFIC Ida Ertmanska Publications for gene: MDFIC were set to PMID: 35235341; 39386015
Primary lymphoedema v4.16 MDFIC Ida Ertmanska Publications for gene: MDFIC were set to PMID: 35235341
Primary lymphoedema v4.15 MDFIC Ida Ertmanska Classified gene: MDFIC as Amber List (moderate evidence)
Primary lymphoedema v4.15 MDFIC Ida Ertmanska Gene: mdfic has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v4.14 MDFIC Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth.

PMID: 39386015 Weidner et al., 2024
13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).; to: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
4 of the probands presented with hydrops - 3 of them fetal (19-22 weeks) and 1 at birth.

PMID: 39386015 Weidner et al., 2024
13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Primary lymphoedema v4.14 MDFIC Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth.

PMID: 39386015 Weidner et al., 2024
13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).; to: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth.

PMID: 39386015 Weidner et al., 2024
13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Primary lymphoedema v4.14 MDFIC Ida Ertmanska edited their review of gene: MDFIC: Added comment: Comment on list classification: There are at least 5 probands reported with biallelic variants in MDFIC, who presented with central conducting lymphatic anomaly - including lymphoedema, pleural effusions, and hydrops. Based on the available evidence, this gene should be promoted to Green for Primary lymphoedema at the next GMS update.; Changed publications to: 35235341, 39386015
Primary lymphoedema v4.14 MDFIC Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).; to: PMID: 35235341 Byrne et al., 2022
Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema.
3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs*3) variant. The parents were confirmed heterozygous in 2 families.
1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124*) variant - absent from gnomAD, parents heterozygous.
Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63*) variant - parents heterozygous, variant absent from gnomAD.
In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs*3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38.
In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth.

PMID: 39386015 Weidner et al., 2024
13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified.

This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
Primary lymphoedema v4.14 MDFIC Ida Ertmanska reviewed gene: MDFIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 35235341; Phenotypes: Lymphatic malformation 12, OMIM:620014, lymphatic malformation 12, MONDO:0031043; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v4.14 HGF Achchuthan Shanmugasundram changed review comment from: PMID:38676400 reported the Brussels PL cohort of 770 primary lymphoedema (PL) patients, of which ten unrelated patients were identified with loss-of-function variants in HGF gene (six nonsense, two frameshift and two splice-site variants). They have not been reported in any disease previously, and only one (p.Arg502Ter) was reported once in GnomAD v3. No likely pathogenic variant was detected in the other known PL genes for these patients. Co-segregation analysis of these variants in available family members identified five additional affected individuals and five unaffected carriers.

In addition, 17 unrelated families were reported with fourteen different rare missense variants in HGF gene. One of the patients carries two HGF missense variants (p.Asn624Lys + p.Gly627Asp), which he inherited from his asymptomatic father. Co-segregation analyses for all likely pathogenic missense variants identified two additional affected carriers and eleven unaffected carriers. There is also functional evidence available for both nonsense and missense variants.

PMID:38791500 reported the identification of a novel heterozygous HGF variant (p.Arg533Ter) in a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.

Monoallelic variants in HGF gene have not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.; to: PMID:38676400 reported the Brussels PL cohort of 770 primary lymphoedema (PL) patients, of which ten unrelated patients were identified with loss-of-function variants in HGF gene (six nonsense, two frameshift and two splice-site variants). They have not been reported in any disease previously, and only one (p.Arg502Ter) was reported once in GnomAD v3. No likely pathogenic variant was detected in the other known PL genes for these patients. Co-segregation analysis of these variants in available family members identified five additional affected individuals and five unaffected carriers.

In addition, 17 unrelated families were reported with fourteen different rare missense variants in HGF gene. One of the patients carries two HGF missense variants (p.Asn624Lys + p.Gly627Asp), which he inherited from his asymptomatic father. Co-segregation analyses for all likely pathogenic missense variants identified two additional affected carriers and eleven unaffected carriers. There is also functional evidence available for both nonsense and missense variants.

PMID:38791500 reported the identification of a novel heterozygous HGF variant (p.Arg533Ter) in a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.

Monoallelic variants in HGF gene have not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype (records accessed 23 July 2025).
Primary lymphoedema v4.14 ERG Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: OMIM phenotype accessed on 28 October 2025; to: Comment on phenotypes: OMIM phenotype accessed on 28 October 2025.
Primary lymphoedema v4.14 ERG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 28 October 2025
Primary lymphoedema v4.14 ERG Achchuthan Shanmugasundram Phenotypes for gene: ERG were changed from primary lymphoedema, MONDO:0019175 to Lymphatic malformation 14, OMIM:620602; lymphatic malformation 14, MONDO:0957954
Primary lymphoedema v4.13 CELSR1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM record last accessed on 28 October 2025.
Primary lymphoedema v4.13 CELSR1 Achchuthan Shanmugasundram Phenotypes for gene: CELSR1 were changed from Lymphatic malformation 9, OMIM:619319 to Lymphatic malformation 9, OMIM:619319
Primary lymphoedema v4.12 ERG Ida Ertmanska Publications for gene: ERG were set to 36928819
Primary lymphoedema v4.11 CELSR1 Ida Ertmanska Publications for gene: CELSR1 were set to 31403174; 26855770; 31215153
Hereditary neuropathy v1.504 ARHGAP19 Achchuthan Shanmugasundram Classified gene: ARHGAP19 as Green List (high evidence)
Hereditary neuropathy v1.504 ARHGAP19 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Shahryar Alavi, there are multiple unrelated families reported with biallelic ARHGAP19 variants and with motor-predominant neuropathy. Hence, this gene has been promoted to green rating on this panel.
Hereditary neuropathy v1.504 ARHGAP19 Achchuthan Shanmugasundram Gene: arhgap19 has been classified as Green List (High Evidence).
Hereditary neuropathy v1.503 ARHGAP19 Achchuthan Shanmugasundram Publications for gene: ARHGAP19 were set to https://www.medrxiv.org/content/10.1101/2024.05.10.24306768v1
Hereditary neuropathy v1.502 ARHGAP19 Achchuthan Shanmugasundram Phenotypes for gene: ARHGAP19 were changed from neuropathy; Charcot-Marie-Tooth disease to motor peripheral neuropathy, MONDO:0002316
Hereditary neuropathy v1.501 ARHGAP19 Achchuthan Shanmugasundram reviewed gene: ARHGAP19: Rating: GREEN; Mode of pathogenicity: None; Publications: 41086021; Phenotypes: motor peripheral neuropathy, MONDO:0002316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.29 ARHGAP19 Achchuthan Shanmugasundram Tag Q3_25_NHS_review tag was added to gene: ARHGAP19.
Hereditary neuropathy or pain disorder v7.29 ARHGAP19 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ARHGAP19.
Hereditary neuropathy or pain disorder v7.29 ARHGAP19 Achchuthan Shanmugasundram Classified gene: ARHGAP19 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.29 ARHGAP19 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there are multiple unrelated families reported with biallelic ARHGAP19 variants and with motor-predominant neuropathy. Hence, this gene should be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.29 ARHGAP19 Achchuthan Shanmugasundram Gene: arhgap19 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.28 ARHGAP19 Achchuthan Shanmugasundram Phenotypes for gene: ARHGAP19 were changed from motor axonal neuropathy to motor peripheral neuropathy, MONDO:0002316
Hereditary neuropathy or pain disorder v7.27 ARHGAP19 Achchuthan Shanmugasundram reviewed gene: ARHGAP19: Rating: GREEN; Mode of pathogenicity: None; Publications: 41086021; Phenotypes: motor peripheral neuropathy, MONDO:0002316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v5.26 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded.
Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene should be rated Amber for Optic neuropathy.; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded.
Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene-disease association is ambiguous and should be rated as Amber.
Optic neuropathy v5.26 PPIB Ida Ertmanska commented on gene: PPIB: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded.
Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene should be rated Amber for Optic neuropathy.
Optic neuropathy v5.26 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.
Sources: Other; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.
Optic neuropathy v5.26 PPIB Ida Ertmanska Classified gene: PPIB as Amber List (moderate evidence)
Optic neuropathy v5.26 PPIB Ida Ertmanska Gene: ppib has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.25 PPIB Ida Ertmanska gene: PPIB was added
gene: PPIB was added to Optic neuropathy. Sources: Other
Mode of inheritance for gene: PPIB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPIB were set to 21282188; 41045073
Phenotypes for gene: PPIB were set to optic atrophy, MONDO:0003608
Review for gene: PPIB was set to AMBER
Added comment: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, no homozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.
Sources: Other
Likely inborn error of metabolism v8.82 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata 176200; Variegate porphyria (Acute neuropathic porphyrias) to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Likely inborn error of metabolism v8.81 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to 27604308; 19460837; 9811936
Likely inborn error of metabolism v8.80 PPOX Achchuthan Shanmugasundram changed review comment from: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' on this panel.; to: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 28th October 2025.

Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' on this panel.
Likely inborn error of metabolism v8.80 PPOX Achchuthan Shanmugasundram edited their review of gene: PPOX: Changed publications to: 9540991, 9811936, 10870850, 12859407, 25778941, 30476629, 32247286, 33159949, 35584894, 37879139, 38940544, 40114189; Changed phenotypes to: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577
Likely inborn error of metabolism v8.80 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Likely inborn error of metabolism v8.80 PPOX Achchuthan Shanmugasundram reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v8.80 PDE12 Achchuthan Shanmugasundram Classified gene: PDE12 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.80 PDE12 Achchuthan Shanmugasundram Added comment: Comment on list classification: PDE12 has already been recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/PDE12/), as detailed in the below reviews copied from that panel.

As there is sufficient evidence available for the association of PDE12 with mitochondrial disease, this gene can be promoted to green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.80 PDE12 Achchuthan Shanmugasundram Gene: pde12 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.79 PDE12 Achchuthan Shanmugasundram Deleted their comment
Likely inborn error of metabolism v8.79 PDE12 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: PDE12.
Likely inborn error of metabolism v8.79 PDE12 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.36
Likely inborn error of metabolism v8.79 PDE12 Achchuthan Shanmugasundram gene: PDE12 was added
gene: PDE12 was added to Likely inborn error of metabolism. Sources: Expert Review Amber,Expert list
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: PDE12.
Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE12 were set to 28745585; 29903433; 39567835
Phenotypes for gene: PDE12 were set to mitochondrial disease, MONDO:0044970
Likely inborn error of metabolism v8.78 GUK1 Achchuthan Shanmugasundram Classified gene: GUK1 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.78 GUK1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with mitochondrial DNA depletion syndrome 21. As this gene has already been recommended for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/GUK1/), this gene should also be considered for green rating on this panel in the next GMS update.
Likely inborn error of metabolism v8.78 GUK1 Achchuthan Shanmugasundram Gene: guk1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.36 GUK1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 28 October 2025.
Mitochondrial disorders v9.36 GUK1 Achchuthan Shanmugasundram Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome 21, OMIM:621071 to Mitochondrial DNA depletion syndrome 21, OMIM:621071; mitochondrial dna depletion syndrome 21, MONDO:0976132
Likely inborn error of metabolism v8.77 GUK1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 28 October 2025.
Likely inborn error of metabolism v8.77 GUK1 Achchuthan Shanmugasundram Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome 21, OMIM:621071 to Mitochondrial DNA depletion syndrome 21, OMIM:621071; mitochondrial dna depletion syndrome 21, MONDO:0976132
Likely inborn error of metabolism v8.76 GUK1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: GUK1.
Likely inborn error of metabolism v8.76 GUK1 Achchuthan Shanmugasundram reviewed gene: GUK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 21, OMIM:621071, mitochondrial dna depletion syndrome 21, MONDO:0976132; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.76 GUK1 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.35
Likely inborn error of metabolism v8.76 GUK1 Achchuthan Shanmugasundram gene: GUK1 was added
gene: GUK1 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: GUK1.
Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUK1 were set to 39230499
Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome 21, OMIM:621071
Likely inborn error of metabolism v8.75 COX18 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the promotion of this gene to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) in support of the association of this gene with mitochondrial disease. This gene should be considered for promotion to green rating on this panel as it has already been tagged for promotion to green rating on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/COX18/).
Likely inborn error of metabolism v8.75 COX18 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.35
Likely inborn error of metabolism v8.75 COX18 Achchuthan Shanmugasundram gene: COX18 was added
gene: COX18 was added to Likely inborn error of metabolism. Sources: NHS GMS,Expert Review Amber
Q3_25_promote_green tags were added to gene: COX18.
Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX18 were set to 37468577; 40830826
Phenotypes for gene: COX18 were set to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Likely inborn error of metabolism v8.74 CMPK2 Achchuthan Shanmugasundram Tag Q2_25_ promote_green was removed from gene: CMPK2.
Tag Q3_25_promote_green tag was added to gene: CMPK2.
Mitochondrial disorders v9.35 CMPK2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM last accessed on 28 October 2025.
Mitochondrial disorders v9.35 CMPK2 Achchuthan Shanmugasundram Phenotypes for gene: CMPK2 were changed from Mitochondrial UMP-CMP kinase 2 deficiency; Developmental delay; Failure to thrive to Basal ganglia calcification, idiopathic, 10, autosomal recessive, OMIM:621018; basal ganglia calcification, idiopathic, 10, autosomal recessive, MONDO:0975875
Likely inborn error of metabolism v8.74 CMPK2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM last accessed on 28 October 2025.
Likely inborn error of metabolism v8.74 CMPK2 Achchuthan Shanmugasundram Phenotypes for gene: CMPK2 were changed from Mitochondrial UMP-CMP kinase 2 deficiency; Developmental delay; Failure to thrive to Basal ganglia calcification, idiopathic, 10, autosomal recessive, OMIM:621018; basal ganglia calcification, idiopathic, 10, autosomal recessive, MONDO:0975875
Likely inborn error of metabolism v8.73 CMPK2 Achchuthan Shanmugasundram reviewed gene: CMPK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.73 CMPK2 Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v9.34
Likely inborn error of metabolism v8.73 CMPK2 Achchuthan Shanmugasundram gene: CMPK2 was added
gene: CMPK2 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber
Q2_25_ promote_green tags were added to gene: CMPK2.
Mode of inheritance for gene: CMPK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CMPK2 were set to 33340416; 36443312
Phenotypes for gene: CMPK2 were set to Mitochondrial UMP-CMP kinase 2 deficiency; Developmental delay; Failure to thrive
Likely inborn error of metabolism v8.72 UGGT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (10 unrelated families and functional evidence) for the association of this gene with congenital disorders of glycoylation panel (https://panelapp.genomicsengland.co.uk/panels/25/gene/UGGT1/). Hence, this gene should be promoted to green rating in this panel on the next GMS update.; to: Comment on list classification: There is sufficient evidence available (10 unrelated families and functional evidence) for the association of this gene with congenital disorders of glycosylation panel (https://panelapp.genomicsengland.co.uk/panels/25/gene/UGGT1/). Hence, this gene should be promoted to green rating in this panel on the next GMS update.
Likely inborn error of metabolism v8.72 UGGT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (10 unrelated families and functional evidence) for the promotion of this gene to green rating in this panel on the next GMS update.; to: Comment on list classification: There is sufficient evidence available (10 unrelated families and functional evidence) for the association of this gene with congenital disorders of glycoylation panel (https://panelapp.genomicsengland.co.uk/panels/25/gene/UGGT1/). Hence, this gene should be promoted to green rating in this panel on the next GMS update.
Likely inborn error of metabolism v8.72 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: UGGT1.
Likely inborn error of metabolism v8.72 UGGT1 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v7.11
Likely inborn error of metabolism v8.72 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: UGGT1.
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to congenital disorder of glycosylation, MONDO:0015286
Early onset or syndromic epilepsy v8.61 SETBP1 Ida Ertmanska Publications for gene: SETBP1 were set to 20436468
Early onset or syndromic epilepsy v8.60 SETBP1 Ida Ertmanska Phenotypes for gene: SETBP1 were changed from Schinzel-Giedion midface retraction syndrome 269150 to Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078; Schinzel-Giedion midface retraction syndrome, OMIM: 269150; Schinzel-Giedion syndrome, MONDO:0010010
Early onset or syndromic epilepsy v8.59 SETBP1 Ida Ertmanska reviewed gene: SETBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20436468, 21037274, 22473152, 23020937, 25217958, 25356899, 25028416, 25082129, 25663181, 26096993, 26188272, 28346496, 29463886, 32445275, 32460883; Phenotypes: Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078, Schinzel-Giedion midface retraction syndrome, OMIM: 269150, Schinzel-Giedion syndrome, MONDO:0010010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.153 SETBP1 Ida Ertmanska Phenotypes for gene: SETBP1 were changed from Schinzel-Giedion midface retraction syndrome, 269150; SCHINZEL-GIEDION MIDFACE RETRACTION SYNDROME (SGMFS) to Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078; Schinzel-Giedion midface retraction syndrome, OMIM: 269150; Schinzel-Giedion syndrome, MONDO:0010010
Intellectual disability v9.152 SETBP1 Ida Ertmanska Publications for gene: SETBP1 were set to 20436468
Intellectual disability v9.151 SETBP1 Ida Ertmanska changed review comment from: SETBP1 is associated with two distinct autosomal dominant disorders: Intellectual developmental disorder, known as SETBP1 disorder, and Schinzel-Giedion syndrome.

SETBP1 disorder (Filges et al., PMID: 21037274) is characterised by intellectual disability, autism, speech difficulty, motor and developmental delays, seizures, hypotonia, and facial dysmorphisms. The mechanism of disease is haploinsufficiency - PMID: 21037274.
There are at least 7 unrelated individuals reported in literature, diagnosed with SETBP1 disorder and harbouring LOF variants in SETBP1 (nonsense, frameshift, large deletions) - PMIDs: 23020937, 25217958, 29463886, 25356899.

Schinzel-Giedion syndrome is caused by missense variants in SETBP1, particularly variants affecting amino acids 868-871 - a specific ‘hotspot’ region of the SETBP1 gene that codes for a degron. Clinical features of Schinzel-Giedion syndrome include developmental delay, epilepsy, facial dysmorphisms, and genitourinary and skeletal anomalies. The proposed mechanism of Schinzel-Giedion syndrome is gain-of-function (GOF), causing SETBP1 protein to accumulate (PMID: 28346496). There are at least 15 unrelated individuals with Schinzel-Giedion syndrome and heterozygous missense variants in SETBP1 reported in literature (PMIDs: 20436468, 26188272, 32460883, 22473152, 25028416, 25082129, 25663181, 26096993, 32445275, 28346496).

SETBP1 is associated with Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078 and Schinzel-Giedion midface retraction syndrome, OMIM: 269150 (OMIM, accessed 28th Oct 2025).; to: SETBP1 is associated with two distinct autosomal dominant disorders: Intellectual developmental disorder, known as SETBP1 disorder, and Schinzel-Giedion syndrome.

SETBP1 disorder is characterised by intellectual disability, autism, speech difficulty, motor and developmental delays, seizures, hypotonia, and facial dysmorphisms (PMID: 21037274). The mechanism of disease is haploinsufficiency (PMID: 21037274).
There are at least 7 unrelated individuals reported in literature, diagnosed with SETBP1 disorder and harbouring LOF variants in SETBP1 (nonsense, frameshift, large deletions) - PMIDs: 23020937, 25217958, 29463886, 25356899.

Schinzel-Giedion syndrome is caused by missense variants in SETBP1, particularly variants affecting amino acids 868-871 - a specific ‘hotspot’ region of the SETBP1 gene that codes for a degron. Clinical features of Schinzel-Giedion syndrome include developmental delay, epilepsy, facial dysmorphisms, and genitourinary and skeletal anomalies. The proposed mechanism of Schinzel-Giedion syndrome is gain-of-function (GOF), causing SETBP1 protein to accumulate (PMID: 28346496). There are at least 15 unrelated individuals with Schinzel-Giedion syndrome and heterozygous missense variants in SETBP1 reported in literature (PMIDs: 20436468, 26188272, 32460883, 22473152, 25028416, 25082129, 25663181, 26096993, 32445275, 28346496).

SETBP1 is associated with Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078 and Schinzel-Giedion midface retraction syndrome, OMIM: 269150 (OMIM, accessed 28th Oct 2025).
Intellectual disability v9.151 SETBP1 Ida Ertmanska reviewed gene: SETBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20436468, 21037274, 22473152, 23020937, 25217958, 25356899, 25028416, 25082129, 25663181, 26096993, 26188272, 28346496, 29463886, 32445275, 32460883; Phenotypes: Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078, Schinzel-Giedion midface retraction syndrome, OMIM: 269150, Schinzel-Giedion syndrome, MONDO:0010010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset neurodegenerative disorder v8.9 ISCA-37446-Loss Arina Puzriakova edited their review of Region: ISCA-37446-Loss: Changed rating: GREEN
Adult onset neurodegenerative disorder v8.9 ISCA-37446-Loss Arina Puzriakova Tag Q3_25_promote_green tag was added to Region: ISCA-37446-Loss.
Tag Q3_25_expert_review tag was added to Region: ISCA-37446-Loss.
Tag Q3_25_NHS_review tag was added to Region: ISCA-37446-Loss.
Adult onset neurodegenerative disorder v8.9 ISCA-37446-Loss Arina Puzriakova Phenotypes for Region: ISCA-37446-Loss were changed from DIGEORGE SYNDROME; DGS (OMIM: 188400) to DiGeorge syndrome, OMIM:188400; Parkinsonism, HP:0001300
Fetal anomalies v6.112 DISP1 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: DISP1.
Adult onset neurodegenerative disorder v8.8 ISCA-37446-Loss Arina Puzriakova Classified Region: ISCA-37446-Loss as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v8.8 ISCA-37446-Loss Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support this gene-disease association. Several cases with 22q11.2 deletions and Parkinson's disease with or without other features of DiGeorge syndrome have been reported. This is a very variable condition and most case would probably be picked up via other routes, as highlighted by Lauren Turton. However, sufficient numbers have presented where parkinsonism was the primary reason for referral, including the case in Sheffield and in the published literature (PMID: 24018986; 27017469).

Although there is sufficient evidence for inclusion, all regions were removed from this panel in 2020 'as testing is not achievable using currently available methodology' (see comment on other regions). It would be worth reviewing whether this is still the case and therefore this region has been tagged for GMS expert review.

If it is agreed that regions can now be included, other regions on this panel should also be revisited to determine whether they should be re-added.
Adult onset neurodegenerative disorder v8.8 ISCA-37446-Loss Arina Puzriakova Region: isca-37446-loss has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.112 DISP1 Ida Ertmanska changed review comment from: There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1. Among fetal cases, there are only 2 biallelic cases with DISP1 variants alone. Other individuals harboured biallelic variants in DISP1, as well as potentially pathogenic variants in other genes. Digenic inheritance appears to be common for this condition.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Fetal anomalies v6.112 DISP1 Ida Ertmanska commented on gene: DISP1: Comment on mode of inheritance: There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1. Among fetal cases, there are only 2 biallelic cases with DISP1 variants alone. Other individuals harboured biallelic variants in DISP1, as well as potentially pathogenic variants in other genes. Digenic inheritance appears to be common for this condition. Gene tagged for expert review to decide the appropriate MOI.
Fetal anomalies v6.112 DISP1 Ida Ertmanska Tag Q3_25_expert_review tag was added to gene: DISP1.
Fetal anomalies v6.112 DISP1 Ida Ertmanska edited their review of gene: DISP1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Haematological malignancies cancer susceptibility v4.34 POT1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotypes (Tumor predisposition syndrome 3, OMIM:615848) accessed on 27-10-2025
Haematological malignancies cancer susceptibility v4.34 POT1 Arina Puzriakova Phenotypes for gene: POT1 were changed from Tumor predisposition syndrome 3, OMIM:615848; Lymphoid and myeloid cancers; Multiple myeloma to Tumor predisposition syndrome 3, OMIM:615848; Lymphoid and myeloid cancers; Multiple myeloma
Hereditary neuropathy or pain disorder v7.27 PNPT1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 27 October 2025.
Hereditary neuropathy or pain disorder v7.27 PNPT1 Achchuthan Shanmugasundram Phenotypes for gene: PNPT1 were changed from Spinocerebellar ataxia 25, OMIM:608703 to Spinocerebellar ataxia 25, OMIM:608703; spinocerebellar ataxia type 25, MONDO:0012103
Hereditary neuropathy or pain disorder v7.26 PNPT1 Achchuthan Shanmugasundram Publications for gene: PNPT1 were set to 14705117; 35411967
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram edited their review of gene: PNPT1: Changed phenotypes to: Spinocerebellar ataxia 25, OMIM:608703, spinocerebellar ataxia type 25, MONDO:0012103
Haematological malignancies cancer susceptibility v4.33 HAVCR2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three different variants reported in patients from multiple descents - the p.Tyr82Cys variant occurs on a potential founder chromosome in patients with East Asian and Polynesian descent, while p.Ile97Met occurs in patients with European ancestry.

This gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three different variants reported in patients from multiple descents - the p.Tyr82Cys variant occurs on a potential founder chromosome in patients with East Asian and Polynesian descent, while p.Ile97Met occurs in patients with European ancestry.

Expert opinion is sought from the Genomic Medicine Service on whether this gene can be promoted to green rating in the next GMS update.
Haematological malignancies cancer susceptibility v4.33 HAVCR2 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: HAVCR2.
Hereditary neuropathy or pain disorder v7.25 ARHGAP19 Alexander Rossor gene: ARHGAP19 was added
gene: ARHGAP19 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ARHGAP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGAP19 were set to 41086021
Phenotypes for gene: ARHGAP19 were set to motor axonal neuropathy
Penetrance for gene: ARHGAP19 were set to Complete
Review for gene: ARHGAP19 was set to GREEN
Added comment: multiple affected families
Sources: Expert list
Monogenic hearing loss v5.47 ARSG Achchuthan Shanmugasundram Publications for gene: ARSG were set to
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel.; to: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 including polyneuropathy as part of the phenotype, and they are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel.
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel..; to: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel.
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, all these recently families do not show any evidence of incompletely penetrance.; to: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel..
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram Classified gene: PNPT1 as Green List (high evidence)
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, all these recently families do not show any evidence of incompletely penetrance.
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram Gene: pnpt1 has been classified as Green List (High Evidence).
Hereditary neuropathy or pain disorder v7.24 PNPT1 Achchuthan Shanmugasundram edited their review of gene: PNPT1: Added comment: There are additional cases reported recently:

PMID:39899068 (2025) reported a 1-year-8-month-old female proband of Brazilian descent with Spinocerebellar Ataxia 25 that presented with progressive ataxia, cerebellar atrophy, and sensory neuropathy. She was identified with a novel heterozygous truncating variant in PNPT1 (c.2068del), which she inherited from her father. Although the father was previously reported as asymptomatic, he was affected with axonal and demyelinating polyneuropathy but not ataxia upon detailed examination.

PMID:39924761 (2025) reported two unrelated families, where all individuals presented with sensory ataxic neuropathy (SAN), while some individuals developed cerebellar signs. Analysis of WGS variant data through the 100,000 Genomes Project identified two different heterozygous variants in these families. Family 1 underwent a 'quad' study and the previously reported c.2014‐3C>G variant segregated in all affected family members and was absent in all unaffected family members. Sanger sequencing confirmed segregation in two other individuals. c.2014‐3C>G is the same variant that was found in the 3-generation Australian family reported by PMID:35411967, where unaffected family members harboured the variant. A novel nonsense variant (c.2143C>T/ p.Arg715Ter) was found in both affected members of Family 2.; Changed publications to: 14705117, 35411967, 37935417, 39899068, 39924761
Haematological malignancies cancer susceptibility v4.33 HAVCR2 Achchuthan Shanmugasundram Tag Q3_25_expert_review was removed from gene: HAVCR2.
Haematological malignancies cancer susceptibility v4.33 HAVCR2 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: HAVCR2.
Haematological malignancies cancer susceptibility v4.33 POT1 Arina Puzriakova Publications for gene: POT1 were set to PMID: 36467798; 30213928
Haematological malignancies cancer susceptibility v4.32 POT1 Arina Puzriakova edited their review of gene: POT1: Changed publications to: 27528712, 29693246, 33216348, 34193977, 34769003, 36467798, 39845416
Haematological malignancies cancer susceptibility v4.32 POT1 Arina Puzriakova changed review comment from: Germline variants in POT1 have been linked to a wide range of haematological malignancies including myeloid and lymphoid neoplasms (PMID: 27528712; 34193977; 34769003) and multiple myeloma (PMID: 36467798; 39845416). POT1 variants lead to telomeric elongation and increased telomere fragility as the main functional effect. However, haematologic malignancies often occur as part of a broader spectrum of POT1-associated cancers and therefore this gene will be flagged for additional GMS expert review to determine whether it is appropriate to include on this panel.; to: Germline variants in POT1 have been linked to a wide range of haematological malignancies including myeloid and lymphoid neoplasms (PMID: 27528712; 29693246; 33216348; 34193977; 34769003) and multiple myeloma (PMID: 36467798; 39845416). POT1 variants lead to telomeric elongation and increased telomere fragility as the main functional effect.
Likely inborn error of metabolism v8.71 GDAP1 Ida Ertmanska reviewed gene: GDAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16172208; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831, Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706, Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340, Charcot-Marie-Tooth disease, type 4A, OMIM:214400; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Haematological malignancies cancer susceptibility v4.32 POT1 Arina Puzriakova Classified gene: POT1 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.32 POT1 Arina Puzriakova Added comment: Comment on list classification: Multiple studies have been published showing germline POT1 variants predispose to a broad spectrum of haematological cancers including chronic lymphocytic leukaemia, lymphomas and myeloid malignancies. Inclusion on this panel may be warranted to allow clinical surveillance of high-risk families.

However, haematologic malignancies often occur as part of a broader spectrum of POT1-associated cancers and therefore this gene will be flagged for additional GMS expert review to determine whether it is appropriate to include on this panel.
Haematological malignancies cancer susceptibility v4.32 POT1 Arina Puzriakova Gene: pot1 has been classified as Amber List (Moderate Evidence).
Haematological malignancies cancer susceptibility v4.31 POT1 Arina Puzriakova Phenotypes for gene: POT1 were changed from Multiple myeloma to Tumor predisposition syndrome 3, OMIM:615848; Lymphoid and myeloid cancers; Multiple myeloma
Haematological malignancies cancer susceptibility v4.30 POT1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: POT1.
Tag Q3_25_expert_review tag was added to gene: POT1.
Haematological malignancies cancer susceptibility v4.30 POT1 Arina Puzriakova changed review comment from: Germline variants in POT1 have been linked to a wide range of haematological malignancies including myeloid and lymphoid neoplasms (PMID: 27528712; 34193977; 34769003) and multiple myeloma (PMID: 36467798; 39845416). POT1 variants lead to telomeric elongation and increased telomere fragility as the main functional effect. However, hematologic malignancies often occur as part of a broader spectrum of POT1-associated cancers and therefore this gene will be flagged for additional GMS expert review to determine whether it is appropriate to include on this panel.; to: Germline variants in POT1 have been linked to a wide range of haematological malignancies including myeloid and lymphoid neoplasms (PMID: 27528712; 34193977; 34769003) and multiple myeloma (PMID: 36467798; 39845416). POT1 variants lead to telomeric elongation and increased telomere fragility as the main functional effect. However, haematologic malignancies often occur as part of a broader spectrum of POT1-associated cancers and therefore this gene will be flagged for additional GMS expert review to determine whether it is appropriate to include on this panel.
Haematological malignancies cancer susceptibility v4.30 POT1 Arina Puzriakova reviewed gene: POT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27528712, 34193977, 34769003, 36467798, 39845416; Phenotypes: Tumor predisposition syndrome 3, OMIM:615848, Lymphoid and myeloid cancers, Multiple myeloma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v5.46 ARSG Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018
Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).

PMID: 35226187 Velde et al., 2022
3 unrelated subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo):
Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).; to: PMID: 29300381 Khateb et al, 2018
Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).

PMID: 35226187 Velde et al., 2022
3 unrelated subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo):
Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).

ARSG is associated with AR Usher syndrome, type IV, 618144 in OMIM (accessed 27th Oct 2025).
Monogenic hearing loss v5.46 ARSG Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018
Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).

PMID: 35226187 Velde et al., 2022
3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo):
Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).; to: PMID: 29300381 Khateb et al, 2018
Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).

PMID: 35226187 Velde et al., 2022
3 unrelated subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo):
Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).
Monogenic hearing loss v5.46 ARSG Ida Ertmanska edited their review of gene: ARSG: Added comment: Comment on list classification: There are at least 8 unrelated individuals reported in literature with biallelic ARSG variants, diagnosed with Usher syndrome. All individuals presented with progressive sensorineural hearing loss (onset around 40 years of age). Based on the available evidence, this gene should be promoted Green for Monogenic hearing loss.; Changed publications to: 29300381, 32455177, 33300174, 33629623, 35226187
Monogenic hearing loss v5.46 ARSG Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018
five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).

PMID: 35226187 Velde et al., 2022
3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo):
Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).; to: PMID: 29300381 Khateb et al, 2018
Reported 5 patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a founder missense variant, c.133G>T (p.D45Y) in ARSG. Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).

PMID: 35226187 Velde et al., 2022
3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo):
Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).
Monogenic hearing loss v5.46 ARSG Ida Ertmanska changed review comment from: PMID: 29300381 Khateb et al, 2018
five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).
Sources: Other; to: PMID: 29300381 Khateb et al, 2018
five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).

PMID: 35226187 Velde et al., 2022
3 subjects reported with Usher syndrome and biallelic variants in ARSG - presented with retinitis pigmentosa (onset 40-60yo) and SNHL (onset 20-40 yo):
Subject N: compound het for c.1212+1G>A, p.(Val405Ilefs*41) and c.275T>C, p.(Leu92Pro).
Subject F: compound het for c.1326del, p.(Ser443Ala fs*12) and c.1024C>T, p.(Arg342Trp).
Subject D: compound het for c.588C>A, p.(Tyr196*) and c.705-3940_ 982+2952del, p.(Ser235Arg fs*29).
Monogenic hearing loss v5.46 ARSG Ida Ertmanska Tag Q3_25_promote_green tag was added to gene: ARSG.
Monogenic hearing loss v5.46 ARSG Ida Ertmanska Classified gene: ARSG as Amber List (moderate evidence)
Monogenic hearing loss v5.46 ARSG Ida Ertmanska Gene: arsg has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.45 ARSG Ida Ertmanska edited their review of gene: ARSG: Changed publications to: 29300381, 32455177, 33300174, 33629623
Fetal anomalies v6.112 DISP1 Ida Ertmanska edited their review of gene: DISP1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.112 DISP1 Ida Ertmanska changed review comment from: MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1. Among fetal cases, there are only 2 biallelic cases with DISP1 variants alone. Other individuals harboured biallelic variants in DISP1, as well as potentially pathogenic variants in other genes. Digenic inheritance appears to be common for this condition.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Fetal anomalies v6.112 DISP1 Ida Ertmanska edited their review of gene: DISP1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v7.92 MT-ND5 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: MT-ND5.
Tag Q3_25_NHS_review tag was added to gene: MT-ND5.
Paediatric or syndromic cardiomyopathy v7.92 MT-ND5 Achchuthan Shanmugasundram changed review comment from: After consultation with the clinical tea, this gene is tagged for expert review by the GLHs on the inclusion of this gene with green rating to this panel.; to: After consultation with the clinical team, this gene is tagged for expert review by the Genomic Laboratory Hubs on the inclusion of this gene with green rating to this panel.
Paediatric or syndromic cardiomyopathy v7.92 MT-ND5 Achchuthan Shanmugasundram commented on gene: MT-ND5: After consultation with the clinical tea, this gene is tagged for expert review by the GLHs on the inclusion of this gene with green rating to this panel.
Monogenic hearing loss v5.40 ARSG Ida Ertmanska gene: ARSG was added
gene: ARSG was added to Monogenic hearing loss. Sources: Other
Mode of inheritance for gene: ARSG was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ARSG were set to Usher syndrome, type IV, OMIM:618144; usher syndrome, type 4, MONDO:0029141
Review for gene: ARSG was set to GREEN
Added comment: PMID: 29300381 Khateb et al, 2018
five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).
Sources: Other
Monogenic hearing loss v5.40 ARSG Ida Ertmanska gene: ARSG was added
gene: ARSG was added to Monogenic hearing loss. Sources: Other
Mode of inheritance for gene: ARSG was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ARSG were set to Usher syndrome, type IV, OMIM:618144; usher syndrome, type 4, MONDO:0029141
Review for gene: ARSG was set to GREEN
Added comment: PMID: 29300381 Khateb et al, 2018
five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and moderate / severe sensorineural hearing loss. All patients homozygous for a afounder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). Vision and hearing loss appeared around the age of 40 years.

PMID: 32455177 Abad-Morales et al., 2020
Case report of a 44-year-old female of Spanish origin; progressive nyctalopia, hearing impairment since infancy, retinal phenotype (onset around 40yo); novel homozygous missense mutation c.130G>A (p.Asp44Asn) in the ARSG gene. Method: WES.

PMID: 33300174 Peter et al., 2021
3 novel ARSG variants in 2 unrelated Portuguese families; affected individuals presented with retinitis pigmentosa and sensorineural hearing loss, with onset around 40 years of age.
Individual 1 = homozygous for NM_014960.4:c.1326del, p.(Ser443AlafsTer12)
Individual 2 = compound het for NM_014960.4:c.253T>C, p.(Ser85Pro) and NM_014960.4:c.338G>A, p.(Gly113Asp).

PMID: 33629623 Fowler et al., 2021
Report of a 60-year-old male of Persian descent, with history of 20 years of progressive SNHL, and 10 years of progressive peripheral vision loss and pigmentary retinopathy. Homozygous for a ARSG variant c.1270C>T, p.(Arg424Cys).
Sources: Other
Monogenic hearing loss v5.39 PTRH2 Achchuthan Shanmugasundram Classified gene: PTRH2 as Amber List (moderate evidence)
Monogenic hearing loss v5.39 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least eight unrelated families with IMNEPD presented with sensorineural hearing loss as part of the phenotype. Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Monogenic hearing loss v5.39 PTRH2 Achchuthan Shanmugasundram Gene: ptrh2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.38 PTRH2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PTRH2.
Haematological malignancies cancer susceptibility v4.30 KDM1A Arina Puzriakova Classified gene: KDM1A as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.30 KDM1A Arina Puzriakova Added comment: Comment on list classification: Significant enrichment of KDM1A germline P/LP variants in MM patients has been identified and independently replicated. KDM1A has since been cited and acknowledged as a germline MM predisposition gene in the scientific literature. This may warrant inclusion on this panel to allow clinical surveillance of high-risk families, and therefore tagging for promotion to Green, subject to GMS expert review.
Haematological malignancies cancer susceptibility v4.30 KDM1A Arina Puzriakova Gene: kdm1a has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.38 PTRH2 Achchuthan Shanmugasundram changed review comment from: PMID:25574476 (2014) reported a consanguineous family of Yazidian-Turkish descent infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). The two affected children presented with intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. They were identified with a homozygous frameshift variant in PTRH2 gene.

PMID:25558065 (2015) reported a patient with global developmental delay, hearing loss, and ataxia and was identified with a homozygous missense variant PTRH2 gene.

PMID:27129381 (2016) reported the identification of a different homozygous missense variant in five further IMNEPD patients from two different families of Tunisian and Saudi Arabian descent. Sensorineural hearing impairment was present in all five reported patients.

PMID:31057140 (2019) reported three brothers of Syrian descent with a novel homozygous stop-gain variant in PTRH2 gene presenting with IMNEPD. All three had hearing loss.

This gene has been associated with IMNEPD in OMIM (MIM #616263, OMIM accessed on 24 October 2025), which includes sensorineural deafness as one of the clinical manifestations.
Sources: Literature; to: PMID:25574476 (2014) reported a consanguineous family of Yazidian-Turkish descent infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). The two affected children presented with intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. They were identified with a homozygous frameshift variant in PTRH2 gene.

PMID:25558065 (2015) reported a patient with global developmental delay, hearing loss, and ataxia and was identified with a homozygous missense variant PTRH2 gene.

PMID:27129381 (2016) reported the identification of a different homozygous missense variant in five further IMNEPD patients from two different families of Tunisian and Saudi Arabian descent. Sensorineural hearing impairment was present in all five reported patients.

PMID:31057140 (2019) reported three brothers of Syrian descent with a novel homozygous stop-gain variant in PTRH2 gene presenting with IMNEPD. All three had hearing loss.

This gene has been associated with IMNEPD in OMIM (MIM #616263, OMIM accessed on 24 October 2025), which includes sensorineural deafness as one of the clinical manifestations. This gene is also associated with relevant phenotypes on the DD panel of Gene2Phenotype with 'definitive' rating.
Sources: Literature
Monogenic hearing loss v5.38 PTRH2 Achchuthan Shanmugasundram gene: PTRH2 was added
gene: PTRH2 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: PTRH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRH2 were set to 25574476; 25558065; 27129381; 31057140
Phenotypes for gene: PTRH2 were set to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Review for gene: PTRH2 was set to GREEN
Added comment: PMID:25574476 (2014) reported a consanguineous family of Yazidian-Turkish descent infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). The two affected children presented with intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. They were identified with a homozygous frameshift variant in PTRH2 gene.

PMID:25558065 (2015) reported a patient with global developmental delay, hearing loss, and ataxia and was identified with a homozygous missense variant PTRH2 gene.

PMID:27129381 (2016) reported the identification of a different homozygous missense variant in five further IMNEPD patients from two different families of Tunisian and Saudi Arabian descent. Sensorineural hearing impairment was present in all five reported patients.

PMID:31057140 (2019) reported three brothers of Syrian descent with a novel homozygous stop-gain variant in PTRH2 gene presenting with IMNEPD. All three had hearing loss.

This gene has been associated with IMNEPD in OMIM (MIM #616263, OMIM accessed on 24 October 2025), which includes sensorineural deafness as one of the clinical manifestations.
Sources: Literature
Haematological malignancies cancer susceptibility v4.29 KDM1A Arina Puzriakova Publications for gene: KDM1A were set to 29559475
Haematological malignancies cancer susceptibility v4.28 KDM1A Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: KDM1A.
Tag Q3_25_expert_review tag was added to gene: KDM1A.
Haematological malignancies cancer susceptibility v4.28 KDM1A Arina Puzriakova reviewed gene: KDM1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 29559475, 39845416; Phenotypes: Multiple myeloma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Haematological malignancies cancer susceptibility v4.28 HAVCR2 Achchuthan Shanmugasundram Classified gene: HAVCR2 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v4.28 HAVCR2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three different variants reported in patients from multiple descents - the p.Tyr82Cys variant occurs on a potential founder chromosome in patients with East Asian and Polynesian descent, while p.Ile97Met occurs in patients with European ancestry.

This gene can be promoted to green rating in the next GMS update.
Haematological malignancies cancer susceptibility v4.28 HAVCR2 Achchuthan Shanmugasundram Gene: havcr2 has been classified as Amber List (Moderate Evidence).
Haematological malignancies cancer susceptibility v4.27 HAVCR2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: HAVCR2.
Haematological malignancies cancer susceptibility v4.27 HAVCR2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene is associated with relevant phenotypes in OMIM (MIM #618398, OMIM accessed on 27 October 2025) and in Gene2Phenotype ('definitive' rating on Skin Panel).

Biallelic variants in this gene are also associated with HAVCR2-related cancer predisposition (MONDO:1060169) with 'moderate' rating by Childhood, Adolescent and Young Adult Cancer Predisposition expert panel in ClinGen.
Haematological malignancies cancer susceptibility v4.27 HAVCR2 Achchuthan Shanmugasundram Phenotypes for gene: HAVCR2 were changed from T-cell lymphoma, subcutaneous panniculitis-like (OMIM: 618398) to T-cell lymphoma, subcutaneous panniculitis-like, OMIM:618398; subcutaneous panniculitis-like T-cell lymphoma, MONDO:0019475
Haematological malignancies cancer susceptibility v4.26 HAVCR2 Achchuthan Shanmugasundram Publications for gene: HAVCR2 were set to PMID: 32005988
Haematological malignancies cancer susceptibility v4.25 HAVCR2 Achchuthan Shanmugasundram reviewed gene: HAVCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30374066, 30792187, 32005988, 32285995; Phenotypes: T-cell lymphoma, subcutaneous panniculitis-like, OMIM:618398, subcutaneous panniculitis-like T-cell lymphoma, MONDO:0019475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v8.20 SIK3 Ida Ertmanska reviewed gene: SIK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 22318228, 30232230; Phenotypes: Spondyloepimetaphyseal dysplasia, Krakow type, OMIM: 618162, spondyloepimetaphyseal dysplasia, Krakow type, MONDO:0032571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v8.20 SIK3 Ida Ertmanska Tag watchlist tag was added to gene: SIK3.
Retinal disorders v8.56 MCDR3 Ida Ertmanska changed review comment from: Comment on list classification: While there is emerging evidence linking duplications at the MCDR3 locus and macular dystrophy, PanelApp panels may only include regions curated in ClinGen with sufficient evidence of dosage sensitivity. As this region in not included in ClinGen, we are unable to add it at this time.; to: Comment on list classification: While there is emerging evidence linking duplications at the MCDR3 locus and macular dystrophy, PanelApp panels currently only include regions curated in ClinGen with sufficient evidence of dosage sensitivity. As this region in not included in ClinGen, we are unable to add it at this time.
Cytopenias and congenital anaemias v1.122 RAP1B Arina Puzriakova Phenotypes for gene: RAP1B were changed from Syndromic intellectual disability; cytopenia to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; Syndromic intellectual disability; Cytopenia
Cytopenias and congenital anaemias v1.121 RAP1B Arina Puzriakova Classified gene: RAP1B as Green List (high evidence)
Cytopenias and congenital anaemias v1.121 RAP1B Arina Puzriakova Added comment: Comment on list classification: There are three unrelated cases with cytopenia and hence this gene has been upgraded from Amber to Green. This gene is already Green on the GMS equivalent panel - https://panelapp.genomicsengland.co.uk/panels/519/gene/RAP1B/

This gene has been associated with relevant phenotype in Gene2Phenotype database (with 'limited' rating in the DD panel), but not yet been associated with phenotypes in OMIM.
Cytopenias and congenital anaemias v1.121 RAP1B Arina Puzriakova Gene: rap1b has been classified as Green List (High Evidence).
Cytopenias and congenital anaemias v1.120 RAP1B Arina Puzriakova Tag watchlist was removed from gene: RAP1B.
Intellectual disability v9.151 RAP1B Arina Puzriakova Phenotypes for gene: RAP1B were changed from Syndromic intellectual disability to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; Syndromic intellectual disability
Cytopenia - NOT Fanconi anaemia v4.25 RAP1B Arina Puzriakova Phenotypes for gene: RAP1B were changed from Syndromic intellectual disability; cytopenia to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; Syndromic intellectual disability; Cytopenia
Hereditary neuropathy or pain disorder v7.24 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 24 October 2025.
Hereditary neuropathy or pain disorder v7.24 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Hereditary neuropathy or pain disorder v7.23 PTRH2 Achchuthan Shanmugasundram edited their review of gene: PTRH2: Changed phenotypes to: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Hereditary ataxia with onset in adulthood v8.11 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 24 October 2025.
Hereditary ataxia with onset in adulthood v8.11 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile multi-system neurologic, endocrine, and pancreatic disease, 616263 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Intellectual disability v9.150 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 24 October 2025.
Intellectual disability v9.150 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Intellectual disability v9.149 PTRH2 Achchuthan Shanmugasundram edited their review of gene: PTRH2: Changed phenotypes to: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Ataxia and cerebellar anomalies - narrow panel v8.30 PTRH2 Achchuthan Shanmugasundram Classified gene: PTRH2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.30 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least five unrelated families with IMNEPD presented with ataxia as part of the phenotype. Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.30 PTRH2 Achchuthan Shanmugasundram Gene: ptrh2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.29 PTRH2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: PTRH2.
Ataxia and cerebellar anomalies - narrow panel v8.29 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Ataxia and cerebellar anomalies - narrow panel v8.28 PTRH2 Achchuthan Shanmugasundram Publications for gene: PTRH2 were set to 25574476; 28328138
Ataxia and cerebellar anomalies - narrow panel v8.27 PTRH2 Achchuthan Shanmugasundram reviewed gene: PTRH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25574476, 25558065, 27129381, 31057140; Phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.59 RAP1B Achchuthan Shanmugasundram Tag somatic tag was added to gene: RAP1B.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.59 RAP1B Achchuthan Shanmugasundram Classified gene: RAP1B as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.59 RAP1B Achchuthan Shanmugasundram Added comment: Comment on list classification: Only one recent case from PMID:39225097 (2024) presented with combined immunodeficiency in addition to thrombocytopenia and other previously reported phenotypes. The variant from this patient was somatic rather than germline. So, the 'somatic' tag has been added.

All the other cases were reported with thrombocytopenia and congenital anomalies. Hence, this gene should be rated red on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.59 RAP1B Achchuthan Shanmugasundram Gene: rap1b has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.58 RAP1B Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 24 October 2025
Primary immunodeficiency or monogenic inflammatory bowel disease v8.58 RAP1B Achchuthan Shanmugasundram Phenotypes for gene: RAP1B were changed from thrombocytopenia; leukopenia; lymphopenia; anemia; splenomegaly; immunodeficiency; preauricular tag; upslanting palpebral fissures; flat midface; scarce eyebrows; low-set and posteriorly rotated ears; hypoplastic teeth; umbilical hernia, and genitourinary abnormalities; hydronephrosis; vesicoureteral reflux; unilateral cryptorchidism to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654; thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, MONDO:0958000
Primary immunodeficiency or monogenic inflammatory bowel disease v8.57 RAP1B Achchuthan Shanmugasundram Publications for gene: RAP1B were set to 39225097
Primary immunodeficiency or monogenic inflammatory bowel disease v8.56 RAP1B Achchuthan Shanmugasundram reviewed gene: RAP1B: Rating: RED; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32627184, 35451551, 37850357, 39225097; Phenotypes: Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654, thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, MONDO:0958000; Mode of inheritance: Other
Hereditary neuropathy or pain disorder v7.23 TDP1 Achchuthan Shanmugasundram Classified gene: TDP1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.23 TDP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least three different variants reported (two published variants including the founder-variant from the Middle East) in five unrelated families including the Sheffield case. There is also sufficient functional evidence available in support of the p.His493Arg founder variant. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.23 TDP1 Achchuthan Shanmugasundram Gene: tdp1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.22 TDP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM accessed 24 October 2025.
Hereditary neuropathy or pain disorder v7.22 TDP1 Achchuthan Shanmugasundram Phenotypes for gene: TDP1 were changed from ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250 to ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, MONDO:0011801
Hereditary neuropathy or pain disorder v7.21 TDP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TDP1.
Hereditary neuropathy or pain disorder v7.21 TDP1 Achchuthan Shanmugasundram changed review comment from: As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also function evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease, This patient was identified with novel missense variant in TDP1 - p.His478Tyr. via WES and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.; to: As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also functional evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease. This patient was identified with a novel missense variant in TDP1 (p.His478Tyr) via WES, and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset of epilepsy compared to other cases (6 yrs), where no developmental deficits were observed before or after seizures.; to: Comment on list classification: Rating Amber on the ID panel, as evidence from 7 unrelated cases reported in PMID:41035394 indicates that developmental and cognitive impairment is not a universal feature and these deficits are likely secondary to early-onset seizures, which represent the most prominent manifestation associated with this gene. This is further supported by a case with later onset epilepsy (6 yrs), where no developmental deficits were observed before (or after) seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset of epilepsy compared to other cases (6 yrs), where no developmental deficits were observed before or after seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appear to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.
Early onset or syndromic epilepsy v8.59 BRSK1 Arina Puzriakova Classified gene: BRSK1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.59 BRSK1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated cases with early onset epilepsy and supportive data from functional and animal model studies (PMID: 41035394)
Early onset or syndromic epilepsy v8.59 BRSK1 Arina Puzriakova Gene: brsk1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.149 BRSK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber on the ID panel as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.; to: Comment on list classification: Rating Amber on the ID panel, as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appear to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova Classified gene: BRSK1 as Amber List (moderate evidence)
Intellectual disability v9.149 BRSK1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber on the ID panel as based on 7 unrelated cases reported in PMID:41035394, developmental and cognitive impairment appears to be secondary to early onset seizures which represent the most prominent feature of the disorder associated with this gene. This is further supported by the case with later onset (6 yrs) who did not exhibit any developmental deficits before or after onset of seizures.
Intellectual disability v9.149 BRSK1 Arina Puzriakova Gene: brsk1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.58 BRSK1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: BRSK1.
Early onset or syndromic epilepsy v8.58 BRSK1 Arina Puzriakova gene: BRSK1 was added
gene: BRSK1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: BRSK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK1 were set to 41035394
Phenotypes for gene: BRSK1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BRSK1 was set to AMBER
Added comment: Zhang et al. 2025 (PMID: 41035394) describe 7 unrelated individuals, born to non-consanguineous Chinese parents, with unexplained epilepsy and heterozygous variants in the BRSK1 gene identified by trio WES. Variants include four SNVs and two indels (2 frameshift, 1 nonsense, 3 missense) - five were de novo, one inherited from an affected parent and one recurrent. No other pathogenic variants in epilepsy genes were identified. BRSK1 is intolerant to LoF variants (pLI = 1 in gnomAD v4.1.0).

Clinical features in affected individuals include epilepsy (7/7) with age of onset before age 1 (with exception of 1 case with age of onset at 6 yrs), variable brain MRI abnormalities (3/7), developmental delay (2 GDD, 1 mental delay, 1 motor delay, 2 without DD). One individual also had ASD and ADHD.

Frameshift and nonsense variants led to complete loss of BRSK1 protein, while one missense variant reduced protein levels. Proteomic analyses demonstrated axonal and synaptic dysfunction. Brsk1 exon 4-7 knockout mice (heterozygous and homozygous) exhibited seizures, neuronal hyperexcitability and neurobehavioral impairments which recapitulated clinical features observed in humans.
Sources: Literature
Intellectual disability v9.148 BRSK1 Arina Puzriakova gene: BRSK1 was added
gene: BRSK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BRSK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK1 were set to 41035394
Phenotypes for gene: BRSK1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BRSK1 was set to AMBER
Added comment: Zhang et al. 2025 (PMID: 41035394) describe 7 unrelated individuals, born to non-consanguineous Chinese parents, with unexplained epilepsy and heterozygous variants in the BRSK1 gene identified by trio WES. Variants include four SNVs and two indels (2 frameshift, 1 nonsense, 3 missense) - five were de novo, one inherited from an affected parent and one recurrent. No other pathogenic variants in epilepsy genes were identified. BRSK1 is intolerant to LoF variants (pLI = 1 in gnomAD v4.1.0).

Clinical features in affected individuals include epilepsy (7/7) with age of onset before age 1 (with exception of 1 case with age of onset at 6 yrs), variable brain MRI abnormalities (3/7), developmental delay (2 GDD, 1 mental delay, 1 motor delay, 2 without DD). One individual also had ASD and ADHD.

Frameshift and nonsense variants led to complete loss of BRSK1 protein, while one missense variant reduced protein levels. Proteomic analyses demonstrated axonal and synaptic dysfunction. Brsk1 exon 4-7 knockout mice (heterozygous and homozygous) exhibited seizures, neuronal hyperexcitability and neurobehavioral impairments which recapitulated clinical features observed in humans.
Sources: Literature
Fetal anomalies v6.112 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. One these cases was a foetus reported with extensive posterior Periventricular nodular heterotopia (PMID:33639934).

In addition, PMID:30266093 (2018) reported a foetus with abnormalities identified via ultrasound and with compound heterozygous LAMC3 variants

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene is also green with biallelic MOI on the Fetal anomalies panel of PanelApp Australia (https://panelapp-aus.org/panels/3763/gene/LAMC3/). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).

This gene should therefore remain green with Biallelic MOI on this panel.; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. One these cases was a foetus reported with extensive posterior Periventricular nodular heterotopia (PMID:33639934).

In addition, PMID:30266093 (2018) reported a foetus with abnormalities identified via ultrasound and with compound heterozygous LAMC3 variants

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene is also green with biallelic MOI on the Fetal anomalies panel of PanelApp Australia (https://panelapp-aus.org/panels/3763/gene/LAMC3/). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Malformations of cortical development v7.12 LAMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: The 'Disputed' rating on ClinGen is only relevant for monoallelic MOI. As there is sufficient evidence available for the association of biallelic variants with the phenotype, this gene should remain green on this panel with biallelic MOI.; to: Comment on list classification: The 'Disputed' rating on ClinGen is only relevant for monoallelic MOI. As there is sufficient evidence available for the association of biallelic variants with the phenotype, this gene should remain green with biallelic MOI on this panel.
Fetal anomalies v6.112 LAMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: The 'Disputed' rating on ClinGen is only relevant for monoallelic MOI. As there is sufficient evidence available for the association of biallelic variants with the phenotype, this gene should remain green on this panel with biallelic MOI.; to: Comment on list classification: The 'Disputed' rating on ClinGen is only relevant for monoallelic MOI. As there is sufficient evidence available for the association of biallelic variants with the phenotype, this gene should remain green with biallelic MOI on this panel.
Fetal anomalies v6.112 LAMC3 Achchuthan Shanmugasundram Classified gene: LAMC3 as Green List (high evidence)
Fetal anomalies v6.112 LAMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: The 'Disputed' rating on ClinGen is only relevant for monoallelic MOI. As there is sufficient evidence available for the association of biallelic variants with the phenotype, this gene should remain green on this panel with biallelic MOI.
Fetal anomalies v6.112 LAMC3 Achchuthan Shanmugasundram Gene: lamc3 has been classified as Green List (High Evidence).
Malformations of cortical development v7.12 LAMC3 Achchuthan Shanmugasundram Classified gene: LAMC3 as Green List (high evidence)
Malformations of cortical development v7.12 LAMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: The 'Disputed' rating on ClinGen is only relevant for monoallelic MOI. As there is sufficient evidence available for the association of biallelic variants with the phenotype, this gene should remain green on this panel with biallelic MOI.
Malformations of cortical development v7.12 LAMC3 Achchuthan Shanmugasundram Gene: lamc3 has been classified as Green List (High Evidence).
Malformations of cortical development v7.11 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265).

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).

This gene should therefore remain green with Biallelic MOI on this panel.; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265).

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Early onset or syndromic epilepsy v8.57 LAMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (six unrelated cases) for the association of biallelic LAMC3 variants with seizures. Hence, this gene should be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (six unrelated cases) for the association of biallelic LAMC3 variants with seizures. The 'Disputed' rating in ClinGen is only relevant to monoallelic MOI. Hence, this gene should be promoted to green rating with biallelic MOI in the next GMS update.
Primary lymphoedema v4.10 MDFIC Pia Ostergaard gene: MDFIC was added
gene: MDFIC was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: MDFIC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDFIC were set to PMID: 35235341
Phenotypes for gene: MDFIC were set to primary lymphoedema; central conducting lymphatic anomaly
Penetrance for gene: MDFIC were set to unknown
Review for gene: MDFIC was set to GREEN
Added comment: Sources: Literature
Primary lymphoedema v4.10 CELSR1 Pia Ostergaard reviewed gene: CELSR1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31215153, 26855770, 31403174, 37225411; Phenotypes: primary lymphoedema; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary lymphoedema v4.10 ERG Pia Ostergaard reviewed gene: ERG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36928819, 38991192; Phenotypes: primary lymphoedema, cytopenia and hematological malignancy predisposition; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary lymphoedema v4.10 HGF Pia Ostergaard reviewed gene: HGF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 18564920, 40245437, 38676400, 38791500; Phenotypes: primary lymphoedema, clinically diverse with variable age of onset, variable degree of lymphoedema but predominantly bilateral in the lower limbs; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Non-acute porphyrias v1.29 HMBS Sharon Whatley commented on gene: HMBS: Update 23/10/2025:
The relevance of the biallelic form of HMBS was discussed at the IPNET (International Porphyria Network) laboratory working group. According to the IPNET definition of acute intermittent porphyria, the biallelic form also meets the definition of an acute porphyria rather than the non-acute. In a clinical context these patients would be investigated using a symptomatic panel. We would recommend that HMBS is not part of the non-acute porphyria panel.
Distal myopathies v6.11 TIA1 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 23rd October 2025
Distal myopathies v6.11 TIA1 Eleanor Williams Phenotypes for gene: TIA1 were changed from Welander distal myopathy, 604454 to Welander distal myopathy, OMIM:604454; distal myopathy, Welander type, MONDO:0011466
Distal myopathies v6.10 TIA1 Eleanor Williams Publications for gene: TIA1 were set to 23401021
Distal myopathies v6.9 TIA1 Eleanor Williams Added comment: Comment on mode of inheritance: Suggested to change the mode of inheritance to monoallelic only following GMS review.
Distal myopathies v6.9 TIA1 Eleanor Williams Mode of inheritance for gene: TIA1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Distal myopathies v6.8 TIA1 Eleanor Williams Tag Q3_25_MOI tag was added to gene: TIA1.
Distal myopathies v6.8 TIA1 Eleanor Williams edited their review of gene: TIA1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Distal myopathies v6.8 TIA1 Eleanor Williams commented on gene: TIA1
Early onset or syndromic epilepsy v8.57 CDK5 Eleanor Williams Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia, MONDO:0014596
Fetal anomalies v6.111 CDK5 Eleanor Williams Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia, MONDO:0014596
Cerebellar hypoplasia v1.82 CDK5 Eleanor Williams Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia, MONDO:0014596
Ataxia and cerebellar anomalies - narrow panel v8.27 CDK5 Eleanor Williams Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia, MONDO:0014596
Malformations of cortical development v7.11 CDK5 Eleanor Williams Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia, MONDO:0014596
Ataxia and cerebellar anomalies - narrow panel v8.26 CDK5 Eleanor Williams Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia
DDG2P v6.8 SIX5 Eleanor Williams commented on gene: SIX5
Proteinuric renal disease v5.6 CD2AP Eleanor Williams Tag Q3_25_expert_review was removed from gene: CD2AP.
Proteinuric renal disease v5.6 CD2AP Eleanor Williams Tag Q3_25_expert_review tag was added to gene: CD2AP.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.56 FLT3LG Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed 22nd October 2025
Primary immunodeficiency or monogenic inflammatory bowel disease v8.56 FLT3LG Eleanor Williams Phenotypes for gene: FLT3LG were changed from ?Immunodeficiency 125 , OMIM:620926 to ?Immunodeficiency 125 , OMIM:620926; immunodeficiency 125, MONDO:0975749
Primary immunodeficiency or monogenic inflammatory bowel disease v8.55 TMEFF1 Achchuthan Shanmugasundram Classified gene: TMEFF1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.55 TMEFF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies, including mice model) for the promotion of this gene to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.55 TMEFF1 Achchuthan Shanmugasundram Gene: tmeff1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.54 TMEFF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TMEFF1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.54 TMEFF1 Achchuthan Shanmugasundram Phenotypes for gene: TMEFF1 were changed from Herpes encephalitis; HSE to encephalitis, acute, infection-induced, susceptibility to, MONDO:0800174
Primary immunodeficiency or monogenic inflammatory bowel disease v8.53 TMEFF1 Achchuthan Shanmugasundram reviewed gene: TMEFF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39048823, 39048830; Phenotypes: encephalitis, acute, infection-induced, susceptibility to, MONDO:0800174; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.71 FECH Achchuthan Shanmugasundram Publications for gene: FECH were set to 27604308
Likely inborn error of metabolism v8.70 FECH Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM accessed on 22 October 2025
Likely inborn error of metabolism v8.70 FECH Achchuthan Shanmugasundram Phenotypes for gene: FECH were changed from Protoporphyria, erythropoietic, 1 177000 to Protoporphyria, erythropoietic, 1, OMIM:177000; protoporphyria, erythropoietic, 1, MONDO:0008319
Paediatric disorders - additional genes v7.21 KCTD15 Achchuthan Shanmugasundram Classified gene: KCTD15 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.21 KCTD15 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated amber as there are only two unrelated families reported with missense variants in KCTD15 and some functional evidence from structural analyses.
Paediatric disorders - additional genes v7.21 KCTD15 Achchuthan Shanmugasundram Gene: kctd15 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.20 KCTD15 Achchuthan Shanmugasundram Phenotypes for gene: KCTD15 were changed from Lipomatous frontonasal malformation; anosmia; cutis aplasia of the scalp; sparse hair; congenital heart disease to frontonasal dysplasia, MONDO:0016643
Paediatric disorders - additional genes v7.19 KCTD15 Achchuthan Shanmugasundram changed review comment from: PMID:38296633 (2024) reported a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in the affected father and daughter via exome sequencing and the variant segregated with the phenotype. A de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was identified via targeted DNA sequencing in a similarly affected sporadic patient.

There is some functional evidence available from structural analyses, which demonstrated that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.; to: PMID:38296633 (2024) reported a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in the affected father and daughter via exome sequencing and the variant segregated with the phenotype. A de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was identified via targeted DNA sequencing in a similarly affected sporadic patient.

There is some functional evidence available from structural analyses, which demonstrated that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

This gene has not yet been associated with any relevant phenotypes in OMIM (OMIM accessed on 22 October 2025) or in Gene2Phenotype.
Paediatric disorders - additional genes v7.19 KCTD15 Achchuthan Shanmugasundram Publications for gene: KCTD15 were set to PMID: 38296633
Paediatric disorders - additional genes v7.18 KCTD15 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCTD15 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Paediatric disorders - additional genes v7.17 KCTD15 Achchuthan Shanmugasundram edited their review of gene: KCTD15: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Paediatric disorders - additional genes v7.17 KCTD15 Achchuthan Shanmugasundram Deleted their comment
Paediatric disorders - additional genes v7.17 KCTD15 Achchuthan Shanmugasundram commented on gene: KCTD15: PMID:38296633 (2024) reported a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in the affected father and daughter via exome sequencing and the variant segregated with the phenotype. A de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was identified via targeted DNA sequencing in a similarly affected sporadic patient.

There is some functional evidence available from structural analyses, which demonstrated that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Paediatric disorders - additional genes v7.17 KCTD15 Achchuthan Shanmugasundram reviewed gene: KCTD15: Rating: AMBER; Mode of pathogenicity: None; Publications: 38296633; Phenotypes: frontonasal dysplasia, MONDO:0016643; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.147 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Branchiootorenal syndrome 2, 610896 to Branchiootorenal syndrome 2, OMIM:610896
Monogenic hearing loss v5.37 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Branchiootorenal syndrome 2, 610896 to Branchiootorenal syndrome 2, OMIM:610896
Deafness and congenital structural abnormalities v1.36 SIX5 Arina Puzriakova Classified gene: SIX5 as Red List (low evidence)
Deafness and congenital structural abnormalities v1.36 SIX5 Arina Puzriakova Added comment: Comment on list classification: This gene-disease association has been rated as 'DISPUTED' by ClinGen (https://search.clinicalgenome.org/CCID:006145) Multiple families reported but reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). Two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668) which are typical of branchio-oto-renal syndrome.

As the evidence for the association of SIX5 with branchio-oto-renal syndrome is disputed, downgraded this gene from Amber to Red.
Deafness and congenital structural abnormalities v1.36 SIX5 Arina Puzriakova Gene: six5 has been classified as Red List (Low Evidence).
Deafness and congenital structural abnormalities v1.35 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Bilateral Microtia; Branchiootorenal syndrome 2 to Branchiootorenal syndrome 2, OMIM:610896
Bilateral congenital or childhood onset cataracts v7.4 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Broanchiootorenal syndrome to Branchiootorenal syndrome 2, OMIM:610896
CAKUT v1.180 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Branchiootorenal syndrome 2, 610896 to Branchiootorenal syndrome 2, OMIM:610896
Unexplained kidney failure in young people v1.122 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from Branchiootorenal syndrome 2, 610896 to Branchiootorenal syndrome 2, OMIM:610896
CAKUT v1.179 SIX5 Arina Puzriakova Classified gene: SIX5 as Red List (low evidence)
CAKUT v1.179 SIX5 Arina Puzriakova Added comment: Comment on list classification: This gene-disease association has been rated as 'DISPUTED' by ClinGen (https://search.clinicalgenome.org/CCID:006145) Multiple families reported but reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). Two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668) which are typical of branchio-oto-renal syndrome.

As the evidence for the association of SIX5 with branchio-oto-renal syndrome is disputed, downgraded this gene from Green to Red.
CAKUT v1.179 SIX5 Arina Puzriakova Gene: six5 has been classified as Red List (Low Evidence).
Unexplained kidney failure in young people v1.121 SIX5 Arina Puzriakova Classified gene: SIX5 as Red List (low evidence)
Unexplained kidney failure in young people v1.121 SIX5 Arina Puzriakova Added comment: Comment on list classification: This gene-disease association has been rated as 'DISPUTED' by ClinGen (https://search.clinicalgenome.org/CCID:006145) Multiple families reported but reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). Two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668) which are typical of branchio-oto-renal syndrome.

As the evidence for the association of SIX5 with branchio-oto-renal syndrome is disputed, downgraded this gene from Green to Red.
Unexplained kidney failure in young people v1.121 SIX5 Arina Puzriakova Gene: six5 has been classified as Red List (Low Evidence).
Fetal anomalies v6.110 SIX5 Arina Puzriakova Classified gene: SIX5 as Green List (high evidence)
Fetal anomalies v6.110 SIX5 Arina Puzriakova Added comment: Comment on list classification: As the evidence for the association of SIX5 with branchio-oto-renal syndrome is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Fetal anomalies v6.110 SIX5 Arina Puzriakova Gene: six5 has been classified as Green List (High Evidence).
Fetal anomalies v6.109 SIX5 Arina Puzriakova reviewed gene: SIX5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v6.109 SIX5 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: SIX5.
Tag disputed tag was added to gene: SIX5.
Tag Q3_25_demote_red tag was added to gene: SIX5.
Fetal anomalies v6.109 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from BRANCHIOOTORENAL SYNDROME TYPE 2 to Branchiootorenal syndrome 2, OMIM:610896
Clefting v6.13 SIX5 Arina Puzriakova Phenotypes for gene: SIX5 were changed from BRANCHIOOTORENAL SYNDROME 2; BOR2 to Branchiootorenal syndrome 2, OMIM:610896
Clefting v6.12 SIX5 Arina Puzriakova Classified gene: SIX5 as Green List (high evidence)
Clefting v6.12 SIX5 Arina Puzriakova Added comment: Comment on list classification: As the evidence for the association of SIX5 with branchio-oto-renal syndrome is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Clefting v6.12 SIX5 Arina Puzriakova Gene: six5 has been classified as Green List (High Evidence).
Clefting v6.11 SIX5 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: SIX5.
Tag disputed tag was added to gene: SIX5.
Tag Q3_25_demote_red tag was added to gene: SIX5.
Clefting v6.11 SIX5 Arina Puzriakova reviewed gene: SIX5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Unexplained young onset end-stage renal disease - additional genes v1.3 SIX5 Arina Puzriakova Classified gene: SIX5 as Green List (high evidence)
Unexplained young onset end-stage renal disease - additional genes v1.3 SIX5 Arina Puzriakova Added comment: Comment on list classification: As the evidence for the association of SIX5 with branchio-oto-renal syndrome is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Unexplained young onset end-stage renal disease - additional genes v1.3 SIX5 Arina Puzriakova Gene: six5 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease - additional genes v1.2 SIX5 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: SIX5.
Tag disputed tag was added to gene: SIX5.
Tag Q3_25_demote_red tag was added to gene: SIX5.
Unexplained young onset end-stage renal disease - additional genes v1.2 SIX5 Arina Puzriakova edited their review of gene: SIX5: Changed rating: RED
Unexplained young onset end-stage renal disease - additional genes v1.2 SIX5 Arina Puzriakova commented on gene: SIX5
Intellectual disability v9.146 LAMC3 Achchuthan Shanmugasundram Classified gene: LAMC3 as Green List (high evidence)
Intellectual disability v9.146 LAMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: The association of monoallelic variants with intellectual disability is disputed by the expert panel in ClinGen. There is no evidence of ID of moderate severity or worse in patients with biallelic variants. The patients only displayed developmental delay or mild ID. Hence, this gene should be demoted from green rating in the next GMS update.
Intellectual disability v9.146 LAMC3 Achchuthan Shanmugasundram Gene: lamc3 has been classified as Green List (High Evidence).
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: LAMC3.
Tag Q3_25_expert_review tag was added to gene: LAMC3.
Tag Q3_25_demote_red tag was added to gene: LAMC3.
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram edited their review of gene: LAMC3: Changed rating: RED; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram edited their review of gene: LAMC3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.145 LAMC3 Achchuthan Shanmugasundram Publications for gene: LAMC3 were set to 21572413; 25529582; 24896178
Intellectual disability v9.144 LAMC3 Achchuthan Shanmugasundram reviewed gene: LAMC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 21572413, 26802095, 29247375, 33639934, 34354730, 38758065; Phenotypes: Cortical malformations, occipital, OMIM:614115, occipital pachygyria and polymicrogyria, MONDO:0013583; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v8.17 TMEM167A Arina Puzriakova Classified gene: TMEM167A as Amber List (moderate evidence)
Severe microcephaly v8.17 TMEM167A Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6 unrelated cases with a concordant phenotype caused by biallelic variants in this gene.
Severe microcephaly v8.17 TMEM167A Arina Puzriakova Gene: tmem167a has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.6 TMEM167A Arina Puzriakova Classified gene: TMEM167A as Amber List (moderate evidence)
Neonatal diabetes v5.6 TMEM167A Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6 unrelated cases with a concordant phenotype caused by biallelic variants in this gene.
Neonatal diabetes v5.6 TMEM167A Arina Puzriakova Gene: tmem167a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.56 TMEM167A Arina Puzriakova Classified gene: TMEM167A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.56 TMEM167A Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6 unrelated cases with a concordant phenotype caused by biallelic variants in this gene.
Early onset or syndromic epilepsy v8.56 TMEM167A Arina Puzriakova Gene: tmem167a has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.5 TMEM167A Arina Puzriakova gene: TMEM167A was added
gene: TMEM167A was added to Neonatal diabetes. Sources: Literature
Q3_25_promote_green tags were added to gene: TMEM167A.
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome, MONDO:0100328
Review for gene: TMEM167A was set to GREEN
Added comment: PMID: 40924476 (2025) - 6 individuals from 6 unrelated families with biallelic variants in the TMEM167A gene identified by WGS. Clinical features in all affected individuals include neonatal diabetes (diagnosed <6 months) and severe microcephaly. 5/6 also had epilepsy in the neonatal period. TMEM167A is highly expressed in the human pancreas and brain. Both the depletion of TMEM167A in EndoC-βH1 cells and knock-in of the p.Val59Glu patient variant in iPSC-derived β cells increased β cells sensitivity to ER stress. The p.Val59Glu variant disrupted proinsulin trafficking to the Golgi and led to dysfunction in iPSC-β cells.
Sources: Literature
Severe microcephaly v8.16 TMEM167A Arina Puzriakova gene: TMEM167A was added
gene: TMEM167A was added to Severe microcephaly. Sources: Literature
Q3_25_promote_green tags were added to gene: TMEM167A.
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome, MONDO:0100328
Review for gene: TMEM167A was set to GREEN
Added comment: PMID: 40924476 (2025) - 6 individuals from 6 unrelated families with biallelic variants in the TMEM167A gene identified by WGS. Clinical features in all affected individuals include neonatal diabetes (diagnosed <6 months) and severe microcephaly. 5/6 also had epilepsy in the neonatal period. TMEM167A is highly expressed in the human pancreas and brain. Both the depletion of TMEM167A in EndoC-βH1 cells and knock-in of the p.Val59Glu patient variant in iPSC-derived β cells increased β cells sensitivity to ER stress. The p.Val59Glu variant disrupted proinsulin trafficking to the Golgi and led to dysfunction in iPSC-β cells.
Sources: Literature
Early onset or syndromic epilepsy v8.55 TMEM167A Arina Puzriakova gene: TMEM167A was added
gene: TMEM167A was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: TMEM167A.
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome, MONDO:0100328
Review for gene: TMEM167A was set to GREEN
Added comment: PMID: 40924476 (2025) - 6 individuals from 6 unrelated families with biallelic variants in the TMEM167A gene identified by WGS. Clinical features in all affected individuals include neonatal diabetes (diagnosed <6 months) and severe microcephaly. 5/6 also had epilepsy in the neonatal period. TMEM167A is highly expressed in the human pancreas and brain. Both the depletion of TMEM167A in EndoC-βH1 cells and knock-in of the p.Val59Glu patient variant in iPSC-derived β cells increased β cells sensitivity to ER stress. The p.Val59Glu variant disrupted proinsulin trafficking to the Golgi and led to dysfunction in iPSC-β cells.
Sources: Literature
Early onset or syndromic epilepsy v8.54 PPOX Arina Puzriakova Phenotypes for gene: PPOX were changed from Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577
Inherited polyposis and early onset colorectal cancer - germline testing v3.8 MSH3 Eleanor Williams Classified gene: MSH3 as Amber List (moderate evidence)
Inherited polyposis and early onset colorectal cancer - germline testing v3.8 MSH3 Eleanor Williams Added comment: Comment on list classification: There are now sufficient cases to promote this gene to green, following GMS review.
Inherited polyposis and early onset colorectal cancer - germline testing v3.8 MSH3 Eleanor Williams Gene: msh3 has been classified as Amber List (Moderate Evidence).
Inherited polyposis and early onset colorectal cancer - germline testing v3.7 MSH3 Eleanor Williams Phenotypes for gene: MSH3 were changed from Familial adenomatous polyposis 4, OMIM:617100 to Familial adenomatous polyposis 4, OMIM:617100; familial adenomatous polyposis 4, MONDO:0044300
Inherited polyposis and early onset colorectal cancer - germline testing v3.6 MSH3 Eleanor Williams Publications for gene: MSH3 were set to 27476653
Inherited polyposis and early onset colorectal cancer - germline testing v3.5 MSH3 Eleanor Williams Tag Q3_25_promote_green tag was added to gene: MSH3.
Inherited polyposis and early onset colorectal cancer - germline testing v3.5 MSH3 Eleanor Williams changed review comment from: In OMIM MSH3 is associated with Endometrial carcinoma, somatic, OMIM:608089 and Familial adenomatous polyposis 4, OMIM:617100 (AR) (accessed 21st October 2025)

MSH3 has a definitive association with familial adenomatous polyposis 4, MONDO:0044300 (last curated May 24, 2024).

As reported by ClinGen, 19 variants (nonsense, frameshift, large deletion, splicing, missense) that have been reported in 10 probands in 6 publications (PMIDs 27476653, 37597744, 35675019, 38243056, 34250384, 37402566). This is also supported by expression studies, in vitro functional assays, and animal models (PMIDs: 18922920, 24013230, 10706084, 27476653).
The mechanism of pathogenicity is known to be loss of function.; to: In OMIM MSH3 is associated with Endometrial carcinoma, somatic, OMIM:608089 and Familial adenomatous polyposis 4, OMIM:617100 (AR) (accessed 21st October 2025)

MSH3 has a definitive association with familial adenomatous polyposis 4, MONDO:0044300 (last curated May 24, 2024).

As reported by ClinGen: 19 variants (nonsense, frameshift, large deletion, splicing, missense) have been reported in 10 probands in 6 publications (PMIDs 27476653, 37597744, 35675019, 38243056, 34250384, 37402566). This is also supported by expression studies, in vitro functional assays, and animal models (PMIDs: 18922920, 24013230, 10706084, 27476653).
The mechanism of pathogenicity is known to be loss of function.
Inherited polyposis and early onset colorectal cancer - germline testing v3.5 MSH3 Eleanor Williams reviewed gene: MSH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27476653, 37597744, 35675019, 38243056, 34250384, 37402566, 18922920, 24013230, 10706084, 27476653; Phenotypes: Familial adenomatous polyposis 4, OMIM:617100, familial adenomatous polyposis 4, MONDO:0044300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.144 MED12L Eleanor Williams changed review comment from: Since the last review additional cases have been reported.
In OMIM this gene is associated with Nizon-Isidor syndrome, OMIM:618872 (AD) - accessed 21st October 2025
In ClinGen the gene has a definitive rating with Nizon-Isidor syndrome, MONDO:0030030

There are now 3 more reports of plausable pathogenic variants in this gene in patients with an intellectual disability phenotype. 2 cases with de novo variants and 1 with a maternally inherited variant.

PMID: 36212160 - Park et al 2022 - WES to analyse 1,180 Korean patients with neurological symptoms. 1 individual with a de novo variant c.1895C>T; p.Ser632Leu in MED12L and a phenotype of global developmental delay and facial dysmorphism.

PMID: 35920825 - Ferraz et al 2022 - a male proband with a confirmed de novo germline frameshift variant in MED12L (NM_053002.6 (MED12L_v001):c.971del;p.(pro324Glnfs∗18)) identified by WES. The clinical phenotype included mild motor and speech delay, oligodontia, and dysmorphic signs. Of note the patient also carried 2 de novo chromosomal balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),t(5;9)(p15;q21) and the authors note that Nizon et al. 2019 report a patient with a balanced reciprocal translocation suggesting that the MED12L loss-of-function variant may contribute to chromosomal instability.

PMID: 40957966 - Dutta et al 2025 - report a proband with likely pathogenic MED12L nonsense variant (p.Arg1210Ter) which is maternally inherited (father also sequenced). At 2.5 yo the proband was diagnosed with global developmental delay, absent speech, ASD, hyperactivity, exophoria and myopia. Developmental regression began between 18 - 24 months. She has frequent respiratory infections. The 19 yo mother has a clinical history which includes speech delay and learning disability, but features are much milder than the proband. The proband also has inherited a pathogenic GAMT variant from her mother and a pathogenic TNFRSF13B variant from her father but these are not thought to contribute to the ID phenotype.; to: Since the last review additional cases have been reported.
In OMIM this gene is associated with Nizon-Isidor syndrome, OMIM:618872 (AD) - accessed 21st October 2025
In ClinGen the gene has a definitive rating with Nizon-Isidor syndrome, MONDO:0030030 (last curated November 19th, 2024)

There are now 3 more reports of plausable pathogenic variants in this gene in patients with an intellectual disability phenotype. 2 cases with de novo variants and 1 with a maternally inherited variant.

PMID: 36212160 - Park et al 2022 - WES to analyse 1,180 Korean patients with neurological symptoms. 1 individual with a de novo variant c.1895C>T; p.Ser632Leu in MED12L and a phenotype of global developmental delay and facial dysmorphism.

PMID: 35920825 - Ferraz et al 2022 - a male proband with a confirmed de novo germline frameshift variant in MED12L (NM_053002.6 (MED12L_v001):c.971del;p.(pro324Glnfs∗18)) identified by WES. The clinical phenotype included mild motor and speech delay, oligodontia, and dysmorphic signs. Of note the patient also carried 2 de novo chromosomal balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),t(5;9)(p15;q21) and the authors note that Nizon et al. 2019 report a patient with a balanced reciprocal translocation suggesting that the MED12L loss-of-function variant may contribute to chromosomal instability.

PMID: 40957966 - Dutta et al 2025 - report a proband with likely pathogenic MED12L nonsense variant (p.Arg1210Ter) which is maternally inherited (father also sequenced). At 2.5 yo the proband was diagnosed with global developmental delay, absent speech, ASD, hyperactivity, exophoria and myopia. Developmental regression began between 18 - 24 months. She has frequent respiratory infections. The 19 yo mother has a clinical history which includes speech delay and learning disability, but features are much milder than the proband. The proband also has inherited a pathogenic GAMT variant from her mother and a pathogenic TNFRSF13B variant from her father but these are not thought to contribute to the ID phenotype.
Intellectual disability v9.144 MED12L Eleanor Williams Classified gene: MED12L as Amber List (moderate evidence)
Intellectual disability v9.144 MED12L Eleanor Williams Added comment: Comment on list classification: There is now sufficient evidence for this gene to be promoted to green following GMS review.
Intellectual disability v9.144 MED12L Eleanor Williams Gene: med12l has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.143 MED12L Eleanor Williams Tag Q3_25_promote_green tag was added to gene: MED12L.
Intellectual disability v9.143 MED12L Eleanor Williams Phenotypes for gene: MED12L were changed from Motor delay; Delayed speech and language development; Intellectual disability; Behavioral abnormality; Abnormality of the abdomen; Seizures; Abnormality of the corpus callosum to Nizon-Isidor syndrome, OMIM:618872; Nizon-Isidor syndrome, MONDO:0030030
Intellectual disability v9.142 MED12L Eleanor Williams Publications for gene: MED12L were set to 31155615
Intellectual disability v9.141 MED12L Eleanor Williams edited their review of gene: MED12L: Added comment: Since the last review additional cases have been reported.
In OMIM this gene is associated with Nizon-Isidor syndrome, OMIM:618872 (AD) - accessed 21st October 2025
In ClinGen the gene has a definitive rating with Nizon-Isidor syndrome, MONDO:0030030

There are now 3 more reports of plausable pathogenic variants in this gene in patients with an intellectual disability phenotype. 2 cases with de novo variants and 1 with a maternally inherited variant.

PMID: 36212160 - Park et al 2022 - WES to analyse 1,180 Korean patients with neurological symptoms. 1 individual with a de novo variant c.1895C>T; p.Ser632Leu in MED12L and a phenotype of global developmental delay and facial dysmorphism.

PMID: 35920825 - Ferraz et al 2022 - a male proband with a confirmed de novo germline frameshift variant in MED12L (NM_053002.6 (MED12L_v001):c.971del;p.(pro324Glnfs∗18)) identified by WES. The clinical phenotype included mild motor and speech delay, oligodontia, and dysmorphic signs. Of note the patient also carried 2 de novo chromosomal balanced reciprocal translocations: 46,XY,t(1;2)(p33;p22),t(5;9)(p15;q21) and the authors note that Nizon et al. 2019 report a patient with a balanced reciprocal translocation suggesting that the MED12L loss-of-function variant may contribute to chromosomal instability.

PMID: 40957966 - Dutta et al 2025 - report a proband with likely pathogenic MED12L nonsense variant (p.Arg1210Ter) which is maternally inherited (father also sequenced). At 2.5 yo the proband was diagnosed with global developmental delay, absent speech, ASD, hyperactivity, exophoria and myopia. Developmental regression began between 18 - 24 months. She has frequent respiratory infections. The 19 yo mother has a clinical history which includes speech delay and learning disability, but features are much milder than the proband. The proband also has inherited a pathogenic GAMT variant from her mother and a pathogenic TNFRSF13B variant from her father but these are not thought to contribute to the ID phenotype.; Changed rating: GREEN; Changed publications to: 31155615, 36212160, 35920825, 40957966; Changed phenotypes to: Nizon-Isidor syndrome, OMIM:618872, Nizon-Isidor syndrome, MONDO:0030030; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurological ciliopathies v6.7 KIAA0556 Eleanor Williams Classified gene: KIAA0556 as Amber List (moderate evidence)
Neurological ciliopathies v6.7 KIAA0556 Eleanor Williams Added comment: Comment on list classification: This gene is recommended for green rating following GMS review since there is a distinct brain phenotype in 4 families in which there are biallelic variants.
Neurological ciliopathies v6.7 KIAA0556 Eleanor Williams Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.; to: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska edited their review of gene: PPOX: Added comment: Comment on list classification: There are at least 4 unrelated individuals with biallelic variants in PPOX that presented with early onset (2-6 months after birth), syndromic epilepsy. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; Changed publications to: 8290408, 9811936, 2004012, 30861571, 35164799, 37879139, 40114189
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
2 siblings with
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
2 siblings with
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
Possible mitochondrial disorder - nuclear genes v4.15 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on the available evidence, this gene should remain Green for Possible mitochondrial disorder - nuclear genes. The mode of inheritance should be set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on the available evidence, this gene should remain Green for Possible mitochondrial disorder - nuclear genes. The mode of inheritance should be set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed phenotypes to: Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, childhood-onset, MONDO:0957577
Possible mitochondrial disorder - nuclear genes v4.15 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed phenotypes to: Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, childhood-onset, MONDO:0957577, Variegate porphyria, OMIM:176200, variegate porphyria, MONDO:0008297
Possible mitochondrial disorder - nuclear genes v4.15 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed phenotypes to: Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, childhood-onset, MONDO:0957577
Neurological ciliopathies v6.6 KIAA0556 Eleanor Williams Phenotypes for gene: KIAA0556 were changed from ?Joubert syndrome 26 to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Neurological ciliopathies v6.5 KIAA0556 Eleanor Williams Publications for gene: KIAA0556 were set to
Neurological ciliopathies v6.4 KIAA0556 Eleanor Williams Classified gene: KIAA0556 as Amber List (moderate evidence)
Neurological ciliopathies v6.4 KIAA0556 Eleanor Williams Gene: kiaa0556 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.3 KIAA0556 Eleanor Williams Tag Q3_25_promote_green tag was added to gene: KIAA0556.
Neurological ciliopathies v6.3 KIAA0556 Eleanor Williams edited their review of gene: KIAA0556: Changed publications to: 26714646, 27245168, 31197031, 31197031, 36580738, 40725402, 40428346, 32164589, 30982090
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska Classified gene: PPOX as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska Gene: ppox has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.52 PPOX Ida Ertmanska Mode of inheritance for gene: PPOX was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.52 PPOX Ida Ertmanska Classified gene: PPOX as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.52 PPOX Ida Ertmanska Gene: ppox has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.3 KIAA0556 Eleanor Williams reviewed gene: KIAA0556: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 26, OMIM:616784, Joubert syndrome 26, MONDO:0014771; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.51 PPOX Ida Ertmanska Publications for gene: PPOX were updated from to 8290408; 9811936; 2004012; 35164799; 37879139; 40114189
Tag Q3_25_promote_green tag was added to PPOX.
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed publications to: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska changed review comment from: Sources: Other; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska gene: PPOX was added
gene: PPOX was added to Early onset or syndromic epilepsy. Sources: Other
Mode of inheritance for gene: PPOX was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PPOX were set to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Review for gene: PPOX was set to GREEN
Added comment: Sources: Other
Possible mitochondrial disorder - nuclear genes v4.15 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on the available evidence, this gene should remain Green for Possible mitochondrial disorder - nuclear genes.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on the available evidence, this gene should remain Green for Possible mitochondrial disorder - nuclear genes. The mode of inheritance should be set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Possible mitochondrial disorder - nuclear genes v4.15 PPOX Ida Ertmanska Deleted their comment
Hereditary neuropathy or pain disorder v7.21 CPOX Ida Ertmanska Phenotypes for gene: CPOX were changed from Coproporphyria, 121300; Harderoporphyria, 121300; Skin photosensitivity and haemolytic anaemia. Can present acutely similar to AIP to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Publications for gene: CPOX were updated from to 8008008; 11074238; 11309681; 21103937; 24353603; 24156084; 35228944; 35584894; 38940544
Hereditary neuropathy v1.501 CPOX Ida Ertmanska Phenotypes for gene: CPOX were changed from Coproporphyria, 121300; Harderoporphyria, 121300; Skin photosensitivity and haemolytic anaemia. Can present acutely similar to AIP to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Publications for gene: CPOX were updated from to 8008008; 11074238; 11309681; 21103937; 24353603; 24156084; 35228944; 35584894; 38940544
Hereditary neuropathy v1.500 CPOX Ida Ertmanska edited their review of gene: CPOX: Added comment: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - only 1 individual with peripheral neuropathy and a heterozygous CPOX variant is included in this review (PMID: 35228944 Upchurch et al., 2025). Biochemical testing of faecal coproporphyrin is a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.500 CPOX Ida Ertmanska reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 8008008, 11074238, 11309681, 21103937, 24353603, 24156084, 35228944, 35584894, 38940544; Phenotypes: Coproporphyria, OMIM:121300, Harderoporphyria, OMIM:618892; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed publications to: 8008008, 11074238, 11309681, 21103937, 24353603, 24156084, 35228944, 35584894, 38940544
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - only 1 individual with peripheral neuropathy and a heterozygous CPOX variant is included in this review (PMID: 35228944 Upchurch et al., 2025). Biochemical testing of faecal coproporphyrin is a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 8008008 Barohn et al. 1994
A 23-year-old man with no genetic diagnosis. Presented with epilepsy and a past history of abdominal pain. Electrophysiologic studies demonstrated a peripheral neuropathy with features of axonal degeneration and demyelination.

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 24353603 Chen et al., 2013
46yo Chinese woman with a biochemical diagnosis of HCP. Phenotype: acute abdominal pain and progressive bilateral weakness and pain in the limbs. She also experienced significant muscle atrophy and decreased strength. Nerve conduction potential study revealed motor-sensory polyneuropathy. Successfully treated with hemin.

PMID: 24156084 Jiménez-Jiménez et al., 2013
44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCP. Heterozygous for p.Q306X.

PMID: 35228944 Upchurch et al., 2025
26-year-old female with HCP who presented with acute ascending flaccid paralysis and respiratory failure after COVID-19 infection and was initially misdiagnosed and treated for Guillain-Barré syndrome. Patient developed progressively worsening abdominal pain; symmetric, distal-predominant, and ascending weakness developed four weeks later, associated with severe headaches and complex visual hallucinosis. Electrodiagnostic testing: profound axonal sensorimotor peripheral polyneuropathy affecting all extremities. No abnormalities on brain MRI. Successfully treated with hemin. Heterozygous for c.1070G>A (p.Cys357Tyr) - rare in gnomAD v4, Revel score = 0.9. Seq method: unknown.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed publications to: 11074238, 11309681, 21103937, 35584894, 38940544
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are not reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed publications to: 11074238, 11309681, 35584894, 38940544
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska commented on gene: CPOX: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are not reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coproporphyria, OMIM:121300, Harderoporphyria, OMIM:618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Retinal disorders v8.56 MCDR3 Ida Ertmanska changed review comment from: While there is emerging evidence linking duplications at the MCDR3 locus and macular dystrophy, PanelApp panels may only include regions curated in ClinGen with sufficient evidence of dosage sensitivity. As this region in not included in ClinGen, we are unable to add it at this time.; to: Comment on list classification: While there is emerging evidence linking duplications at the MCDR3 locus and macular dystrophy, PanelApp panels may only include regions curated in ClinGen with sufficient evidence of dosage sensitivity. As this region in not included in ClinGen, we are unable to add it at this time.
Retinal disorders v8.56 MCDR3 Ida Ertmanska Source Literature was removed from Region: MCDR3.
Source NHS GMS was added to Region: MCDR3.
Phenotypes for Region: MCDR3 were changed from Macular Dystrophy to Macular dystrophy, retinal, 3, OMIM:608850
Tag curated_removed was added to Region: MCDR3.
Retinal disorders v8.55 MCDR3 Ida Ertmanska reviewed Region: MCDR3: Rating: ; Mode of pathogenicity: None; Publications: 28790370; Phenotypes: Macular dystrophy, retinal, 3, OMIM:608850; Mode of inheritance: None
Proteinuric renal disease v5.6 CD2AP Ida Ertmanska Mode of inheritance for gene CD2AP was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CD2AP were updated from 10514378; 12764198; 17713465; 30348286; 30612599; 34408996; 36964972 to 10514378; 12764198; 17713465; 19131354; 25501161; 26997877; 30348286; 30612599; 34408996; 36964972
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). Several reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed (PMIDs:19131354; 26997877) . However, there are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP that are sufficiently rare (12764198; 19131354; 34408996). This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
; to: Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). Several reported heterozygous variants have high allele frequencies in the general population, including in homozygosity, and their pathogenicity is disputed (PMIDs:19131354; 26997877) . However, there are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP that are sufficiently rare (12764198; 19131354; 34408996). This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). Several reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed. However, there are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP that are sufficiently rare. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
; to: Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). Several reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed (PMIDs:19131354; 26997877) . However, there are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP that are sufficiently rare (12764198; 19131354; 34408996). This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP. Several other reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
; to: Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). Several reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed. However, there are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP that are sufficiently rare. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP. Several other reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
; to: Comment on list classification: There are at least 4 unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP. Several other reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.; to: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP. Several other reported heterozygous variants have high allele frequencies in the general population and their pathogenicity is disputed. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes; not likely to be disease causing.
c.1120A>G, (p.Thr374Ala) - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes; not likely to be disease causing.
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 25501161 Feng et al., 2014
Patient 2- presented nephrotic syndrome at 8yo - steroid resistant. Renal biopsy showed MCNS; heterozygous for a CD2AP mutation, IVS7-135G>A (intron 7).
Patient 25 - FSGS onset at 4.5yrs - steroid resistant; went into remission after receiving cyclosporin A. Het for IVS13-137G>A (intron 13).
Method: sequenced NPHS1, NPHS2, CD2AP, and WT1 only.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. PCR sequencing of CD2AP only. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes; not likely to be disease causing.
c.1120A>G, (p.Thr374Ala) - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes; not likely to be disease causing.
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 25501161 Feng et al., 2014
Patient 2- presented nephrotic syndrome at 8yo - steroid resistant. Renal biopsy showed MCNS; heterozygous for a CD2AP mutation, IVS7-135G>A (intron 7).
Patient 25 - FSGS onset at 4.5yrs - steroid resistant; went into remission after receiving cyclosporin A. Het for IVS13-137G>A (intron 13).
Method: sequenced NPHS1, NPHS2, CD2AP, and WT1 only.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.; to: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least 3 unrelated individuals reported with FSGS and heterozygous variants in CD2AP. This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, (p.Thr374Ala) - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes;
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 25501161 Feng et al., 2014
Patient 2- presented nephrotic syndrome at 8yo - steroid resistant. Renal biopsy showed MCNS; heterozygous for a CD2AP mutation, IVS7-135G>A (intron 7).
Patient 25 - FSGS onset at 4.5yrs - steroid resistant; went into remission after receiving cyclosporin A. Het for IVS13-137G>A (intron 13).
Method: sequenced NPHS1, NPHS2, CD2AP, and WT1 only.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes; not likely to be disease causing.
c.1120A>G, (p.Thr374Ala) - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes; not likely to be disease causing.
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 25501161 Feng et al., 2014
Patient 2- presented nephrotic syndrome at 8yo - steroid resistant. Renal biopsy showed MCNS; heterozygous for a CD2AP mutation, IVS7-135G>A (intron 7).
Patient 25 - FSGS onset at 4.5yrs - steroid resistant; went into remission after receiving cyclosporin A. Het for IVS13-137G>A (intron 13).
Method: sequenced NPHS1, NPHS2, CD2AP, and WT1 only.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.; to: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). There are at least This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska edited their review of gene: CD2AP: Changed publications to: 10514378, 12764198, 17713465, 19131354, 25501161, 26997877, 30348286, 30612599, 34408996, 36964972; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, p.Thr374Ala - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes;
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, (p.Thr374Ala) - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes;
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 25501161 Feng et al., 2014
Patient 2- presented nephrotic syndrome at 8yo - steroid resistant. Renal biopsy showed MCNS; heterozygous for a CD2AP mutation, IVS7-135G>A (intron 7).
Patient 25 - FSGS onset at 4.5yrs - steroid resistant; went into remission after receiving cyclosporin A. Het for IVS13-137G>A (intron 13).
Method: sequenced NPHS1, NPHS2, CD2AP, and WT1 only.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Early onset or syndromic epilepsy v8.49 LAMC3 Achchuthan Shanmugasundram Classified gene: LAMC3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.49 LAMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (six unrelated cases) for the association of biallelic LAMC3 variants with seizures. Hence, this gene should be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.49 LAMC3 Achchuthan Shanmugasundram Gene: lamc3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.48 LAMC3 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LAMC3.
Early onset or syndromic epilepsy v8.48 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. Childhood-onset seizures is the most common clinical manifestation that is reported in all patients except the foetal case.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene has also been rated green on the epilepsy panel in PanelApp Australia. Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Sources: Literature; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. Childhood-onset seizures is the most common clinical manifestation that is reported in all patients except the foetal case.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene has also been rated green with biallelic MOI on Genetic epilepsy panel in PanelApp Australia (https://panelapp-aus.org/panels/202/gene/LAMC3/). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Sources: Literature
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, p.Thr374Ala - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes;
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, p.Thr374Ala - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes;
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:
In addition, two heterozygous variants (c.730-1_730delinsCT and c.1734dup, (p.Lys579GlufsTer7)) have been reported in 2 unrelated probands (PMIDs: 12764198, 34408996).

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, p.Thr374Ala - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:

PMID: 12764198 Kim et al 2003
Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. Variant c.730-1_730delinsCT was found in 2 patients with primary FSGS; CD2AP protein levels were lower in these patients. Variant not present in gnomAD v4. CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria.

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, p.Thr374Ala - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes;
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

PMID: 34408996 Liu et al., 2021
Chinese family of four generations with unexplained proteinuria. The proband IV-1, a 12-year-old boy, had steroid resistant high proteinuria (2+). He was reported as heterozygous for c.1734_1735insG, p.Lys579Glufs*7 in CD2AP - AF in gnomAD v4: 6.198e-7. Seq method: WES. Variant shown to segregate with disease in this family. 10 other possibly pathogenic variants detected but not associated with kidney disease.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Early onset or syndromic epilepsy v8.48 LAMC3 Achchuthan Shanmugasundram gene: LAMC3 was added
gene: LAMC3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: LAMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMC3 were set to 21572413; 26802095; 29247375; 33639934; 34354730
Phenotypes for gene: LAMC3 were set to Cortical malformations, occipital, OMIM:614115; occipital pachygyria and polymicrogyria, MONDO:0013583
Review for gene: LAMC3 was set to GREEN
Added comment: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. Childhood-onset seizures is the most common clinical manifestation that is reported in all patients except the foetal case.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene has also been rated green on the epilepsy panel in PanelApp Australia. Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Sources: Literature
Proteinuric renal disease v5.5 CD2AP Ida Ertmanska changed review comment from: Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

In addition, two heterozygous variants (c.730-1_730delinsCT and c.1734dup, (p.Lys579GlufsTer7)) have been reported in 2 unrelated probands (PMIDs: 12764198, 34408996). More evidence is required to support the autosomal dominant mode of inheritance.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Biallelic cases:
Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

Monoallelic cases:
In addition, two heterozygous variants (c.730-1_730delinsCT and c.1734dup, (p.Lys579GlufsTer7)) have been reported in 2 unrelated probands (PMIDs: 12764198, 34408996).

PMID: 19131354 Gigante et al., 2009
3 unrelated Italian patients with idiopathic nephrotic syndrome, heterozygous for one mutation each:
c.902A>T, (p.Lys301Met) - total AF in gnomAD v.4 = 0.0001904 including 5 homozygotes;
c.1120A>G, p.Thr374Ala - total AF in gnomAD v.4 = 0.005488 including 48 homozygotes
c.1569AGA[2] (p.Glu525del) - total AF in gnomD v.4 = 0.0003639, no homozygotes reported.

PMID: 26997877 Tsvetkov et al., 2016
Male patient, German ancestry, presented with a nephrotic syndrome (proteinuria >3.5 g/day) at 28yo; kidney biopsy confirmed FSGS diagnosis; heterozygous for c.1120A>G, p.(Thr374Ala) in CD2AP - variant too common in population to cause disease. Mother and brother also have kidney disease, not genotyped. Seq method: sequencing of exons only of the following genes: TRPC6, ACTN4, WT1, CD2AP, and INF2.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Fetal anomalies v6.108 LAMC3 Achchuthan Shanmugasundram Publications for gene: LAMC3 were set to 30266093
Fetal anomalies v6.107 LAMC3 Achchuthan Shanmugasundram reviewed gene: LAMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21572413, 26802095, 29247375, 30266093, 33639934, 34354730; Phenotypes: Cortical malformations, occipital, OMIM:614115, occipital pachygyria and polymicrogyria, MONDO:0013583; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.141 LAMC3 Eleanor Williams Publications for gene: LAMC3 were set to
Intellectual disability v9.140 LAMC3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 21st October 2025
Intellectual disability v9.140 LAMC3 Eleanor Williams Phenotypes for gene: LAMC3 were changed from Cortical malformations, occipital, 614115; OCCIPITAL CORTICAL MALFORMATIONS to Cortical malformations, occipital, OMIM:614115; occipital pachygyria and polymicrogyria, MONDO:0013583
Fetal anomalies v6.107 LAMC3 Eleanor Williams Publications for gene: LAMC3 were set to
Fetal anomalies v6.106 LAMC3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 21st October 2025
Fetal anomalies v6.106 LAMC3 Eleanor Williams Phenotypes for gene: LAMC3 were changed from OCCIPITAL CORTICAL MALFORMATIONS to Cortical malformations, occipital, OMIM:614115; occipital pachygyria and polymicrogyria, MONDO:0013583
Monogenic hearing loss v5.36 RIPOR2 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotypes accessed on 21st October 2025
Monogenic hearing loss v5.36 RIPOR2 Eleanor Williams Phenotypes for gene: RIPOR2 were changed from Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515 to Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515
Malformations of cortical development v7.10 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265).

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265).

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).

This gene should therefore remain green with Biallelic MOI on this panel.
Malformations of cortical development v7.10 LAMC3 Achchuthan Shanmugasundram Publications for gene: LAMC3 were set to 21572413
Malformations of cortical development v7.9 LAMC3 Achchuthan Shanmugasundram Phenotypes for gene: LAMC3 were changed from Cortical malformations, occipital 614115 to Cortical malformations, occipital, OMIM:614115; occipital pachygyria and polymicrogyria, MONDO:0013583
Malformations of cortical development v7.8 LAMC3 Achchuthan Shanmugasundram Deleted their comment
Malformations of cortical development v7.8 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265).
This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265).

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Malformations of cortical development v7.8 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265). This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265).
This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Malformations of cortical development v7.8 LAMC3 Achchuthan Shanmugasundram commented on gene: LAMC3: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265). This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Malformations of cortical development v7.8 LAMC3 Achchuthan Shanmugasundram reviewed gene: LAMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21572413, 26802095, 29247375, 33639934, 34354730; Phenotypes: Cortical malformations, occipital, OMIM:614115, occipital pachygyria and polymicrogyria, MONDO:0013583; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.35 RIPOR2 Arina Puzriakova changed review comment from: PMID: 37864412 - a distinct homozygous LOF variant (c.1561C>T (p.Arg521*)) in exon 14 of the RIPOR2 gene was identified by WES in three siblings from a consanguineous Tunisian family with non-syndromic bilateral profound hearing and vestibular dysfunctions. Parents were unaffected heterozygous carriers. No other variants in hearing loss genes were found. Zebrafish model with a stop codon inserted within ripor2 exon 14 showed that F2 larva did not exhibit a different hearing or balance behaviour compared to wild-type.; to: PMID: 37864412 (2023) - a distinct homozygous LOF variant (c.1561C>T (p.Arg521*)) in exon 14 of the RIPOR2 gene was identified by WES in three siblings from a consanguineous Tunisian family with non-syndromic bilateral profound hearing and vestibular dysfunctions. Parents were unaffected heterozygous carriers. No other variants in hearing loss genes were found. Zebrafish model with a stop codon inserted within ripor2 exon 14 showed that F2 larva did not exhibit a different hearing or balance behaviour compared to wild-type.
Monogenic hearing loss v5.35 RIPOR2 Arina Puzriakova Tag watchlist tag was added to gene: RIPOR2.
Monogenic hearing loss v5.35 RIPOR2 Arina Puzriakova Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v5.34 RIPOR2 Arina Puzriakova Classified gene: RIPOR2 as Amber List (moderate evidence)
Monogenic hearing loss v5.34 RIPOR2 Arina Puzriakova Added comment: Comment on list classification: There are now 2 unrelated consanguineous families with biallelic variants and 12 families with the same monoallelic founder variant in this gene linked to hearing loss (PMIDs: 24958875; 32631815; 37864412). The presence of unaffected carriers calls into question the penetrance of heterozygous variants. Animal studies have yielded variable results.

ClinGen have classified the association with autosomal recessive nonsyndromic genetic hearing loss as Strong, and autosomal dominant nonsyndromic hearing loss as Limited (both last assessed on 15-05-2024).

Overall the evidence is still borderline and therefore this gene should remain Amber.
Monogenic hearing loss v5.34 RIPOR2 Arina Puzriakova Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.33 RIPOR2 Arina Puzriakova edited their review of gene: RIPOR2: Changed rating: AMBER
Monogenic hearing loss v5.33 RIPOR2 Arina Puzriakova edited their review of gene: RIPOR2: Changed publications to: 24958875, 32631815, 37864412; Changed phenotypes to: Deafness, autosomal dominant 21, OMIM:607017, Deafness, autosomal recessive 104, OMIM:616515; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v5.33 RIPOR2 Arina Puzriakova edited their review of gene: RIPOR2: Added comment: PMID: 37864412 - a distinct homozygous LOF variant (c.1561C>T (p.Arg521*)) in exon 14 of the RIPOR2 gene was identified by WES in three siblings from a consanguineous Tunisian family with non-syndromic bilateral profound hearing and vestibular dysfunctions. Parents were unaffected heterozygous carriers. No other variants in hearing loss genes were found. Zebrafish model with a stop codon inserted within ripor2 exon 14 showed that F2 larva did not exhibit a different hearing or balance behaviour compared to wild-type.; Changed phenotypes to: Deafness, autosomal recessive 104, OMIM:616515
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotypes accessed on 20th October 2025
Cutaneous photosensitivity with a likely genetic cause v3.13 CPOX Eleanor Williams Phenotypes for gene: CPOX were changed from Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892 to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Fetal anomalies v6.105 PTBP1 Arina Puzriakova edited their review of gene: PTBP1: Changed rating: GREEN; Changed publications to: 40965981; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.139 PTBP1 Arina Puzriakova edited their review of gene: PTBP1: Changed publications to: 40965981; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v8.20 PTBP1 Arina Puzriakova edited their review of gene: PTBP1: Changed rating: GREEN; Changed publications to: 40965981; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.139 PTBP1 Arina Puzriakova edited their review of gene: PTBP1: Changed rating: GREEN
Intellectual disability v9.139 PTBP1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

Skeletal anomalies were seen in 24 (89%), with the most prominent abnormalities comprising shortening and dysplasia of long bones and phalanges. Radiographic features included brachymetacarpia, brachymetatarsia, brachydactyly, brachytelephalangy, brachymesophalangy, and rhizomelia. Advanced bone maturation, cone-shaped epiphyses, and other features such as vertebral dysplasia were also observed.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

DD was noted in 78%, behavioural problems in 30%, and ID in 26%, generally mild to moderate. Although ID is only seen in a subset of cases, inclusion on this panel would be beneficial in cases where other features such as skeletal abnormalities are less prominent or non existent. Inclusion on this panel would also ensure inclusion on the Hypotonic infant super panel which is plausibly relevant to younger patients with this condition.
Fetal anomalies v6.105 PTBP1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

Skeletal anomalies were seen in 24 (89%), with the most prominent abnormalities comprising shortening and dysplasia of long bones and phalanges. Radiographic features included brachymetacarpia, brachymetatarsia, brachydactyly, brachytelephalangy, brachymesophalangy, and rhizomelia. Advanced bone maturation, cone-shaped epiphyses, and other features such as vertebral dysplasia were also observed.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

Prenatal ultrasound was abnormal in thirteen (48%), revealing short femora (5/13, 38%), IUGR (31%), hydramnios (2/13, 15%), increased nuchal translucency (15%), asymmetry of heart cavities (1/13, 8%), and bilateral hydronephrosis (8%). It led to the diagnosis of skeletal dysplasia in two.
Intellectual disability v9.139 PTBP1 Arina Puzriakova Tag Q3_25_NHS_review was removed from gene: PTBP1.
Fetal anomalies v6.105 PTBP1 Arina Puzriakova Tag Q3_25_NHS_review was removed from gene: PTBP1.
Fetal anomalies v6.105 PTBP1 Arina Puzriakova Entity copied from Skeletal dysplasia v8.20
Fetal anomalies v6.105 PTBP1 Arina Puzriakova gene: PTBP1 was added
gene: PTBP1 was added to Fetal anomalies. Sources: Literature,Expert Review Amber,NHS GMS
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: PTBP1.
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to 40965981
Phenotypes for gene: PTBP1 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: PTBP1 were set to unknown
Intellectual disability v9.139 PTBP1 Arina Puzriakova Entity copied from Skeletal dysplasia v8.20
Intellectual disability v9.139 PTBP1 Arina Puzriakova gene: PTBP1 was added
gene: PTBP1 was added to Intellectual disability. Sources: Literature,Expert Review Amber,NHS GMS
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: PTBP1.
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to 40965981
Phenotypes for gene: PTBP1 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: PTBP1 were set to unknown
Skeletal dysplasia v8.20 PTBP1 Arina Puzriakova Classified gene: PTBP1 as Amber List (moderate evidence)
Skeletal dysplasia v8.20 PTBP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update based on 27 individuals from 25 families identified in PMID: 40965981 with start-loss (89%) or missense (11%) variants, confirmed de novo in 23/27 (plus 2 sibs with variant inherited from symptomatic mother, and segregation data unavailable in 2 others).

Skeletal anomalies were seen in 24 (89%), with the most prominent abnormalities comprising shortening and dysplasia of long bones and phalanges. Radiographic features included brachymetacarpia, brachymetatarsia, brachydactyly, brachytelephalangy, brachymesophalangy, and rhizomelia. Advanced bone maturation, cone-shaped epiphyses, and other features such as vertebral dysplasia were also observed.
Skeletal dysplasia v8.20 PTBP1 Arina Puzriakova Gene: ptbp1 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v5.5 CD2AP Eleanor Williams changed review comment from: Associated with Glomerulosclerosis, focal segmental, 3 #607832 in OMIM (no inheritance given)

Mouse knockout model supports renal involvement. 2 cases with heterozgous variants and FSGS but only CD2AP looked at. Two familial cases of homozygous variants (in one only CD2AP screened) and FSGS.

PMID: 10514378 - Shih et al 1999 - In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells.

PMID: 12764198 - Kim et al 2003 - CD2AP+/- showed glomerular abnormalities at 9 months of age but not proteinuria. Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. One variant, predicted to affect the splice acceptor of exon 7 in one allele, was found in 2 patients with primary FSGS and expression of the protein was lower in these patients.

PMID:17713465 - Löwik et al 2007 - report a homozygous variant in a proband with primary Focal segmental glomerulosclerosis, from a consanguineous family of Mediterranean ancestry. A homozygous c1834 C>T (R612Stop) variant was found. Both parents were proven to be heterozygous for this mutation. An immunoblot shows no CD2AP expression in the patient carrying the R612Stop mutation homozygously

PMID: 30612599 - Takano et al 2019 - Using WES, they identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease. When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure. (Abstract only accessed).; to: Associated with Glomerulosclerosis, focal segmental, 3 #607832 in OMIM (no inheritance given)

Mouse knockout model supports renal involvement. 2 cases with heterozgous variants and FSGS but only CD2AP looked at. Two familial cases of homozygous variants (in one only CD2AP screened) and FSGS.

PMID: 10514378 - Shih et al 1999 - In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells.

PMID: 12764198 - Kim et al 2003 - CD2AP+/- mice showed glomerular abnormalities at 9 months of age but not proteinuria. Screened 30 African-Americans with idiopathic FSGS and 15 African-Americans with HIV-associated FSGS for changes in CD2AP. One variant, predicted to affect the splice acceptor of exon 7 in one allele, was found in 2 patients with primary FSGS and expression of the protein was lower in these patients.

PMID:17713465 - Löwik et al 2007 - report a homozygous variant in a proband with primary Focal segmental glomerulosclerosis, from a consanguineous family of Mediterranean ancestry. A homozygous c1834 C>T (R612Stop) variant was found. Both parents were proven to be heterozygous for this mutation. An immunoblot shows no CD2AP expression in the patient carrying the R612Stop mutation homozygously

PMID: 30612599 - Takano et al 2019 - Using WES, they identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease. When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure. (Abstract only accessed).
Proteinuric renal disease v5.5 CD2AP Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 21st October 2025
Proteinuric renal disease v5.5 CD2AP Eleanor Williams Phenotypes for gene: CD2AP were changed from Glomerulosclerosis, focal segmental, 3, OMIM:607832; focal segmental glomerulosclerosis 3, susceptibility to, MONDO:0011917 to Glomerulosclerosis, focal segmental, 3, OMIM:607832; focal segmental glomerulosclerosis 3, susceptibility to, MONDO:0011917
Skeletal dysplasia v8.19 PTBP1 Arina Puzriakova Phenotypes for gene: PTBP1 were changed from to Neurodevelopmental disorder, MONDO:0700092
Skeletal dysplasia v8.18 PTBP1 Arina Puzriakova Publications for gene: PTBP1 were set to PMID:40965981
Skeletal dysplasia v8.17 PTBP1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PTBP1.
Tag Q3_25_NHS_review tag was added to gene: PTBP1.
Proteinuric renal disease v5.4 CD2AP Ida Ertmanska Phenotypes for gene: CD2AP were changed from Glomerulosclerosis, focal segmental, 3 #607832 to Glomerulosclerosis, focal segmental, 3, OMIM:607832; focal segmental glomerulosclerosis 3, susceptibility to, MONDO:0011917
Publications for gene: CD2AP were updated from 12764198; 17713465; 30348286; 30612599; 34408996; 36964972 to 10514378; 12764198; 17713465; 30348286; 30612599; 34408996; 36964972
Proteinuric renal disease v5.3 CD2AP Ida Ertmanska edited their review of gene: CD2AP: Changed publications to: 10514378, 12764198, 17713465, 30348286, 30612599, 34408996, 36964972
Proteinuric renal disease v5.3 CD2AP Ida Ertmanska changed review comment from: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). This gene-disease relationship is also supported by functional studies in mice. Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.; to: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). This gene-disease relationship is also supported by functional studies in mice (PMIDs: 10514378; 30612599). Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram commented on gene: RELN: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Seizures are recorded as part of this phenotype in majority of the cases.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, this phenotype did not include the cases with autosomal-dominant lateral temporal epilepsy reported in PMID:26046367.

As there are sufficient monoallelic and biallelic cases reported with epilepsy as part of this phenotype, this gene can remain green with 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as the MOI.
Fetal anomalies v6.104 KIAA0556 Eleanor Williams commented on gene: KIAA0556
Fetal anomalies v6.104 KIAA0556 Eleanor Williams Tag new-gene-name tag was added to gene: KIAA0556.
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: Both monoallelic and biallelic variants in this gene has been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).; to: Comment on phenotypes: Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Both monoallelic and biallelic variants in this gene has been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; {Epilepsy, familial temporal lobe, 7}, OMIM:616436 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; Norman-Roberts syndrome, MONDO:0009760; {Epilepsy, familial temporal lobe, 7}, OMIM:616436; familial temporal lobe epilepsy 7, MONDO:0014639
Early onset or syndromic epilepsy v8.46 RELN Achchuthan Shanmugasundram Publications for gene: RELN were set to 26046367; 17431900; 10973257
Early onset or syndromic epilepsy v8.45 RELN Achchuthan Shanmugasundram changed review comment from: Monoallelic variants:
PMID:26046367 (2015) reported the identification of seven different heterozygous missense variants in RELN gene in seven unrelated families with autosomal-dominant lateral temporal epilepsy. These variants were identified by performing SNP-array linkage analysis and whole-exome sequencing. Of these seven variants, six of these are either absent or present with a very low allele frequency in gnomAD v4.1.0. However, c.2015C>T (p.Pro672Leu) variant is present in gnomAD with higher allele frequency.

Biallelic variants:

PMID:10973257 (2000) reported two unrelated consanguineous pedigrees segregating an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem. They were identified with homozygous variants in RELN gene and had seizures.

PMID:27000652 (2016) reported a Moroccan female patient with lissencephaly and with homozygous RELN variant. This patient presented with neonatal seizures that were controlled with medication.

PMID:35769015 (2022) reported the identification of biallelic RELN variants in seven patients from four unrelated families and monoalellic RELN variants from 13 individuals from seven families with frontotemporal or temporal-predominant lissencephaly. Five patients from three different families with biallelic variants presented with seizures as part of the phenotype, while detailed phenotypic information was not available in two patients from the first family with biallelic variants. However, seizure was only reported in three of 13 individuals with monoallelic variants (all three are unrelated).; to: Monoallelic variants:

PMID:26046367 (2015) reported the identification of seven different heterozygous missense variants in RELN gene in seven unrelated families with autosomal-dominant lateral temporal epilepsy. These variants were identified by performing SNP-array linkage analysis and whole-exome sequencing. Of these seven variants, six of these are either absent or present with a very low allele frequency in gnomAD v4.1.0. However, c.2015C>T (p.Pro672Leu) variant is present in gnomAD with higher allele frequency.

Biallelic variants:

PMID:10973257 (2000) reported two unrelated consanguineous pedigrees segregating an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem. They were identified with homozygous variants in RELN gene and had seizures.

PMID:27000652 (2016) reported a Moroccan female patient with lissencephaly and with homozygous RELN variant. This patient presented with neonatal seizures that were controlled with medication.

PMID:35769015 (2022) reported the identification of biallelic RELN variants in seven patients from four unrelated families and monoalellic RELN variants from 13 individuals from seven families with frontotemporal or temporal-predominant lissencephaly. Five patients from three different families with biallelic variants presented with seizures as part of the phenotype, while detailed phenotypic information was not available in two patients from the first family with biallelic variants. However, seizure was only reported in three of 13 individuals with monoallelic variants (all three are unrelated).
Early onset or syndromic epilepsy v8.45 RELN Achchuthan Shanmugasundram reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 10973257, 26046367, 27000652, 35769015; Phenotypes: Lissencephaly 2 (Norman-Roberts type), OMIM:257320, Norman-Roberts syndrome, MONDO:0009760, {Epilepsy, familial temporal lobe, 7}, OMIM:616436, familial temporal lobe epilepsy 7, MONDO:0014639; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.17 RBFOX2 Arina Puzriakova changed review comment from: Comment on list classification: Details on patient cases in the literature are limited, however, the same clinical phenotype of hypoplastic left heart syndrome is reported in multiple unrelated individuals with monoallelic variants in the RBFOX2 gene.

ClinGen have classified this association as definitive (assessed 05/14/2024 - https://search.clinicalgenome.org/CCID:008203).

On this basis, this gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: Details on patient cases in the literature are limited, however, the same clinical phenotype of hypoplastic left heart syndrome is reported in multiple unrelated individuals with monoallelic variants in the RBFOX2 gene.

ClinGen have classified this association as definitive (assessed 14/05/2024) - https://search.clinicalgenome.org/CCID:008203

On this basis, this gene should be promoted to Green at the next GMS panel update.
Paediatric disorders - additional genes v7.17 RBFOX2 Arina Puzriakova changed review comment from: Comment on list classification: Details on patient cases in the literature are limited, however, the same clinical phenotype of hypoplastic left heart syndrome is reported in multiple unrelated individuals with monoallelic variants in the RBFOX2 gene.

ClinGen have classified this association as definitive (assessed 05/14/2024 - https://search.clinicalgenome.org/CCID:008203) and on this basis this gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: Details on patient cases in the literature are limited, however, the same clinical phenotype of hypoplastic left heart syndrome is reported in multiple unrelated individuals with monoallelic variants in the RBFOX2 gene.

ClinGen have classified this association as definitive (assessed 05/14/2024 - https://search.clinicalgenome.org/CCID:008203).

On this basis, this gene should be promoted to Green at the next GMS panel update.
Paediatric disorders - additional genes v7.17 RBFOX2 Arina Puzriakova changed review comment from: Comment on list classification: Details on patient cases in the literature are limited, however, the same clinical phenotype of hypoplastic left heart syndrome is reported in multiple unrelated individuals. ClinGen have classified this association as definitive (assessed 05/14/2024 - https://search.clinicalgenome.org/CCID:008203) and on this basis this gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: Details on patient cases in the literature are limited, however, the same clinical phenotype of hypoplastic left heart syndrome is reported in multiple unrelated individuals with monoallelic variants in the RBFOX2 gene.

ClinGen have classified this association as definitive (assessed 05/14/2024 - https://search.clinicalgenome.org/CCID:008203) and on this basis this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v6.104 RBFOX2 Arina Puzriakova Phenotypes for gene: RBFOX2 were changed from Congenital heart disease, MONDO:0005453 to Congenital heart disease, MONDO:0005453; hypoplastic left heart syndrome, MONDO:0004933
Paediatric disorders - additional genes v7.17 RBFOX2 Arina Puzriakova Phenotypes for gene: RBFOX2 were changed from Congenital heart disease, MONDO:0005453; hypoplastic left heart syndrome to Congenital heart disease, MONDO:0005453; hypoplastic left heart syndrome, MONDO:0004933
Paediatric disorders - additional genes v7.16 RBFOX2 Arina Puzriakova Classified gene: RBFOX2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.16 RBFOX2 Arina Puzriakova Added comment: Comment on list classification: Details on patient cases in the literature are limited, however, the same clinical phenotype of hypoplastic left heart syndrome is reported in multiple unrelated individuals. ClinGen have classified this association as definitive (assessed 05/14/2024 - https://search.clinicalgenome.org/CCID:008203) and on this basis this gene should be promoted to Green at the next GMS panel update.
Paediatric disorders - additional genes v7.16 RBFOX2 Arina Puzriakova Gene: rbfox2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.15 RBFOX2 Arina Puzriakova gene: RBFOX2 was added
gene: RBFOX2 was added to Paediatric disorders - additional genes. Sources: ClinGen,Literature
Q3_25_promote_green tags were added to gene: RBFOX2.
Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX2 were set to 26785492; 25205790; 28991257; 35137168; 37165897
Phenotypes for gene: RBFOX2 were set to Congenital heart disease, MONDO:0005453; hypoplastic left heart syndrome
Review for gene: RBFOX2 was set to GREEN
Added comment: - PMID: 25205790 - de novo copy number loss that encompasses RBFOX2 in another proband with hypoplastic left heart syndrome

- PMID: 26785492 - three unrelated cases with distinct de novo LOF variants in the RBFOX2 gene and hypoplastic left heart syndrome

- PMID: 28991257 - de novo missense variant identified in a patient with congenital heart disease (conotruncal defects)

- PMID: 36198703 - zebrafish model lacking two Rbfox2 orthologs exhibited ventricular size and contractility deficits, which were rescued by injection of human RBFOX2 mRNA

- PMID: 35137168 - Rbfox2 conditional knockout mouse model showed embryonic heart developmental defects and recapitulated several molecular and phenotypic features hypoplastic left heart syndrome

- PMID: 37165897 - de novo missense variant identified in patient with hypoplastic left heart syndrome
Sources: ClinGen, Literature
Intellectual disability v9.138 AP1B1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: AP1B1.
Intellectual disability v9.138 AP1B1 Achchuthan Shanmugasundram Publications for gene: AP1B1 were set to 31630788; 31630791
Intellectual disability v9.137 AP1B1 Achchuthan Shanmugasundram Phenotypes for gene: AP1B1 were changed from Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781
Undiagnosed metabolic disorders v1.637 CPOX Ida Ertmanska Mode of inheritance for gene CPOX was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v8.69 CPOX Ida Ertmanska Phenotypes for gene: CPOX were changed from Harderoporphyria 121300; Coproporphyria 121300; Hereditary coproporphyria (Acute neuropathic porphyrias) to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Publications for gene: CPOX were updated from 27604308 to 6886003; 7757079; 8012360; 9454777; 10505225; 11074238; 11309681; 16159891; 21103937; 23236641; 23605133; 30828546; 33008663; 37540847; 38940544; 40296768
Tag Q3_25_MOI tag was added to CPOX.
Undiagnosed metabolic disorders v1.636 CPOX Ida Ertmanska Tag Q3_25_MOI was removed from CPOX.
Likely inborn error of metabolism v8.68 CPOX Ida Ertmanska reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 6886003, 7757079, 8012360, 9454777, 10505225, 11074238, 11309681, 16159891, 21103937, 23236641, 23605133, 30828546, 33008663, 37540847, 38940544, 40296768; Phenotypes: Coproporphyria, OMIM:121300, Harderoporphyria, OMIM:618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.635 CPOX Ida Ertmanska Phenotypes for gene: CPOX were changed from Hereditary coproporphyria (Acute neuropathic porphyrias); Coproporphyria 121300; Harderoporphyria 121300 to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Publications for gene: CPOX were updated from 27604308 to 6886003; 7757079; 8012360; 9454777; 10505225; 11074238; 11309681; 16159891; 21103937; 23236641; 23605133; 30828546; 33008663; 37540847; 38940544; 40296768
Tag Q3_25_MOI tag was added to CPOX.
Undiagnosed metabolic disorders v1.634 CPOX Ida Ertmanska reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 6886003, 7757079, 8012360, 9454777, 10505225, 11074238, 11309681, 16159891, 21103937, 23236641, 23605133, 30828546, 33008663, 37540847, 38940544, 40296768; Phenotypes: Coproporphyria, OMIM:121300, Harderoporphyria, OMIM:618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.12 CPOX Ida Ertmanska Phenotypes for gene: CPOX were changed from Harderoporphyria 121300; Coproporphyria 121300; Hereditary coproporphyria (Acute neuropathic porphyrias) to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Publications for gene: CPOX were updated from to 6886003; 7757079; 8012360; 9454777; 10505225; 11074238; 16159891; 21103937; 23236641; 30828546; 33008663; 40296768
Tag Q3_25_MOI tag was added to CPOX.
Cutaneous photosensitivity with a likely genetic cause v3.11 CPOX Ida Ertmanska reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 6886003, 7757079, 8012360, 9454777, 10505225, 11074238, 16159891, 21103937, 23236641, 30828546, 33008663, 40296768; Phenotypes: Coproporphyria, OMIM:121300, Harderoporphyria, OMIM:618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Non-acute porphyrias v1.29 CPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive disease. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the MOI should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).
Non-acute porphyrias v1.29 CPOX Ida Ertmanska Phenotypes for gene: CPOX were changed from Harderoporphyria OMIM:618892; harderoporphyria MONDO:0030048; Coproporphyria OMIM:121300; hereditary coproporphyria MONDO:0007369 to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Publications for gene: CPOX were updated from 27604308; 12227458; 8159699; 7987309; 8990017 to 6886003; 7757079; 8012360; 9454777; 10505225; 11309681; 11074238; 16159891; 21103937; 23236641; 30828546; 33008663; 40296768
Tag Q3_25_MOI tag was added to CPOX.
Fetal anomalies v6.103 PLD1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PLD1.
Tag Q3_25_expert_review tag was added to gene: PLD1.
Paediatric disorders - additional genes v7.14 PLD1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PLD1.
Tag Q3_25_expert_review tag was added to gene: PLD1.
Fetal anomalies v6.103 PLD1 Arina Puzriakova commented on gene: PLD1: This gene was previously downgraded from Green to Amber following review by Jesse Hayesmoore highlighting the presence of homozygotes in population databases, including some patient variants. However, additional cases have continued to be published albeit often with limited information and no extensive functional studies. This gene-condition has been reviewed by multiple resources including:

- ClinGen: definitive (classified on 12-02-2024) - https://search.clinicalgenome.org/CCID:008897
- G2P: definitive (classified on 19-02-2025) - https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03704
- PanelApp Australia: green on multiple panels - https://panelapp-aus.org/panels/entities/PLD1
- OMIM (last updated on 30-09-2022) - https://www.omim.org/entry/212093

Given the classification on Genomics England PanelApp currently conflicts with multiple other resources, this gene will be flagged for additional expert review during the next GMS panel release.
Paediatric disorders - additional genes v7.14 PLD1 Arina Puzriakova commented on gene: PLD1: This gene was previously downgraded from Green to Amber following review by Jesse Hayesmoore highlighting the presence of homozygotes in population databases, including some patient variants. However, additional cases have continued to be published albeit often with limited information and no extensive functional studies. This gene-condition has been reviewed by multiple resources including:

- ClinGen: definitive (classified on 12-02-2024) - https://search.clinicalgenome.org/CCID:008897
- G2P: definitive (classified on 19-02-2025) - https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03704
- PanelApp Australia: green on multiple panels - https://panelapp-aus.org/panels/entities/PLD1
- OMIM (last updated on 30-09-2022) - https://www.omim.org/entry/212093

Given the classification on Genomics England PanelApp currently conflicts with multiple other resources, this gene will be flagged for additional expert review during the next GMS panel release.
Non-acute porphyrias v1.28 CPOX Ida Ertmanska reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 6886003, 7757079, 8012360, 9454777, 10505225, 11309681, 11074238, 16159891, 21103937, 23236641, 30828546, 33008663, 40296768; Phenotypes: Coproporphyria, OMIM:121300, Harderoporphyria, OMIM:618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.14 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 27799408; 33645542
Fetal anomalies v6.103 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 33645542; 27799408; 33142350
Fetal anomalies v6.102 PLD1 Arina Puzriakova Added comment: Comment on phenotypes: Updated OMIM:212093 phenotype from 'Cardiac valvular defect, developmental' to 'Cardiac valvular dysplasia 1' (accessed on 20-10-2025)
Fetal anomalies v6.102 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093; Cardiomyopathy; Congenital heart malformations to Cardiac valvular dysplasia 1, OMIM:212093; Congenital heart malformations
Paediatric disorders - additional genes v7.13 PLD1 Arina Puzriakova Added comment: Comment on phenotypes: Updated OMIM:212093 phenotype from 'Cardiac valvular defect, developmental' to 'Cardiac valvular dysplasia 1' (accessed on 20-10-2025)
Paediatric disorders - additional genes v7.13 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093 to Cardiac valvular dysplasia 1, OMIM:212093
Fetal anomalies v6.101 PLD1 Arina Puzriakova edited their review of gene: PLD1: Added comment: Additional cases reported (not reviewed previously):

- PMID: 38171566 - based on the abstract (translated from Chinese, full-text not available) a fetus with generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes was identified with compound heterozygous variants (c.1460G>A (p.W487*); c.2977C>T (p.R993*)) in the PLD1 gene. No functional studies mentioned.

- PMID: 39553471 - a fetus with compound heterozygous variants (c.1937G>C (p.G646A); c.1062-59A>G) was found with congenital heart disease including pulmonary atresia, regurgitation and tricuspid valve dysplasia. In silico analysis of c.1062-59A>G indicated the variant affected splicing, and subsequent RT-PCR and TA clone sequencing revealed a 76-bp intron retention and skipping of exon 11, causing a frameshift and premature stop codon in PLD1. Both variants were classified as VUS according to ACMG guidelines.

- PMID: 39681445 - title 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there is another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.; Changed publications to: 27799408, 33142350, 33645542, 35380090, 36923242, 37770978, 38171566, 39553471, 39681445; Changed phenotypes to: Cardiac valvular dysplasia 1, OMIM:212093; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.12 PLD1 Arina Puzriakova edited their review of gene: PLD1: Added comment: Additional cases reported (not reviewed previously):

- PMID: 38171566 - based on the abstract (translated from Chinese, full-text not available) a fetus with generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes was identified with compound heterozygous variants (c.1460G>A (p.W487*); c.2977C>T (p.R993*)) in the PLD1 gene. No functional studies mentioned.

- PMID: 39553471 - a fetus with compound heterozygous variants (c.1937G>C (p.G646A); c.1062-59A>G) was found with congenital heart disease including pulmonary atresia, regurgitation and tricuspid valve dysplasia. In silico analysis of c.1062-59A>G indicated the variant affected splicing, and subsequent RT-PCR and TA clone sequencing revealed a 76-bp intron retention and skipping of exon 11, causing a frameshift and premature stop codon in PLD1. Both variants were classified as VUS according to ACMG guidelines.

- PMID: 39681445 - title 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there is another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.; Changed publications to: 27799408, 33142350, 33645542, 35380090, 36923242, 37770978, 38171566, 39553471, 39681445; Changed phenotypes to: Cardiac valvular dysplasia 1, OMIM:212093; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v7.92 PLD1 Arina Puzriakova edited their review of gene: PLD1: Changed rating: AMBER
Paediatric or syndromic cardiomyopathy v7.92 PLD1 Arina Puzriakova changed review comment from: Title of PMID: 39681445 - 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there is another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.

As already highlighted in previous reviews, the presenting phenotype in most cases is valvular defects rather than cardiomyopathy.; to: Title of PMID: 39681445 - 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there is another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.

As already highlighted in previous reviews, the presenting phenotype in most cases is valvular defects rather than cardiomyopathy, so this gene should remain amber on this panel.
Ectodermal dysplasia v4.10 KDF1 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed 20th October 2025
Ectodermal dysplasia v4.10 KDF1 Eleanor Williams Phenotypes for gene: KDF1 were changed from ?Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, OMIM:617337; ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MONDO:0015024 to ?Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, OMIM:617337; ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MONDO:0015024
Ectodermal dysplasia v4.9 KDF1 Eleanor Williams Classified gene: KDF1 as Amber List (moderate evidence)
Ectodermal dysplasia v4.9 KDF1 Eleanor Williams Added comment: Comment on list classification: Promoting to amber but with a recommendation for green rating following GMS review. There are multiple families with variants in this gene and an ectodermal phenotype.
Ectodermal dysplasia v4.9 KDF1 Eleanor Williams Gene: kdf1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v4.8 KDF1 Eleanor Williams Added comment: Comment on mode of pathogenicity: There is a proposed mechanism of gain-of-function for the missense variants in this gene.
Ectodermal dysplasia v4.8 KDF1 Eleanor Williams Mode of pathogenicity for gene: KDF1 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Ectodermal dysplasia v4.7 KDF1 Eleanor Williams gene: KDF1 was added
gene: KDF1 was added to Ectodermal dysplasia. Sources: Literature
Q3_25_promote_green tags were added to gene: KDF1.
Mode of inheritance for gene: KDF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KDF1 were set to 27838789; 24075906; 30384154; 30977908; 36293320; 37144643; 38501196; 40554824
Phenotypes for gene: KDF1 were set to ?Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, OMIM:617337; ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, MONDO:0015024
Review for gene: KDF1 was set to GREEN
Added comment: There is a provisional association with ?Ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, OMIM:617337 in OMIM but the entry has not been updated since 2017 (accessed 20th October 2025).

In ClinGen there is a definitive association with KDF1 - ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type (https://search.clinicalgenome.org/CCID:008901).

Numerous cases reported e.g.

PMID: 27838789 - Shamseldin et al. 2017 - a multigenerational Saudi family with an autosomal dominant form of hypohidrotic ectodermal dysplasia who had a missense varient in KDF1 (c.753C>A;p.F251L) which segregated with the disease (7 affected, 6 non-affected). Hair, skin and teeth were affected. A mouse knockout of KDF1-/- (PMID: 24075906, 2013) shows an epidermal phenotype.                      

PMID: 30384154 - Zeng et al 2019 - missense variant in KDF1 identified in a family with non-syndromic tooth agenesis.

PMID: 30977908 - Manaspon et al 2019 - 5 year old Thai boy with ectodermal dysplasia - sparse hair, absent eyebrows and eyelashes, absence of sweating and dry skin. Using exome and sanger sequencing he was found to have a de novo heterozygous missense variant in KDF1

Further findings of KDF1 missense variants in ectodermal dysplasia patients are reported in PMIDs: 36293320, 37144643, 38501196, 40554824) spanning 2022 to 2025.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.92 PLD1 Arina Puzriakova changed review comment from: Title of PMID: 39681445 - 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there may be another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.

As already highlighted in previous reviews, the presenting phenotype in most cases is valvular defects rather than cardiomyopathy.; to: Title of PMID: 39681445 - 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there is another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.

As already highlighted in previous reviews, the presenting phenotype in most cases is valvular defects rather than cardiomyopathy.
Proteinuric renal disease v5.3 CD2AP Ida Ertmanska Publications for gene: CD2AP were updated from 30612599; 17713465 to 12764198; 17713465; 30348286; 30612599; 34408996; 36964972
Tag Q3_25_promote_green tag was added to CD2AP.
Paediatric or syndromic cardiomyopathy v7.92 PLD1 Arina Puzriakova changed review comment from: Title of PMID: 39681445 - 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there may be another case of cardiomyopathy linked to this gene. However, the article is in Chinese and therefore cannot be curated.

As already highlighted in previous reviews, the presenting phenotype in most cases is valvular defects rather than cardiomyopathy.; to: Title of PMID: 39681445 - 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there may be another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.

As already highlighted in previous reviews, the presenting phenotype in most cases is valvular defects rather than cardiomyopathy.
Proteinuric renal disease v5.2 CD2AP Ida Ertmanska changed review comment from: Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

In addition, two variants (c.730-1_730delinsCT and c.1734dup, (p.Lys579GlufsTer7)) have been reported in 2 unrelated probands (PMIDs: 12764198, 34408996).

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

In addition, two heterozygous variants (c.730-1_730delinsCT and c.1734dup, (p.Lys579GlufsTer7)) have been reported in 2 unrelated probands (PMIDs: 12764198, 34408996). More evidence is required to support the autosomal dominant mode of inheritance.

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Proteinuric renal disease v5.2 CD2AP Ida Ertmanska commented on gene: CD2AP: Comment on list classification: There are at least four unrelated cases reported with homozygous variants in CD2AP and Focal segmental glomerulosclerosis / nephropathy (PMIDs: 17713465, 30348286, 30612599, 36964972). This gene-disease relationship is also supported by functional studies in mice. Based on the available evidence, this gene should be rated Green for Proteinuric renal disease.
Proteinuric renal disease v5.2 CD2AP Ida Ertmanska changed review comment from: Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6 ESRD at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

In addition, there are two individuals with

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. ; to: Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6; End stage renal disease at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

In addition, two variants (c.730-1_730delinsCT and c.1734dup, (p.Lys579GlufsTer7)) have been reported in 2 unrelated probands (PMIDs: 12764198, 34408996).

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Paediatric or syndromic cardiomyopathy v7.92 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 27799408; 33645542; 39472908
Paediatric or syndromic cardiomyopathy v7.91 PLD1 Arina Puzriakova commented on gene: PLD1: Title of PMID: 39681445 - 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there may be another case of cardiomyopathy linked to this gene. However, the article is in Chinese and therefore cannot be curated.

As already highlighted in previous reviews, the presenting phenotype in most cases is valvular defects rather than cardiomyopathy.
Proteinuric renal disease v5.2 CD2AP Ida Ertmanska changed review comment from: 2 probands with inherited AD FSGS: PMIDs: 12764198, 34408996, 4 probands with AR mode:PMIDs: 17713465, 30348286, 30612599, 36964972, also some case-control data.

This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed. CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).; to: Two articles reviewed previously by Eleanor Williams report 2 unrelated cases with homozygous nonsense variants in CD2AP and Focal segmental glomerulosclerosis (PMID:17713465 - Löwik et al 2007 & PMID: 30612599 - Takano et al 2019). Extra case reports:

PMID: 30348286 Gribouval O, et al., 2018,
Male individual homozygous for NM_012120.3 (CD2AP):c.634C>T (p.Arg212Ter) Focal segmental glomerulosclerosis - age of onset 24yo; eGFR at onset: 12 Albuminemia g/l: 28 Proteinuria g/g: 3.6 ESRD at 25yo. Method: NGS panel of 35 genes.

PMID: 36964972 Gorukmez O, et al., 2023
23 year old male with a homozygous variant in CD2AP who presented with nephropathy. Variant: NM_012120.3 (CD2AP):c.1742del (p.Asn581IlefsTer17). Method: clinical WES.

In addition, there are two individuals with

CD2AP is classified Definitive for AR 'focal segmental glomerulosclerosis 3, susceptibility to', and Moderate for AD 'inherited focal segmental glomerulosclerosis' in ClinGen (curated by the Glomerulopathy Gene Curation Expert Panel in 2024).
This gene is associated with Glomerulosclerosis, focal segmental, 3, 607832 in OMIM (accessed 20th Oct 2025) - no mode of inheritance listed.
Proteinuric renal disease v5.2 CD2AP Ida Ertmanska reviewed gene: CD2AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12764198, 17713465, 30348286, 30612599, 34408996, 36964972; Phenotypes: Glomerulosclerosis, focal segmental, 3, OMIM:607832, focal segmental glomerulosclerosis 3, susceptibility to, MONDO:0011917; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.55 MCDR3 Ronnie Wright Region: MCDR3 was added
Region: MCDR3 was added to Retinal disorders. Sources: Literature
Mode of inheritance for Region: MCDR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for Region: MCDR3 were set to 28790370
Phenotypes for Region: MCDR3 were set to Macular Dystrophy
Penetrance for Region: MCDR3 were set to Complete
Review for Region: MCDR3 was set to GREEN
Region: MCDR3 was marked as current diagnostic
Added comment: The precise 'critical' region and the aetiological mechanism by which this duplication causes disease is not fully understood, yet the coordinates specified above reflect the 'British' origin variant at the MCDR3 locus (for which the greatest evidence is available - segregating in multiple families), identified by Cipriani et al (PMID:28790370).

OMIM #608850
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.25 HEATR5B Arina Puzriakova edited their review of gene: HEATR5B: Changed rating: GREEN
Cerebellar hypoplasia v1.81 HEATR5B Arina Puzriakova edited their review of gene: HEATR5B: Changed rating: GREEN
Corneal dystrophy v4.6 AP1B1 Achchuthan Shanmugasundram Classified gene: AP1B1 as Amber List (moderate evidence)
Corneal dystrophy v4.6 AP1B1 Achchuthan Shanmugasundram Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v4.5 AP1B1 Achchuthan Shanmugasundram Publications for gene: AP1B1 were set to
Corneal dystrophy v4.4 AP1B1 Achchuthan Shanmugasundram Phenotypes for gene: AP1B1 were changed from to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781
Intestinal failure or congenital diarrhoea v3.6 AP1B1 Achchuthan Shanmugasundram Classified gene: AP1B1 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v3.6 AP1B1 Achchuthan Shanmugasundram Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
DDG2P v6.8 AP1B1 Ida Ertmanska Deleted their review
Palmoplantar keratodermas v4.6 AP1B1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: AP1B1.
Palmoplantar keratodermas v4.6 AP1B1 Achchuthan Shanmugasundram Classified gene: AP1B1 as Amber List (moderate evidence)
Palmoplantar keratodermas v4.6 AP1B1 Achchuthan Shanmugasundram Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v4.5 AP1B1 Achchuthan Shanmugasundram Phenotypes for gene: AP1B1 were changed from to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781
Palmoplantar keratodermas v4.4 AP1B1 Achchuthan Shanmugasundram Publications for gene: AP1B1 were set to
Fetal anomalies v6.101 DISP1 Ida Ertmanska changed review comment from: MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. There are at least 10 individuals with holoprosencephaly with monoallelic variants in DISP1, and at least 10 with biallelic / compound heterozygous variants in DISP1.

PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). 9/25 individuals were fetuses with antenatal signs of failure of the prosencephalon to divide. As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Monogenic hearing loss v5.33 AP1B1 Achchuthan Shanmugasundram Classified gene: AP1B1 as Amber List (moderate evidence)
Monogenic hearing loss v5.33 AP1B1 Achchuthan Shanmugasundram Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.32 AP1B1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: AP1B1.
Monogenic hearing loss v5.32 AP1B1 Achchuthan Shanmugasundram Phenotypes for gene: AP1B1 were changed from Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; ichthyosiform erythroderma, corneal involvement, and hearing loss, MONDO:0009440 to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781
DDG2P v6.8 DISP1 Ida Ertmanska Deleted their review
DDG2P v6.8 DISP1 Ida Ertmanska Deleted their comment
Ichthyosis and erythrokeratoderma v4.8 AP1B1 Achchuthan Shanmugasundram Classified gene: AP1B1 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v4.8 AP1B1 Achchuthan Shanmugasundram Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v4.7 AP1B1 Achchuthan Shanmugasundram Phenotypes for gene: AP1B1 were changed from Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; ichthyosiform erythroderma, corneal involvement, and hearing loss, MONDO:0009440 to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781
Ichthyosis and erythrokeratoderma v4.6 AP1B1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: AP1B1.
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense and two splice site variants). Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent or present at a very low allele frequency in gnomAD v4.1.0.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia.; to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense and two splice site variants). Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent or present at a very low allele frequency in gnomAD v4.1.0.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia.

This gene can therefore remain green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on this panel.
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0; to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense and two splice site variants). Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent or present at a very low allele frequency in gnomAD v4.1.0.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia.
Palmoplantar keratodermas v4.3 AP1B1 Ida Ertmanska commented on gene: AP1B1: Comment on list classification: At least 6 unrelated individuals harbouring biallelic variants in AP1B1, diagnosed with Keratitis-ichthyosis-deafness syndrome, presented with syndromic palmoplantar hyperkeratosis. Based on the available evidence, this gene should be rated Green for Palmoplantar hyperkeratosis.
Palmoplantar keratodermas v4.3 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, erythroderma, palmoplantar keratoderma, hearing loss, ichthyosis. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, palmoplantar keratoderma, moderate motor & mental retardation, failed the auditory brainstem response test bilaterally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, erythroderma, palmoplantar keratoderma, hearing loss, ichthyosis. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature
Palmoplantar keratodermas v4.3 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, erythroderma, palmoplantar keratoderma, hearing loss, ichthyosis. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0); to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram changed review comment from: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with seven different heterozygous variants. Of these 13 individuals, 6 patients from four families had moderate/ severe intellectual disability, while 4 patients had mild ID and one had ID of unspecified severity.; to: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with six different heterozygous variants (four missense, one frameshift and one exon. Of these 13 individuals, 11 had intellectual disability of variable severity (two severe, four moderate, four mild and one borderline). The missense variants were either absent present at a very low allele frequency in gnomAD v4.1.0)
Palmoplantar keratodermas v4.3 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Changed publications to: 31630791, 31630788, 33452671, 33349978, 32969855, 35144013
Palmoplantar keratodermas v4.3 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature
Palmoplantar keratodermas v4.3 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Changed publications to: 31630791, 33452671, 33349978, 32969855, 35144013; Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, KID syndrome, MONDO:0018781
Palmoplantar keratodermas v4.3 AP1B1 Ida Ertmanska gene: AP1B1 was added
gene: AP1B1 was added to Palmoplantar keratodermas. Sources: Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: AP1B1 was set to GREEN
Added comment: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: Literature
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
DDG2P v6.8 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Intestinal failure or congenital diarrhoea v3.5 AP1B1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals from 2 families reported in literature presenting with neonatal onset enteropathy and/or chronic diarrhea (PMIDs:32969855; 31630791). The individuals were diagnosed with Keratitis-ichthyosis-deafness syndrome and harboured biallelic variants in AP1B1. Several other individuals with biallelic AP1B1 variants did not present with diarrhea. Hence, this gene should be rated Amber for Intestinal failure or congenital diarrhoea.
Sources: Literature; to: Comment on list classification: There are 3 individuals from 2 families reported in literature presenting with neonatal onset enteropathy and/or chronic diarrhea (PMIDs:32969855; 31630791). The individuals were diagnosed with Keratitis-ichthyosis-deafness syndrome and harboured biallelic variants in AP1B1. Several other individuals with biallelic AP1B1 variants did not present with diarrhea. Hence, this gene should be rated Amber for Intestinal failure or congenital diarrhoea.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Ichthyosis and erythrokeratoderma v4.6 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Corneal dystrophy v4.3 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, hearing loss, palmoplantar keratoderma, sparse hair, erythroderma; ophthalmologic examination: photophobia, corneal scarring, and eyelid swelling.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).; to: PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, hearing loss, palmoplantar keratoderma, sparse hair, erythroderma; ophthalmologic examination: photophobia, corneal scarring, and eyelid swelling.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Corneal dystrophy v4.3 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, hearing loss, palmoplantar keratoderma, sparse hair, erythroderma; ophthalmologic examination: photophobia, corneal scarring, and eyelid swelling.

This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).; to: PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, hearing loss, palmoplantar keratoderma, sparse hair, erythroderma; ophthalmologic examination: photophobia, corneal scarring, and eyelid swelling.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Corneal dystrophy v4.3 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, hearing loss, palmoplantar keratoderma, sparse hair, erythroderma; ophthalmologic examination: photophobia, corneal scarring, and eyelid swelling.
Sources: Literature; to: PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, hearing loss, palmoplantar keratoderma, sparse hair, erythroderma; ophthalmologic examination: photophobia, corneal scarring, and eyelid swelling.

This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Monogenic hearing loss v5.31 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Monogenic hearing loss v5.31 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
This gene was classified as Definitive for AR ichthyosiform erythroderma, corneal involvement, and hearing loss by ClinGen (General Inborn Errors of Metabolism Expert Panel, Aug 2024).
Sources: ClinGen, Literature
DDG2P v6.8 DISP1 Ida Ertmanska edited their review of gene: DISP1: Changed publications to: 38529886; Changed phenotypes to: Holoprosencephaly 10, OMIM:621143, holoprosencephaly 10, MONDO:0976262
DDG2P v6.8 DISP1 Ida Ertmanska commented on gene: DISP1
Fetal anomalies v6.101 DISP1 Ida Ertmanska reviewed gene: DISP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38529886; Phenotypes: Holoprosencephaly 10, OMIM:621143; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Corneal dystrophy v4.3 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Added comment: Comment on list classification: While there are at least 4 reported unrelated individuals with photophobia and / or corneal scarring attributed to biallelic variants in AP1B1, in depth ophthalmologic examination and disease mechanism are lacking. Photophobia is only seen in a subset of Keratitis-ichthyosis-deafness syndrome patients. Hence, the gene is rated Amber for Corneal dystrophy.; Changed publications to: 31630788, 33452671, 32969855, 35144013; Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, KID syndrome, MONDO:0018781
Corneal dystrophy v4.3 AP1B1 Ida Ertmanska gene: AP1B1 was added
gene: AP1B1 was added to Corneal dystrophy. Sources: Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: AP1B1 was set to AMBER
Added comment: PMID: 31630788 Boyden et al., 2019
Individual 424, adult male, born with normal skin; diagnosed with ichthyosis at 2 months old; developmental delay, growth delay, partial hearing loss, tooth loss, profound photophobia, and
corneal scarring leading to near complete vision loss. At age 33 had erythroderma with thin palmoplantar
keratoderma, and a fissured tongue; noted thickening of his palms and soles since childhood.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, hearing loss, palmoplantar keratoderma, sparse hair, erythroderma; ophthalmologic examination: photophobia, corneal scarring, and eyelid swelling.
Sources: Literature
Holoprosencephaly v5.6 DISP1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: DISP1.
Holoprosencephaly v5.6 DISP1 Achchuthan Shanmugasundram Phenotypes for gene: DISP1 were changed from Holoprosencephaly 10, OMIM:621143 to Holoprosencephaly 10, OMIM:621143; holoprosencephaly 10, MONDO:0976262
Holoprosencephaly v5.5 DISP1 Achchuthan Shanmugasundram Publications for gene: DISP1 were set to 27363716; 19184110; 26748417; 23542665
Holoprosencephaly v5.4 DISP1 Achchuthan Shanmugasundram Mode of inheritance for gene: DISP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As there are three unrelated cases reported with familial sleep-related hypermotor epilepsy phenotype despite limited rating in ClinGen, this gene can remain amber on this panel.; to: Comment on list classification: As there are three unrelated cases reported with familial sleep-related hypermotor epilepsy phenotype despite limited rating in ClinGen, this gene can remain green on this panel.
Intestinal failure or congenital diarrhoea v3.5 AP1B1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals from 2 families reported in literature presenting with early onset enteropathy and/or chronic diarrhea (PMIDs:32969855; 31630791). The individuals were diagnosed with Keratitis-ichthyosis-deafness syndrome and harboured biallelic variants in AP1B1. Several other individuals with biallelic AP1B1 variants did not present with diarrhea. Hence, this gene should be rated Amber for Intestinal failure or congenital diarrhoea.
Sources: Literature; to: Comment on list classification: There are 3 individuals from 2 families reported in literature presenting with neonatal onset enteropathy and/or chronic diarrhea (PMIDs:32969855; 31630791). The individuals were diagnosed with Keratitis-ichthyosis-deafness syndrome and harboured biallelic variants in AP1B1. Several other individuals with biallelic AP1B1 variants did not present with diarrhea. Hence, this gene should be rated Amber for Intestinal failure or congenital diarrhoea.
Sources: Literature
Intestinal failure or congenital diarrhoea v3.5 AP1B1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals from 2 families reported in literature presenting with early onset enteropathy and/or chronic diarrhea. The individuals were diagnosed with Keratitis-ichthyosis-deafness syndrome and harboured biallelic variants in AP1B1. Several other individuals with biallelic AP1B1 variants did not present with diarrhea. Hence, this gene should be rated Amber for Intestinal failure or congenital diarrhoea.
Sources: Literature; to: Comment on list classification: There are 3 individuals from 2 families reported in literature presenting with early onset enteropathy and/or chronic diarrhea (PMIDs:32969855; 31630791). The individuals were diagnosed with Keratitis-ichthyosis-deafness syndrome and harboured biallelic variants in AP1B1. Several other individuals with biallelic AP1B1 variants did not present with diarrhea. Hence, this gene should be rated Amber for Intestinal failure or congenital diarrhoea.
Sources: Literature
Intestinal failure or congenital diarrhoea v3.5 AP1B1 Ida Ertmanska gene: AP1B1 was added
gene: AP1B1 was added to Intestinal failure or congenital diarrhoea. Sources: Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to 32969855; 31630791
Phenotypes for gene: AP1B1 were set to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; KID syndrome, MONDO:0018781
Review for gene: AP1B1 was set to AMBER
Added comment: Comment on list classification: There are 3 individuals from 2 families reported in literature presenting with early onset enteropathy and/or chronic diarrhea. The individuals were diagnosed with Keratitis-ichthyosis-deafness syndrome and harboured biallelic variants in AP1B1. Several other individuals with biallelic AP1B1 variants did not present with diarrhea. Hence, this gene should be rated Amber for Intestinal failure or congenital diarrhoea.
Sources: Literature
DDG2P v6.8 AP1B1 Ida Ertmanska reviewed gene: AP1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31630791, 33452671, 33349978, 32969855, 35144013; Phenotypes: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, KID syndrome, MONDO:0018781; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v4.6 AP1B1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with ichthyosis, as well as associated conditions: erythroderma, palmoplantar hyperkeratosis, keratitis. Hence, this gene fits into the scope of the Monogenic hearing loss panel, and should be promoted to Green at the next GMS update.; to: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with ichthyosis, as well as associated conditions: erythroderma, palmoplantar hyperkeratosis, keratitis. Hence, this gene fits into the scope of the Ichthyosis and erythrokeratoderma panel, and should be promoted to Green at the next GMS update.
Intellectual disability v9.136 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, KID syndrome, MONDO:0018781
Ichthyosis and erythrokeratoderma v4.6 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, KID syndrome, MONDO:0018781
Ichthyosis and erythrokeratoderma v4.6 AP1B1 Ida Ertmanska commented on gene: AP1B1: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with ichthyosis, as well as associated conditions: erythroderma, palmoplantar hyperkeratosis, keratitis. Hence, this gene fits into the scope of the Monogenic hearing loss panel, and should be promoted to Green at the next GMS update.
Monogenic hearing loss v5.31 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, KID syndrome, MONDO:0018781
Ichthyosis and erythrokeratoderma v4.6 AP1B1 Ida Ertmanska gene: AP1B1 was added
gene: AP1B1 was added to Ichthyosis and erythrokeratoderma. Sources: ClinGen,Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to 31630791; 33452671; 33349978; 32969855; 35144013
Phenotypes for gene: AP1B1 were set to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; ichthyosiform erythroderma, corneal involvement, and hearing loss, MONDO:0009440
Review for gene: AP1B1 was set to GREEN
Added comment: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature
Monogenic hearing loss v5.31 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Monogenic hearing loss v5.31 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia; developed bilateral deafness and moderate photophobia.. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature
Monogenic hearing loss v5.31 AP1B1 Ida Ertmanska commented on gene: AP1B1: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals developed bilateral sensorineural hearing loss. Hence, this gene fits into the scope of the Monogenic hearing loss panel, and should be promoted to Green at the next GMS update.
Monogenic hearing loss v5.31 AP1B1 Ida Ertmanska gene: AP1B1 was added
gene: AP1B1 was added to Monogenic hearing loss. Sources: ClinGen,Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to 31630791; 33452671; 33349978; 32969855; 35144013
Phenotypes for gene: AP1B1 were set to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; ichthyosiform erythroderma, corneal involvement, and hearing loss, MONDO:0009440
Review for gene: AP1B1 was set to GREEN
Added comment: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Sources: ClinGen, Literature
Intellectual disability v9.136 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150, ichthyosiform erythroderma, corneal involvement, and hearing loss, MONDO:0009440
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with global developmental delay from birth - including delayed motor milestones and delay in speech development. While there is severe developmental delay within the first months of life, it seems to mostly resolve in later childhood, it may be the first presenting symptom, alongside ichthyosis. Hence, this gene fits into the scope of the Intellectual disability panel, and should be promoted to Green at the next GMS update.; to: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with global developmental delay from birth - including delayed motor milestones and delay in speech development. While the severe developmental delay in the neonatal period seems to mostly resolve in later childhood, it may be the first presenting symptom, alongside ichthyosis. Hence, this gene fits into the scope of the Intellectual disability panel, and should be promoted to Green at the next GMS update.
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska edited their review of gene: AP1B1: Added comment: Comment on list classification: There are at least 6 unrelated individuals with Keratitis-ichthyosis-deafness syndrome, harbouring biallelic variants in AP1B1. 6/6 individuals presented with global developmental delay from birth - including delayed motor milestones and delay in speech development. While there is severe developmental delay within the first months of life, it seems to mostly resolve in later childhood, it may be the first presenting symptom, alongside ichthyosis. Hence, this gene fits into the scope of the Intellectual disability panel, and should be promoted to Green at the next GMS update.; Changed rating: GREEN; Changed publications to: 31630791, 33452671, 33349978, 32969855, 35144013; Changed phenotypes to: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, OMIM:242150; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

PMID: 35144013 Faghihi et al., 2022
Proband: 6.5yr old boy, consanguineous parents. Homozygous for AP1B1 (NM_001127.4: c.1263C>A, p.Tyr421*) - WES. Presented with developmental delay, keratitis, ichthyosis, and hearing loss. Plasma copper (9 mmol/L) was decreased on several occasions.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.

AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

PMID: 32969855 Meriç et al., 2021
11mo Turkish girl; consanguineous parents. Homozygous for (AP1B1:NM_001127) c.668T>C, p.Leu223Pro - WES. Presented with ichthyosis and developmental delay. Other symptoms: hearing loss, hepatomegaly, chronic diarrhea, partial alopecia, hyperkeratosis; eye examination showed photophobia and high myopia; diagnosed with mild ID at 7yo. Serum copper within normal limits.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska changed review comment from: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss. Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease).
Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.
Persistently low plasma copper in both siblings.

PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).; to: PMID: 31630791 Alsaif et al., 2019
Family 1: UK and Pakistani origin, consanguineous. Individual II:1, female, presented with congenital ichthyosis, enteropathy, and mild persisting hepatopathy, followed by failure to thrive, global developmental delay, and bilateral severe to profound sensorineural hearing loss.
Similarly affected brother II:2: ichthyosis with erythroderma and diarrhea in the neonatal period. Subsequent problems included enteropathy, severe failure to thrive, global developmental delay, hearing loss, narrow and incomplete cleft of the soft palate, anemia, and respiratory infections. Both homozygous for a gross deletion, (GRCh37/hg19) chr22: 29758984–29815476, which spans AP1B1 and RFPL1 (not yet associated with a disease). Persistently low plasma copper in both siblings.

Family 2: individual II:2 - 4yo boy born to consanguineous healthy Saudi parents. Phenotype: scaly skin, which evolved into generalized ichthyosis with associated palmoplantar hyperkeratosis. He later developed developmental delay, bilateral profound sensorineural deafness, and failure to thrive. Homozygous for AP1B1 NM_001127:c.38-1G>A, p.(Glu14Argfs∗5) - clinical exome.


PMID: 33452671 Vornweg et al., 2021
Female patient with compound het mutations in AP1B1: c.322C>T (p. Arg108Trp) and c.2254delC (p.Leu752Serfs*26). Method: WES + Sanger. Presented with ichthyosiform erythroderma and chronic, severe pruritus from birth; global developmental delay and failure to thrive, thickened plantar surface, bilateral ectropion and partial alopecia. Molecular examination demonstrated complete loss of AP1B1 protein in epidermis and isolated keratinocytes from patient’s skin.

PMID: 33349978 Ito et al., 2021
Report of 2yo Japanese boy. Compound het for AP1B1 c.1852C>T p.Gln618* and 2677C>T p.Gln893*. Method: WES. Presented with ichthyosis, moderate motor & mental retardation, failed the auditory brainstem response test bilatreally. Low calcium and serum copper levels.

Severe failure to thrive and developmental delay within the first months of life seem to be compensated in later childhood.


AP1B1 is associated with Keratitis-ichthyosis-deafness syndrome, autosomal recessive, 242150 in OMIM (accessed 17th Oct 2025).
Intellectual disability v9.136 AP1B1 Ida Ertmanska commented on gene: AP1B1
Ataxia and cerebellar anomalies - narrow panel v8.25 HEATR5B Arina Puzriakova changed review comment from: Comment on list classification: There are three unrelated cases (2 published, 1 NHS-diagnosed) with pontocerebellar hypoplasia due to biallelic LOF variants in this gene. Tagging for additional expert review to gain approval for including the unpublished case as evidence to promote this gene to Green.; to: Comment on list classification: There are three unrelated cases (2 published, 1 NHS-diagnosed) with pontocerebellar hypoplasia due to biallelic LOF variants in this gene. Tagging for expert review to gain GMS approval for including the unpublished case as evidence to promote this gene to Green.
Ataxia and cerebellar anomalies - narrow panel v8.25 HEATR5B Arina Puzriakova Classified gene: HEATR5B as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.25 HEATR5B Arina Puzriakova Added comment: Comment on list classification: There are three unrelated cases (2 published, 1 NHS-diagnosed) with pontocerebellar hypoplasia due to biallelic LOF variants in this gene. Tagging for additional expert review to gain approval for including the unpublished case as evidence to promote this gene to Green.
Ataxia and cerebellar anomalies - narrow panel v8.25 HEATR5B Arina Puzriakova Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v5.3 DISP1 Ida Ertmanska commented on gene: DISP1: Comment on list classification: As reviewed by Nour Elkhateeb, there are at least 25 individuals reported in literature with DISP1 variants, who presented with Holoprosencephaly of variable severity. Hence, DISP1 should be rated green on the Holoprosencephaly - NOT chromosomal panel. The MOI should be set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v8.24 HEATR5B Arina Puzriakova Tag watchlist was removed from gene: HEATR5B.
Tag Q3_25_promote_green tag was added to gene: HEATR5B.
Tag Q3_25_expert_review tag was added to gene: HEATR5B.
Ataxia and cerebellar anomalies - narrow panel v8.24 HEATR5B Arina Puzriakova commented on gene: HEATR5B
Cerebellar hypoplasia v1.81 HEATR5B Arina Puzriakova Classified gene: HEATR5B as Green List (high evidence)
Cerebellar hypoplasia v1.81 HEATR5B Arina Puzriakova Added comment: Comment on list classification: Upgrading from Amber to Green on this 100K panel as there are three unrelated cases (2 published, 1 NHS-diagnosed) with pontocerebellar hypoplasia due to biallelic variants in this gene.
Cerebellar hypoplasia v1.81 HEATR5B Arina Puzriakova Gene: heatr5b has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.80 HEATR5B Arina Puzriakova Tag watchlist was removed from gene: HEATR5B.
Cerebellar hypoplasia v1.80 HEATR5B Arina Puzriakova commented on gene: HEATR5B
Holoprosencephaly v5.3 DISP1 Ida Ertmanska changed review comment from: PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7). As 5 out of 9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. Sequencing method: WES. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7/25). As 5/9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Holoprosencephaly v5.3 DISP1 Ida Ertmanska changed review comment from: PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7). As 5 out of 9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).; to: PMID: 38529886 Lavillaureix et al., 2024
25 individuals with midline craniofacial defects, harbouring 23 DISP1 variants identified in heterozygous, compound heterozygous or homozygous states. The patients presented with holoprosencephaly of variable severity: microform (14/25), lobar (2/25), semi-alobar (2/25), and alobar (7). As 5 out of 9 patients with severe (alobar or semi-lobar) HPE had DISP1 variants as well as variants in other known HPE-linked genes from the SHH pathway (eg, SIX3, SHH, and PTCH1), the authors suggest oligogenic inheritance. Milder presentations (microform and lobar generally seem to arise either from monoallelic truncating variants, or biallelic missense variants in DISP1.

This gene is associated with AR/AD Holoprosencephaly 10, 621143 in OMIM (accessed 17th Oct 2025).
Holoprosencephaly v5.3 DISP1 Ida Ertmanska edited their review of gene: DISP1: Changed phenotypes to: Holoprosencephaly 10, OMIM:621143, holoprosencephaly 10, MONDO:0976262
Holoprosencephaly v5.3 DISP1 Ida Ertmanska reviewed gene: DISP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38529886; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.136 RELN Achchuthan Shanmugasundram commented on gene: RELN: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Intellectual disability is one of the presenting phenotypes of this disease as recorded in OMIM (MIM # 257320, record accessed on 17 October 2025). Biallelic RELN variants are also associated with the same phenotype with 'definitive' rating on the DD panel in Gene2Phenotype.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, the recent cases reported in PMID:35769015 were not included in ClinGen curation.

PMID:35769015 reported 13 individuals from seven families with seven different heterozygous variants. Of these 13 individuals, 6 patients from four families had moderate/ severe intellectual disability, while 4 patients had mild ID and one had ID of unspecified severity.
Intellectual disability v9.136 SOD1 Arina Puzriakova Classified gene: SOD1 as Amber List (moderate evidence)
Intellectual disability v9.136 SOD1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Inclusion on this panel would also ensure inclusion on the Hypotonic Infant super panel which is a significant feature observed in affected individuals.
Intellectual disability v9.136 SOD1 Arina Puzriakova Gene: sod1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.22 SOD1 Arina Puzriakova Classified gene: SOD1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.22 SOD1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v8.22 SOD1 Arina Puzriakova Gene: sod1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.135 SOD1 Arina Puzriakova changed review comment from: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature; to: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy (PMIDs: 31314961; 31332433; 34380534; 34788402; 36935613; 39629626)

This gene is associated with a relevant phenotype in OMIM - Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598 (accessed on 17-10-2025)
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.21 SOD1 Arina Puzriakova changed review comment from: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature; to: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy. (PMIDs: 31314961; 31332433; 34380534; 34788402; 36935613; 39629626)

This gene is associated with a relevant phenotype in OMIM - Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598 (accessed on 17-10-2025)
Sources: Literature
Intellectual disability v9.135 SOD1 Arina Puzriakova gene: SOD1 was added
gene: SOD1 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: SOD1.
Mode of inheritance for gene: SOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOD1 were set to 31314961; 31332433; 34380534; 34788402; 36935613; 39629626
Phenotypes for gene: SOD1 were set to Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598
Review for gene: SOD1 was set to GREEN
Added comment: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.21 SOD1 Arina Puzriakova gene: SOD1 was added
gene: SOD1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: SOD1.
Mode of inheritance for gene: SOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOD1 were set to 31314961; 31332433; 34380534; 34788402; 36935613; 39629626
Phenotypes for gene: SOD1 were set to Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598
Review for gene: SOD1 was set to GREEN
Added comment: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature
Intellectual disability v9.134 RELN Achchuthan Shanmugasundram changed review comment from: In addition to previously reported cases, PMID:35769015 reported four families with biallelic RELN variants and neurodevelopmental disorder, of which one patient had global developmental delay and patients from another unrelated family had severe intellectual disability.

PMID:35769015 also reported seven unrelated families with monoallelic RELN variants and neurodevelopmental disorder, of which patients from three families had mild-severe intellectual disability.

Biallelic variants have been associated with Lissencephaly 2 in both OMIM (MIM #257320) and Gene2Phenotype (with 'definitive' rating in the DD panel), and impaired intellectual development has been associated as one of the clinical presentations in OMIM. Monoallelic variants have been associated with "{Epilepsy, familial temporal lobe, 7}" (MIM # 616436) in OMIM, which does not currently record ID as one of the clinical presentations.; to: In addition to previously reported cases, PMID:35769015 reported four families with biallelic RELN variants and neurodevelopmental disorder, of which one patient had global developmental delay and patients from another unrelated family had severe intellectual disability.

PMID:35769015 also reported seven unrelated families with monoallelic RELN variants and neurodevelopmental disorder, of which patients from all seven families had mild-severe intellectual disability.

Biallelic variants have been associated with Lissencephaly 2 in both OMIM (MIM #257320) and Gene2Phenotype (with 'definitive' rating in the DD panel), and impaired intellectual development has been associated as one of the clinical presentations in OMIM. Monoallelic variants have been associated with "{Epilepsy, familial temporal lobe, 7}" (MIM # 616436) in OMIM, which does not currently record ID as one of the clinical presentations.
Primary lymphoedema v4.10 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed phenotypes to: Aagenaes syndrome, MONDO:0008966
Primary immunodeficiency or monogenic inflammatory bowel disease v8.53 CD274 Arina Puzriakova edited their review of gene: CD274: Changed rating: RED
Primary immunodeficiency or monogenic inflammatory bowel disease v8.53 CD274 Arina Puzriakova Classified gene: CD274 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.53 CD274 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single family has been reported to date with a biallelic variant (c.682+1G>A) in this gene linked to an autoimmune disorder characterised by neonatal-onset type 1 diabetes mellitus due to complete insulin deficiency (PMID: 38634869)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.53 CD274 Arina Puzriakova Gene: cd274 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.52 CD274 Arina Puzriakova Publications for gene: CD274 were set to PMID: 38634869
Primary immunodeficiency or monogenic inflammatory bowel disease v8.51 CD274 Arina Puzriakova Phenotypes for gene: CD274 were changed from ?Autoimmune disease, multisystem, infantile-onset, 5 to ?Autoimmune disease, multisystem, infantile-onset, 5, OMIM:621235
Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Classified gene: KIRREL3 as Green List (high evidence)
Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As the evidence for the association of KIRREL3 gene with neurodevelopmental disorder is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Intellectual disability v9.134 KIRREL3 Achchuthan Shanmugasundram Gene: kirrel3 has been classified as Green List (High Evidence).
Intellectual disability v9.133 KIRREL3 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: KIRREL3.
Tag disputed tag was added to gene: KIRREL3.
Tag Q3_25_demote_red tag was added to gene: KIRREL3.
Intellectual disability v9.133 KIRREL3 Achchuthan Shanmugasundram Phenotypes for gene: KIRREL3 were changed from Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947 to complex neurodevelopmental disorder, MONDO:0100038
Intellectual disability v9.132 KIRREL3 Achchuthan Shanmugasundram Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164
Intellectual disability v9.131 NAA60 Arina Puzriakova Phenotypes for gene: NAA60 were changed from Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786; basal ganglia calcification, idiopathic, 9, autosomal recessive, MONDO:0968977 to Basal ganglia calcification, idiopathic, 9, autosomal recessive, OMIM:620786; basal ganglia calcification, idiopathic, 9, autosomal recessive, MONDO:0968977
Intellectual disability v9.130 KIRREL3 Achchuthan Shanmugasundram edited their review of gene: KIRREL3: Added comment: Monoallelic variants in KIRREL3 gene have been associated with complex neurodevelopmental disorder (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005235).

ClinGen curation reported the reason for 'Disputed' rating as below:
To date, over 20 probands (PMIDs: 29271092, 32503885, 37007974) with KIRREL3 truncating or missense variants and complex neurodevelopmental disorder have been reported. However, none of the missense variants were scored due to their presence in gnomAD and/or inheritance from reportedly unaffected parents and a lack of evidence of pathogenicity. Although three truncating variants were reported, KIRREL3 is not constrained for truncating variants (pLI = 0, gnomAD v4.0.0) or missense variants (Z = 1.59). Hence, the truncating variants were also not scored. Although functional in vitro studies of five KIRREL3 missense variants observed in affected individuals showed decreased synapse formation in hippocampal neurons, and studies in homozygous null Kirrel3-/- mice and synapse deficits in cultured Kirrel3+/- mouse hippocampal neurons suggest that KIRREL3 plays a role in central nervous system development, none of the experimental evidence was scored due to the lack of compelling genetic evidence.

Small variants in this gene have not been associated with any phenotypes ion OMIM (record accessed on 17 October 2025). This gene is also associated with 'limited' rating on the DD panel of Gene2Phenotype and with red rating on the 'Intellectual disability syndromic and non-syndromic' panel of PanelApp Australia (https://panelapp-aus.org/panels/250/gene/KIRREL3/).; Changed rating: RED; Changed publications to: 19012874, 29271092, 32503885, 37007974
Intellectual disability v9.130 NAA60 Arina Puzriakova Classified gene: NAA60 as Red List (low evidence)
Intellectual disability v9.130 NAA60 Arina Puzriakova Gene: naa60 has been classified as Red List (Low Evidence).
Cholestasis v3.12 UNC45A Arina Puzriakova Publications for gene: UNC45A were set to 29429573
Primary lymphoedema v4.10 UNC45A Arina Puzriakova Publications for gene: UNC45A were set to PMID: 37328071; PMID: 39887522
Primary lymphoedema v4.9 UNC45A Arina Puzriakova Phenotypes for gene: UNC45A were changed from lymphedema in the lower and upper limbs; cholestasis; hyperbilirubinemia; increased concentrations of bile acids in blood to Aagenaes syndrome, MONDO:0008966
Cholestasis v3.11 UNC45A Arina Puzriakova Phenotypes for gene: UNC45A were changed from Cholestasis; Diarrhoea; Bone fragility; Impaired hearing to Osteootohepatoenteric syndrome, OMIM:619377; Aagenaes syndrome, MONDO:0008966
Primary lymphoedema v4.8 UNC45A Arina Puzriakova Classified gene: UNC45A as Amber List (moderate evidence)
Primary lymphoedema v4.8 UNC45A Arina Puzriakova Gene: unc45a has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v4.7 UNC45A Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: UNC45A.
Tag Q3_25_NHS_review tag was added to gene: UNC45A.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.50 INO80 Achchuthan Shanmugasundram Classified gene: INO80 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.50 INO80 Achchuthan Shanmugasundram Added comment: Comment on list classification: As the evidence for the association of INO80 gene with immunodeficiency is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.50 INO80 Achchuthan Shanmugasundram Gene: ino80 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.49 INO80 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: INO80.
Tag disputed tag was added to gene: INO80.
Tag Q3_25_demote_red tag was added to gene: INO80.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.49 INO80 Achchuthan Shanmugasundram Phenotypes for gene: INO80 were changed from INO80 deficiency, HIGM; severe bacterial infections; Severe bacterial infections; Predominantly Antibody Deficiencies to common variable immunodeficiency, MONDO:0015517
Primary immunodeficiency or monogenic inflammatory bowel disease v8.48 INO80 Achchuthan Shanmugasundram Publications for gene: INO80 were set to 25883595; 25312759
Primary immunodeficiency or monogenic inflammatory bowel disease v8.47 INO80 Achchuthan Shanmugasundram reviewed gene: INO80: Rating: RED; Mode of pathogenicity: None; Publications: 25312759; Phenotypes: common variable immunodeficiency, MONDO:0015517; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-syndromic familial congenital anorectal malformations v1.13 LINC01082 Achchuthan Shanmugasundram Classified gene: LINC01082 as Red List (low evidence)
Non-syndromic familial congenital anorectal malformations v1.13 LINC01082 Achchuthan Shanmugasundram Gene: linc01082 has been classified as Red List (Low Evidence).
Non-syndromic familial congenital anorectal malformations v1.12 LINC01082 Achchuthan Shanmugasundram Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317
Non-syndromic familial congenital anorectal malformations v1.11 LINC01081 Achchuthan Shanmugasundram Classified gene: LINC01081 as Red List (low evidence)
Non-syndromic familial congenital anorectal malformations v1.11 LINC01081 Achchuthan Shanmugasundram Gene: linc01081 has been classified as Red List (Low Evidence).
Non-syndromic familial congenital anorectal malformations v1.10 LINC01081 Achchuthan Shanmugasundram Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317
Glaucoma (developmental) v1.46 FOXD3 Achchuthan Shanmugasundram Classified gene: FOXD3 as Red List (low evidence)
Glaucoma (developmental) v1.46 FOXD3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As the evidence for the association of FOXD3 gene with eye disorder is disputed, this gene is demoted to red rating.
Glaucoma (developmental) v1.46 FOXD3 Achchuthan Shanmugasundram Gene: foxd3 has been classified as Red List (Low Evidence).
Structural eye disease v4.34 FOXD3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As the evidence for the association of FOXDe3 gene with eye disorder is disputed, this gene should be considered for demotion to red rating in the next GMS update.; to: Comment on list classification: As the evidence for the association of FOXD3 gene with eye disorder is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Glaucoma (developmental) v1.45 FOXD3 Achchuthan Shanmugasundram reviewed gene: FOXD3: Rating: RED; Mode of pathogenicity: None; Publications: 22815627; Phenotypes: aniridia, MONDO:0019172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v4.34 FOXD3 Achchuthan Shanmugasundram Tag disputed tag was added to gene: FOXD3.
Structural eye disease v4.34 FOXD3 Achchuthan Shanmugasundram Classified gene: FOXD3 as Green List (high evidence)
Structural eye disease v4.34 FOXD3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As the evidence for the association of FOXDe3 gene with eye disorder is disputed, this gene should be considered for demotion to red rating in the next GMS update.
Structural eye disease v4.34 FOXD3 Achchuthan Shanmugasundram Gene: foxd3 has been classified as Green List (High Evidence).
Structural eye disease v4.33 FOXD3 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: FOXD3.
Tag Q3_25_demote_red tag was added to gene: FOXD3.
Structural eye disease v4.33 FOXD3 Achchuthan Shanmugasundram reviewed gene: FOXD3: Rating: RED; Mode of pathogenicity: None; Publications: 22815627; Phenotypes: aniridia, MONDO:0019172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram Classified gene: CHRNA2 as Green List (high evidence)
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are three unrelated cases reported with familial sleep-related hypermotor epilepsy phenotype despite limited rating in ClinGen, this gene can remain amber on this panel.
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram Gene: chrna2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.

This gene is also present with monoallelic MOI and green rating in Genetic Epilepsy panel of PanelApp Australia (https://panelapp-aus.org/panels/202/gene/CHRNA2/).; to: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.

This gene is also present with monoallelic MOI and green rating in Genetic Epilepsy panel of PanelApp Australia (https://panelapp-aus.org/panels/202/gene/CHRNA2/).
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.; to: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.

This gene is also present with monoallelic MOI and green rating in Genetic Epilepsy panel of PanelApp Australia (https://panelapp-aus.org/panels/202/gene/CHRNA2/).
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram edited their review of gene: CHRNA2: Changed publications to: 16826524, 25770198, 25847220, 30809122
Rare anaemia v3.13 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia.

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12 - transient. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Schmitt et al., 2005). The presentation does not usually include anaemia.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram Publications for gene: CHRNA2 were set to 16826524; 2577019; 25847220; 30809122
Early onset or syndromic epilepsy v8.43 CHRNA2 Achchuthan Shanmugasundram Publications for gene: CHRNA2 were set to Aridon et al (2006) Am J Hum Genet 79: 342-350
Early onset or syndromic epilepsy v8.42 CHRNA2 Achchuthan Shanmugasundram Phenotypes for gene: CHRNA2 were changed from Epilepsy, nocturnal frontal lobe, type 4 to Epilepsy, nocturnal frontal lobe, type 4, OMIM:610353; autosomal dominant nocturnal frontal lobe epilepsy 4, MONDO:0012474
Early onset or syndromic epilepsy v8.41 CHRNA2 Achchuthan Shanmugasundram reviewed gene: CHRNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826524, 2577019, 25847220, 30809122; Phenotypes: Epilepsy, nocturnal frontal lobe, type 4, OMIM:610353, autosomal dominant nocturnal frontal lobe epilepsy 4, MONDO:0012474; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Non-syndromic familial congenital anorectal malformations v1.9 LINC01082 Ida Ertmanska reviewed gene: LINC01082: Rating: RED; Mode of pathogenicity: None; Publications: 27071622; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Non-syndromic familial congenital anorectal malformations v1.9 LINC01081 Ida Ertmanska reviewed gene: LINC01081: Rating: RED; Mode of pathogenicity: None; Publications: 27071622; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.6 LINC01082 Ida Ertmanska edited their review of gene: LINC01082: Changed phenotypes to: Alveolar capillary dysplasia with misalignment of pulmonary veins
Fetal anomalies v6.101 LINC01082 Ida Ertmanska edited their review of gene: LINC01082: Changed phenotypes to: Alveolar capillary dysplasia with misalignment of pulmonary veins
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.6 LINC01081 Ida Ertmanska edited their review of gene: LINC01081: Changed phenotypes to: Alveolar capillary dysplasia with misalignment of pulmonary veins
Fetal anomalies v6.101 LINC01081 Ida Ertmanska edited their review of gene: LINC01081: Changed phenotypes to: Alveolar capillary dysplasia with misalignment of pulmonary veins
Primary immunodeficiency or monogenic inflammatory bowel disease v8.47 ANKZF1 Achchuthan Shanmugasundram commented on gene: ANKZF1: ClinGen has classified this gene as 'No Known Disease Relationship' based on mode of inheritance is undertemined by the Primary Immune Regulatory Disorders expert panel (https://search.clinicalgenome.org/CCID:008790). However, they made the decision based on the evidence provided only from PMID:28302725. This publication reported two biallelic cases and two monoallelic cases. However, there was third monoallelic case reported in PMID:36857589.

This gene is also rated green for monoallelic MOI by PanelApp Australia on Inflammatory bowel disease panel (https://panelapp-aus.org/panels/123/gene/ANKZF1/).

This gene should therefore remain green on this panel.
Likely inborn error of metabolism v8.68 CD320 Achchuthan Shanmugasundram Classified gene: CD320 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.68 CD320 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there is sufficient evidence available (at least eight unrelated families) for the association of biallelic CD320 variants with 'Methylmalonic aciduria, transient, due to transcobalamin receptor defect', the reported individuals had no major health or developmental concerns.

As it is a benign condition, this gene is rated amber for now.
Likely inborn error of metabolism v8.68 CD320 Achchuthan Shanmugasundram Gene: cd320 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.67 CD320 Achchuthan Shanmugasundram Phenotypes for gene: CD320 were changed from Methylmalonic aciduria due to transcobalamin receptor defect to Methylmalonic aciduria, transient, due to transcobalamin receptor defect, OMIM:613646; methylmalonic acidemia due to transcobalamin receptor defect, MONDO:0013341
Likely inborn error of metabolism v8.66 CD320 Achchuthan Shanmugasundram Publications for gene: CD320 were set to 27604308; 20524213
Likely inborn error of metabolism v8.65 CD320 Achchuthan Shanmugasundram Mode of inheritance for gene: CD320 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.64 CD320 Achchuthan Shanmugasundram reviewed gene: CD320: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria, transient, due to transcobalamin receptor defect, OMIM:613646, methylmalonic acidemia due to transcobalamin receptor defect, MONDO:0013341; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.6 LINC01081 Achchuthan Shanmugasundram Tag cnv tag was added to gene: LINC01081.
Fetal anomalies v6.101 LINC01081 Achchuthan Shanmugasundram Tag cnv tag was added to gene: LINC01081.
Tag Q3_25_promote_green tag was added to gene: LINC01081.
Tag Q3_25_expert_review tag was added to gene: LINC01081.
Tag Q3_25_NHS_review tag was added to gene: LINC01081.
Fetal anomalies v6.101 LINC01081 Achchuthan Shanmugasundram Classified gene: LINC01081 as Amber List (moderate evidence)
Fetal anomalies v6.101 LINC01081 Achchuthan Shanmugasundram Gene: linc01081 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.100 LINC01081 Achchuthan Shanmugasundram Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.6 LINC01082 Achchuthan Shanmugasundram Tag cnv tag was added to gene: LINC01082.
Fetal anomalies v6.99 LINC01082 Achchuthan Shanmugasundram Tag cnv tag was added to gene: LINC01082.
Tag Q3_25_promote_green tag was added to gene: LINC01082.
Tag Q3_25_expert_review tag was added to gene: LINC01082.
Tag Q3_25_NHS_review tag was added to gene: LINC01082.
Fetal anomalies v6.99 LINC01082 Achchuthan Shanmugasundram Classified gene: LINC01082 as Amber List (moderate evidence)
Fetal anomalies v6.99 LINC01082 Achchuthan Shanmugasundram Gene: linc01082 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.98 LINC01082 Achchuthan Shanmugasundram Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317
Structural eye disease v4.33 RDH5 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed 15th October 2025
Structural eye disease v4.33 RDH5 Eleanor Williams Phenotypes for gene: RDH5 were changed from Fundus albipunctatus, 136880; Eye Disorders to Fundus albipunctatus, OMIM:136880 fundus albipunctatus, MONDO:0007639
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.6 LINC01082 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LINC01082.
Tag Q3_25_expert_review tag was added to gene: LINC01082.
Tag Q3_25_NHS_review tag was added to gene: LINC01082.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.6 LINC01082 Achchuthan Shanmugasundram Classified gene: LINC01082 as Amber List (moderate evidence)
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.6 LINC01082 Achchuthan Shanmugasundram Gene: linc01082 has been classified as Amber List (Moderate Evidence).
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.5 LINC01082 Achchuthan Shanmugasundram Publications for gene: LINC01082 were set to PMID: 27071622; PMID: 27822317
Retinal disorders v8.55 RDH5 Eleanor Williams Added comment: Comment on mode of inheritance: Recommendation that the mode of inheritance be updated to Biallelic only. Only 2 cases with single heterozygous variants were reported in a single publication from 2012 with no further cases reported since
Retinal disorders v8.55 RDH5 Eleanor Williams Mode of inheritance for gene: RDH5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v8.54 RDH5 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 15th October 2025
Retinal disorders v8.54 RDH5 Eleanor Williams Phenotypes for gene: RDH5 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Congenital Stationary Night Blindness; Fundus albipunctatus, 136880; Fundus albipunctatus to Fundus albipunctatus, OMIM:136880; fundus albipunctatus, MONDO:0007639
Retinal disorders v8.53 RDH5 Eleanor Williams Publications for gene: RDH5 were set to 21529959; 34726233
Retinal disorders v8.52 RDH5 Eleanor Williams Tag Q3_25_MOI tag was added to gene: RDH5.
Retinal disorders v8.52 RDH5 Eleanor Williams edited their review of gene: RDH5: Changed phenotypes to: Fundus albipunctatus, OMIM:136880, fundus albipunctatus, MONDO:0007639
Retinal disorders v8.52 RDH5 Eleanor Williams reviewed gene: RDH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 21529959,, 22815624, 10369264, 25820994, 32232344; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.4 LINC01081 Achchuthan Shanmugasundram Publications for gene: LINC01081 were set to PMID: 27071622; PMID: 27822317
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.3 LINC01081 Achchuthan Shanmugasundram Classified gene: LINC01081 as Amber List (moderate evidence)
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.3 LINC01081 Achchuthan Shanmugasundram Gene: linc01081 has been classified as Amber List (Moderate Evidence).
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Achchuthan Shanmugasundram Tag Q3_25_NHS_review tag was added to gene: LINC01081.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LINC01081.
Tag Q3_25_expert_review tag was added to gene: LINC01081.
Likely inborn error of metabolism v8.64 ACOX2 Achchuthan Shanmugasundram Classified gene: ACOX2 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.64 ACOX2 Achchuthan Shanmugasundram Gene: acox2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.63 ACOX2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ACOX2.
Likely inborn error of metabolism v8.63 ACOX2 Achchuthan Shanmugasundram Publications for gene: ACOX2 were set to 27647924; 27884763; 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated individuals with biallelic variants in ACOX2, presenting with persistent elevation of transaminase levels and C27 intermediate bile acids. 2 patients had liver fibrosis and developmental delay. Based on the available evidence, this gene should be rated Green for Likely inborn error of metabolism.; to: Comment on list classification: There are at least 7 unrelated individuals with biallelic variants in ACOX2, presenting with persistent elevation of transaminase levels and C27 intermediate bile acids. 2 patients had liver fibrosis and developmental delay. The association is supported by a mouse model, where Acox2 knockout resulted in elevated hepatic transaminases, liver fibrosis and hepatic inflammation.
Based on the available evidence, this gene should be rated Green for Likely inborn error of metabolism.
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska commented on gene: ACOX2: Comment on list classification: There are at least 7 unrelated individuals with biallelic variants in ACOX2, presenting with persistent elevation of transaminase levels and C27 intermediate bile acids. 2 patients had liver fibrosis and developmental delay. Based on the available evidence, this gene should be rated Green for Likely inborn error of metabolism.
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Paediatric disorders - additional genes v7.12 ISL1 Achchuthan Shanmugasundram Classified gene: ISL1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.12 ISL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic ISL1 variants with congenital heart disease. Hence, this gene should be promoted to green rating in the next GMS update.
Paediatric disorders - additional genes v7.12 ISL1 Achchuthan Shanmugasundram Gene: isl1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 29287774, 33340570, 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.


PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018
Report of a girl of Pakistani origin, consanguineous parents. Homozygous for a 4-nucleotide deletion in ACOX2: c.461-464delTCTG (p.Thr154Serfs*25). Presented at birth with thoracolumbar scoliosis, arthrogryposis, neuropathy and myopathy. Patient died at around 6 months, after intensive support was withdrawn. Disproportionate increase of the peroxisomal C27-bile acid intermediates was observed. Absence of ACOX2 protein in patient's fibroblast homogenate was shown by immunoblot. Seq method: panel 26 peroxisomal genes - other variants likely contributed to the severity of the phenotype in this patient.


PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Paediatric disorders - additional genes v7.11 ISL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ISL1.
Paediatric disorders - additional genes v7.11 ISL1 Achchuthan Shanmugasundram gene: ISL1 was added
gene: ISL1 was added to Paediatric disorders - additional genes. Sources: ClinGen
Mode of inheritance for gene: ISL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ISL1 were set to 25077177; 30390123; 31484864; 32820510; 34260301
Phenotypes for gene: ISL1 were set to congenital heart disease, MONDO:0005453
Review for gene: ISL1 was set to GREEN
Added comment: Monoallelic variants in ISL1 have been associated with 'congenital heart disease' (MONDO:0005453) with a 'definitive' rating by the Congenital Heart Disease expert panel in ClinGen (https://search.clinicalgenome.org/CCID:008371).

There are at least five unrelated patients reported with CHD and with heterozygous ISL1 variants (including gene deletion, nonsense and promotor variants).

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Sources: ClinGen
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 29287774, 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal. This variants seems to be associated with a mild phenotype.

PMID: 29287774 Ferdinandusse et al., 2018

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.


This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.
Case 3: 15yo male, Spanish; presented with abdominal distension, steatorrhea, and hypertransaminasemia with childhood onset; liver biopsy showed slight fibrosis. Compound het for c.673C>T, p.(Arg225Trp) and c.456_459del, p.(Thr154Serfs*25). Het parents unaffected.
Case 4: 7yo boy; presented with congenital heart disease (mild mitral stenosis, and moderate‐severe aortic insufficiency) with slight developmental delay and oscillating hypertransaminasemia. Compound het: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). Elevated C27‐BA proportion, treated with UDCA.

Zhang Y, et al., 2021, PMID: 33340570: ACOX2 KO mice had elevated hepatic transaminases, liver fibrosis and hepatic inflammation.

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

PMID: 35395098 Alonso-Pena et al., 2022
c.673C>T (p.Arg225Trp) was found in homozygosity in two patients (Case 1 & Case 2) with unexplained hypertransaminasemia. Impaired liver expression of ACOX2 was found by immunohistochemistry. Hypertransaminasemia was successfully treated with UDCA.


This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Congenital disorders of glycosylation v7.11 A4GALT Achchuthan Shanmugasundram Classified gene: A4GALT as No list
Congenital disorders of glycosylation v7.11 A4GALT Achchuthan Shanmugasundram Gene: a4galt has been removed from the panel.
Congenital disorders of glycosylation v7.10 A4GALT Achchuthan Shanmugasundram Tag curated_removed tag was added to gene: A4GALT.
Congenital disorders of glycosylation v7.10 A4GALT Achchuthan Shanmugasundram Phenotypes for gene: A4GALT were changed from congenital disorder of glycosylation, MONDO:0015286 to [Blood group, P1Pk system, p phenotype], OMIM:111400
Congenital disorders of glycosylation v7.9 A4GALT Achchuthan Shanmugasundram Publications for gene: A4GALT were set to 12823750,15142124; 10747952; 10993874; 11896312; 27612185
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Method: Exome sequencing. Patient presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017
16yo male with persistent hypertransaminasemia, homozygous for c.673C>T; R225W. Patient's serum and urine showed negligible amounts of C24 bile acids, but augmented levels of C27 intermediates. Liver histology was normal.

This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098).

The association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024). The gene is also associated with Bile acid synthesis defect, congenital, 6, 617308 in OMIM (accessed 15th Oct 2025).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 35395098
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

PMID:27884763 Monte et al., 2017

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska changed review comment from: The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Sources: Other, ClinGen; to: PMID: 27647924 Vilarinho et al., 2016
8-y-old Turkish male from a consanguineous family. Homozygous for NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter). Presented with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Proband’s plasma and urine had strikingly elevated levels of the C27 intermediate bile acids. Absence of ACOX2 in the proband’s liver demonstrated using immunohistochemistry.

The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Likely inborn error of metabolism v8.62 ACOX2 Ida Ertmanska edited their review of gene: ACOX2: Changed publications to: 27647924, 27884763, 2928777435395098
Primary immunodeficiency or monogenic inflammatory bowel disease v8.47 IFNAR1 Achchuthan Shanmugasundram Classified gene: IFNAR1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.47 IFNAR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of biallelic IFNAR1 variants with immunodeficiency, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.47 IFNAR1 Achchuthan Shanmugasundram Gene: ifnar1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.46 IFNAR1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: IFNAR1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.46 IFNAR1 Achchuthan Shanmugasundram Phenotypes for gene: IFNAR1 were changed from IFNAR1 associated adverse reactions to certain live attenuated viral vaccines to Immunodeficiency 106, susceptibility to viral infections, OMIM:619935; immunodeficiency 106, susceptibility to viral infections, MONDO:0030970
Primary immunodeficiency or monogenic inflammatory bowel disease v8.45 IFNAR1 Achchuthan Shanmugasundram Publications for gene: IFNAR1 were set to 31270247; 26676772; 20020050
Primary immunodeficiency or monogenic inflammatory bowel disease v8.44 IFNAR1 Achchuthan Shanmugasundram reviewed gene: IFNAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31270247, 33252644, 32960813, 35442418, 35091979; Phenotypes: Immunodeficiency 106, susceptibility to viral infections, OMIM:619935, immunodeficiency 106, susceptibility to viral infections, MONDO:0030970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.52 DHX38 Arina Puzriakova Classified gene: DHX38 as Amber List (moderate evidence)
Retinal disorders v8.52 DHX38 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - three different homozygous variants identified in four families with retinitis pigmentosa and a zebrafish knockout model supporting a role in retinal development (PMID: 24737827; 30208423; 35719279; 37867960)
Retinal disorders v8.52 DHX38 Arina Puzriakova Gene: dhx38 has been classified as Amber List (Moderate Evidence).
Extreme early-onset hypertension v1.22 HSD11B2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes last accessed on 15 October 2025.
Extreme early-onset hypertension v1.22 HSD11B2 Achchuthan Shanmugasundram Phenotypes for gene: HSD11B2 were changed from Apparent mineralocorticoid excess, 218030 to Apparent mineralocorticoid excess, OMIM:218030; apparent mineralocorticoid excess, MONDO:0009025
Likely inborn error of metabolism v8.62 HSD11B2 Achchuthan Shanmugasundram Classified gene: HSD11B2 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.62 HSD11B2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic HSD11B2 variants with AME. Hence, this gene can be promoted to green rating in the next GMS update.
Likely inborn error of metabolism v8.62 HSD11B2 Achchuthan Shanmugasundram Gene: hsd11b2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.51 DHX38 Arina Puzriakova Publications for gene: DHX38 were set to 24737827; 30208423
Retinal disorders v8.50 DHX38 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: DHX38.
Retinal disorders v8.50 DHX38 Arina Puzriakova reviewed gene: DHX38: Rating: GREEN; Mode of pathogenicity: None; Publications: 24737827, 30208423, 35719279, 37867960; Phenotypes: Retinitis pigmentosa 84, OMIM:618220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.61 HSD11B2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: HSD11B2.
Likely inborn error of metabolism v8.61 HSD11B2 Achchuthan Shanmugasundram gene: HSD11B2 was added
gene: HSD11B2 was added to Likely inborn error of metabolism. Sources: ClinGen
Mode of inheritance for gene: HSD11B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSD11B2 were set to 7670488; 7608290; 9683587; 17314322
Phenotypes for gene: HSD11B2 were set to Apparent mineralocorticoid excess, OMIM:218030; apparent mineralocorticoid excess, MONDO:0009025
Review for gene: HSD11B2 was set to GREEN
Added comment: Apparent mineralocorticoid excess (AME) is an autosomal recessive genetic disorder caused by the deficiency of the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2). This disorder is characterised by severe juvenile hypertension, metabolic alkalosis, hypernatremia, and hypokalemia.

Biallelic variants in HSD11B2 gene have been associated with apparent mineralocorticoid excess (MONDO:0009025) with a 'definitive' rating by the Tubulopathy expert panel in ClinGen (https://search.clinicalgenome.org/CCID:008414).

This gene is also associated with relevant phenotype in OMIM (MIM #218030, OMIM phenotype accessed on 15 October 2025).

There are more than 10 unrelated families reported with biallelic HSD11B2 variants and AME.
Sources: ClinGen
Likely inborn error of metabolism v8.60 ACOX2 Ida Ertmanska gene: ACOX2 was added
gene: ACOX2 was added to Likely inborn error of metabolism. Sources: Other,ClinGen
Mode of inheritance for gene: ACOX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACOX2 were set to 27647924; 27884763; 35395098
Phenotypes for gene: ACOX2 were set to Bile acid synthesis defect, congenital, 6, OMIM:617308
Review for gene: ACOX2 was set to GREEN
Added comment: The clinical presentation may be variable, but all reported probands to date have had elevated serum C27 bile acid intermediates, consistent with loss of ACOX2 enzyme activity. Three variants (missense, nonsense, frameshift) that have been reported in six probands in three publications (PMID: 27647924, 27884763, 35395098) are included in this publication. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, biochemical function, and an animal model (PMID: 8387517, 8943006, 29287774, 33736801, 31533369, 33340570, 35395098). Based on the available genetic and experimental evidence, the association between ACOX2 and autosomal recessive congenital bile acid synthesis defect 6 has been classified as Definitive in ClinGen (July 2024).
Sources: Other, ClinGen
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska edited their review of gene: A4GALT: Changed phenotypes to: [Blood group, P1Pk system, p phenotype], OMIM:111400
Retinal disorders v8.50 RLBP1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: All patients reported with the four different, but related phenotypes (MIMs #607475, #136880 & #607476) were identified with biallelic RLBP1 variants. There are no published reports associating monoallelic RLBP1 variants with any relevant phenotype. Hence, the MOI should be updated to 'BIALLELIC, autosomal or pseudoautosomal' in the next GMS update.
Retinal disorders v8.50 RLBP1 Achchuthan Shanmugasundram Mode of inheritance for gene: RLBP1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska changed review comment from: LoF variants in this gene lead to a rare 'P-Null' blood type (absence of P and Pk blood group antigens). The phenotype is usually spontaneous abortions and significant haemolytic complications upon transfusion of incompatible blood (PMID: 27612185 Li et al., 2017). While the mechanism is indeed a Congenital disorders of glycosylation (impaired Gb3/CD77 synthase activity), this phenotype does not fit into the scope of the panel.; to: LoF variants in this gene lead to a rare 'P-Null' blood type (absence of P and Pk blood group antigens). The phenotype is usually spontaneous abortions and significant haemolytic complications upon transfusion of incompatible blood (PMID: 27612185 Li et al., 2017). While the mechanism is indeed a Congenital disorders of glycosylation (impaired Gb3/CD77 synthase activity), testing for a rare blood group antigen does not fit into the scope of the panel.
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska edited their review of gene: A4GALT: Changed publications to: 27612185; Changed phenotypes to: [Blood group, P1PK system, P(k) phenotype], OMIM:111400; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska commented on gene: A4GALT
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska Deleted their review
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska changed review comment from: LoF variants in this gene lead to a rare 'P-Null' blood type (absence of P and Pk blood group antigens). The phenotype is usually spontaneous abortions and significant haemolytic complications upon transfusion of incompatible blood (PMID: 27612185 Li et al., 2017). While the mechanism is indeed a Congenital disorders of glycosylation (impaired Gb3/CD77 synthase activity), this phenotype does not fit into the scope of the panel. Hence, A4GALT should be rated Red for Congenital disorders of glycosylation.; to: LoF variants in this gene lead to a rare 'P-Null' blood type (absence of P and Pk blood group antigens). The phenotype is usually spontaneous abortions and significant haemolytic complications upon transfusion of incompatible blood (PMID: 27612185 Li et al., 2017). While the mechanism is indeed a Congenital disorders of glycosylation (impaired Gb3/CD77 synthase activity), this phenotype does not fit into the scope of the panel.
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska reviewed gene: A4GALT: Rating: RED; Mode of pathogenicity: None; Publications: 27612185; Phenotypes: [Blood group, P1Pk system, p phenotype], OMIM:111400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.49 RLBP1 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: RLBP1.
Retinal disorders v8.49 RLBP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 15 October 2025.
Retinal disorders v8.49 RLBP1 Achchuthan Shanmugasundram Phenotypes for gene: RLBP1 were changed from Bothnia retinal dystrophy; Fundus albipunctatus; Newfoundland rod - cone dystrophy; Retinitis punctata albescens; Fundus albipunctatus, 136880; Fundus Albipunctatus; Eye Disorders; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa to Fundus albipunctatus, OMIM:136880; Retinitis punctata albescens, OMIM:136880; Bothnia retinal dystrophy, OMIM:607475; Newfoundland rod-cone dystrophy, OMIM:607476
Retinal disorders v8.48 RLBP1 Achchuthan Shanmugasundram Publications for gene: RLBP1 were set to
Retinal disorders v8.47 RLBP1 Achchuthan Shanmugasundram reviewed gene: RLBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11176989, 11868161, 11453974, 21447491, 32345050, 37883093; Phenotypes: Fundus albipunctatus, OMIM:136880, Retinitis punctata albescens, OMIM:136880, Bothnia retinal dystrophy, OMIM:607475, Newfoundland rod-cone dystrophy, OMIM:607476; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). The majority of CNVs arose de novo on the maternal allele - suspected imprinting of paternal allele.
Based on the available evidence, this gene should be rated GREEN for Alveolar capillary dysplasia with misalignment of pulmonary veins.; to: Comment on list classification: There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Hence, the testing region should be expanded to include the enhancer.
The majority of CNVs arose de novo on the maternal allele - suspected imprinting of paternal allele.
Based on the available evidence, this gene should be rated GREEN for Alveolar capillary dysplasia with misalignment of pulmonary veins.
Fetal anomalies v6.97 LINC01082 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

There is only 1 individual with ACDMPV where only LINC01082 has been deleted, without affecting FOXF1 or LINC01081 (PMID: 24842713). At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01082 Ida Ertmanska edited their review of gene: LINC01082: Changed publications to: 19500772, 23034409, 24842713, 27071622, 36157490, 40869921
Fetal anomalies v6.97 LINC01082 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

Genomic positions reference (GRh37/hg19):
FOXF1 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01082 Ida Ertmanska Deleted their comment
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01082 Ida Ertmanska commented on gene: LINC01082: Comment on list classification: Genes in the FOXF1 enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). There is only 1 individual with ACDMPV where only LINC01082 has been deleted, without affecting FOXF1 or LINC01081 (PMID: 24842713). At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Hence, the testing region should be expanded to include the enhancer.
The majority of CNVs arose de novo on the maternal allele - suspected imprinting of paternal allele.
Based on the available evidence, this gene should be rated GREEN for Alveolar capillary dysplasia with misalignment of pulmonary veins.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01082 Ida Ertmanska reviewed gene: LINC01082: Rating: GREEN; Mode of pathogenicity: None; Publications: 19500772, 23034409, 24842713, 27071622; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.97 LINC01082 Ida Ertmanska commented on gene: LINC01082: Comment on list classification: Genes in the FOXF1 enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). There is only 1 individual with ACDMPV where only LINC01082 has been deleted, without affecting FOXF1 or LINC01081 (PMID: 24842713). At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Hence, the testing region should be expanded to include the enhancer.
The majority of CNVs arose de novo on the maternal allele - suspected imprinting of paternal allele.
Based on the available evidence, this gene should be rated GREEN for Alveolar capillary dysplasia with misalignment of pulmonary veins.
Fetal anomalies v6.97 LINC01082 Ida Ertmanska reviewed gene: LINC01082: Rating: GREEN; Mode of pathogenicity: None; Publications: 19500772, 23034409, 24842713, 27071622; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v4.32 DHX38 Arina Puzriakova Phenotypes for gene: DHX38 were changed from Retinitis pigmentosa 84, OMIM:618220 to Retinitis pigmentosa 84, OMIM:618220; coloboma of macula, MONDO:0007351
Structural eye disease v4.31 DHX38 Arina Puzriakova Phenotypes for gene: DHX38 were changed from Retinitis Pigmentosa and Macular Coloboma, 618220 to Retinitis pigmentosa 84, OMIM:618220
Retinal disorders v8.47 DHX38 Arina Puzriakova Phenotypes for gene: DHX38 were changed from Retinitis pigmentosa 84, 618220 to Retinitis pigmentosa 84, OMIM:618220
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

Genomic positions reference (GRh37/hg19):
FOXF1 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

Genomic positions reference (GRh37/hg19):
FOXF1 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

Genomic positions reference (GRh37/hg19):
FOXF1 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01081 Ida Ertmanska edited their review of gene: LINC01081: Changed publications to: 19500772, 23034409, 24842713, 27071622, 36157490, 40869921
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype.

There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409) - with LINC01082 and FOXF1 being intact. At least 10 other patients harboured a deletion that affected the wider FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622).
Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 40869921 Fumini et al., 2025
Review of nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward.

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Retinal disorders v8.46 SAG Achchuthan Shanmugasundram changed review comment from: PMID:28549094 (2017) reported the identification of a novel heterozygous variant in the SAG gene (c.440G>T/ p.Cys147Phe) in eight families in a cohort of 300 autosomal dominant retinitis pigmentosa (adRP) families. There were four additional families with adRP were reported in this study with the same heterozygous variant. All 12 families are of Hispanic descent from South Western United States. Haplotype analysis was consistent with a founder mutation event and a distant relationship between all of the families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls.

PMID:33047631 (2021) reported the identification of the same variant p.Cys147Phe variant in a 3-generation Australian family segregating with adRP. The mutation was found in the proband, his brother, and the brother's affected son, as well as in the proband's asymptomatic 10-year-old son who had not been examined. The variant was not found in the brother's asymptomatic son, who had a normal retinal examination at age 35 years.

PMID:40461169 (2025) reported the identification of a novel heterozygous SAG variant (c.442G>A/ p.Gly148Arg) in five unrelated families of Southern Chinese descent from Singapore with adRP. A shared haplotype of 3.2 Mb among four families suggested a founder effect.; to: PMID:28549094 (2017) reported the identification of a novel heterozygous variant in the SAG gene (c.440G>T/ p.Cys147Phe) in eight families in a cohort of 300 autosomal dominant retinitis pigmentosa (adRP) families. There were four additional families with adRP were reported in this study with the same heterozygous variant. All 12 families are of Hispanic descent from South Western United States. Haplotype analysis was consistent with a founder mutation event and a distant relationship between all of the families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls.

PMID:33047631 (2021) reported the identification of the same variant p.Cys147Phe variant in a 3-generation Australian family segregating with adRP. The mutation was found in the proband, his brother, and the brother's affected son, as well as in the proband's asymptomatic 10-year-old son who had not been examined. The variant was not found in the brother's asymptomatic son, who had a normal retinal examination at age 35 years.

PMID:40461169 (2025) reported the identification of a novel heterozygous SAG variant (c.442G>A/ p.Gly148Arg) in five unrelated families of Southern Chinese descent from Singapore with adRP. A shared haplotype of 3.2 Mb among four families suggested a founder effect.

The 'founder-effect' tag has been added as the two reported heterozygous variants are suggested to be founder variants.
Retinal disorders v8.46 SAG Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence for the association of both monoallelic and biallelic SAG variants with phenotypes relevant to retinal disorders panel. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Retinal disorders v8.46 SAG Achchuthan Shanmugasundram Mode of inheritance for gene: SAG was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.45 SAG Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: SAG.
Tag Q3_25_MOI tag was added to gene: SAG.
Retinal disorders v8.45 SAG Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: Both monoallelic and biallelic variants in SAG gene are associated with relevant phenotypes in OMIM (OMIM records accessed on 15 October 2025).; to: Comment on phenotypes: Both monoallelic and biallelic variants in SAG gene are associated with relevant phenotypes in OMIM (MIMs #258100, #613758 & #620228). OMIM records were accessed on 15 October 2025.
Retinal disorders v8.45 SAG Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Both monoallelic and biallelic variants in SAG gene are associated with relevant phenotypes in OMIM (OMIM records accessed on 15 October 2025).
Retinal disorders v8.45 SAG Achchuthan Shanmugasundram Phenotypes for gene: SAG were changed from Oguchi disease-1, OMIM:258100; Retinitis pigmentosa 47, autosomal recessive, OMIM:613758; Retinitis pigmentosa 96, autosomal dominant, OMIM:620228 to Oguchi disease-1, OMIM:258100; Retinitis pigmentosa 47, autosomal recessive, OMIM:613758; Retinitis pigmentosa 96, autosomal dominant, OMIM:620228
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Retinal disorders v8.44 SAG Achchuthan Shanmugasundram Phenotypes for gene: SAG were changed from Oguchi disease - 1; Retinitis pigmentosa 47; Oguchi Disease; Congenital Stationary Night Blindness; Oguchi disease-1, 258100; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa to Oguchi disease-1, OMIM:258100; Retinitis pigmentosa 47, autosomal recessive, OMIM:613758; Retinitis pigmentosa 96, autosomal dominant, OMIM:620228
Retinal disorders v8.43 SAG Achchuthan Shanmugasundram Publications for gene: SAG were set to 28549094; 33047631
Retinal disorders v8.42 SAG Achchuthan Shanmugasundram edited their review of gene: SAG: Changed phenotypes to: Oguchi disease-1, OMIM:258100, Retinitis pigmentosa 47, autosomal recessive, OMIM:613758, Retinitis pigmentosa 96, autosomal dominant, OMIM:620228
Retinal disorders v8.42 SAG Achchuthan Shanmugasundram reviewed gene: SAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 28549094, 33047631, 40461169; Phenotypes: Retinitis pigmentosa 47, autosomal recessive, OMIM:613758, Retinitis pigmentosa 96, autosomal dominant, OMIM:620228; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.97 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) - which may present with a severe neonatal phenotype. Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Fetal anomalies v6.97 LINC01081 Ida Ertmanska reviewed gene: LINC01081: Rating: GREEN; Mode of pathogenicity: None; Publications: 19500772, 23034409, 24842713, 27071622; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska commented on gene: LINC01081: Comment on list classification: There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). The majority of CNVs arose de novo on the maternal allele - suspected imprinting of paternal allele.
Based on the available evidence, this gene should be rated GREEN for Alveolar capillary dysplasia with misalignment of pulmonary veins.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska edited their review of gene: LINC01081: Changed publications to: 19500772, 23034409, 24842713, 27071622
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in ACDMPV. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function
Adult onset neurodegenerative disorder v8.7 DNAJC7 Ida Ertmanska edited their review of gene: DNAJC7: Changed phenotypes to: familial amyotrophic lateral sclerosis, MONDO:0005144
Adult onset neurodegenerative disorder v8.7 DNAJC7 Ida Ertmanska reviewed gene: DNAJC7: Rating: ; Mode of pathogenicity: None; Publications: 40802071; Phenotypes: familial amyotrophic lateral sclerosis MONDO:0005144; Mode of inheritance: None
Rare anaemia v3.13 CPOX Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CPOX.
Rare anaemia v3.13 CPOX Achchuthan Shanmugasundram Classified gene: CPOX as Amber List (moderate evidence)
Rare anaemia v3.13 CPOX Achchuthan Shanmugasundram Gene: cpox has been classified as Amber List (Moderate Evidence).
Rare anaemia v3.12 CPOX Achchuthan Shanmugasundram Mode of inheritance for gene: CPOX was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Rare anaemia v3.11 PPOX Achchuthan Shanmugasundram Classified gene: PPOX as No list
Rare anaemia v3.11 PPOX Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ida Ertmanska, PPOX gene is not relevant to Rare anaemia panel. Hence, the rating should be grey and 'curated_removed' tag added to reflect this.
Rare anaemia v3.11 PPOX Achchuthan Shanmugasundram Gene: ppox has been removed from the panel.
Rare anaemia v3.10 PPOX Achchuthan Shanmugasundram Tag curated_removed tag was added to gene: PPOX.
Intellectual disability v9.129 CDK9 Achchuthan Shanmugasundram Phenotypes for gene: CDK9 were changed from Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures to Global developmental delay HP:0001263; syndromic intellectual disability MONDO:0000508
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function; to: As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in ACDMPV. Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function; to: Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:

P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function; to: Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:

P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function; to: Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. Aside from Alveolar capillary dysplasia with misalignment of pulmonary veins, cardiac, gastrointestinal and genitourinary phenotypes are also common.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:

P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska changed review comment from: PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:

P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

Article also summarised novel and previous cases (42 reported deletion CNVs) reported in Stankiewicz et al. (2009), Yu et al. (2010), Zufferey et al (2011), Garabedian et al. (2012), Handrigan et al. (2013), Sen et al. (2013b), Szafranski et al. (2013a), Szafranski et al. (2014), Prothro et al. (2015), PMID: 27071622 Szafranski et al., 2016:; to: PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs harbored only the upstream enhancer, leaving FOXF1 intact.

FOXF1 GRh37/hg19 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 GRh37/hg19 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 GRh37/hg19 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:

P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both enhancers affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both enhancers affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both enhancers affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595); additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both enhancers affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both enhancers affected, IRF8 also deleted.

Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both enhancers affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both enhancers deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both enhancers are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both enhancers affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.2 LINC01081 Ida Ertmanska reviewed gene: LINC01081: Rating: GREEN; Mode of pathogenicity: None; Publications: 27071622; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, OMIM:265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.128 CDK9 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CDK9.
Variegate porphyria v1.3 PPOX Ida Ertmanska Deleted their comment
Variegate porphyria v1.3 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Variegate porphyria.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Variegate porphyria.
Variegate porphyria v1.3 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on the available evidence, this gene should remain Green for Variegate porphyria.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental
Based on the available evidence, this gene should remain Green for Variegate porphyria.
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska Deleted their review
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska edited their review of gene: A4GALT: Changed publications to: 12823750, 15142124, 10747952, 10993874, 11896312, 27612185
Congenital disorders of glycosylation v7.8 A4GALT Ida Ertmanska gene: A4GALT was added
gene: A4GALT was added to Congenital disorders of glycosylation. Sources: ClinGen
Mode of inheritance for gene: A4GALT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: A4GALT were set to 12823750,15142124; 10747952; 10993874; 11896312; 27612185
Phenotypes for gene: A4GALT were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: A4GALT was set to GREEN
Added comment: A4GALT was first reported in relation to autosomal recessive congenital disorder of glycosylation in 2000 (Steffensen et al., PMID: 10747952). A4GALT-congenital disorder of glycosylation presents as the blood group phenotype p null. Persons affected with this condition may present with no phenotype beyond abnormal agglutination in standard blood group serological testing or may present with recurrent spontaneous abortion or congenital hemolytic anemia.
14 variants (missense, in-frame indel, nonsense, frameshift) that have been reported in 13 probands in 6 publications (PMIDs: 12823750, 15142124, 10747952, 10993874, 11896312, 27612185) are included in this curation. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by in vitro functional assays. (PMIDs: 23927681, 18067504).
The gene-disease relationship is classified as Definitive in ClinGen (May 2025).
Sources: ClinGen
Paediatric disorders - additional genes v7.10 KCTD15 Verity Hartill gene: KCTD15 was added
gene: KCTD15 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: KCTD15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCTD15 were set to PMID: 38296633
Phenotypes for gene: KCTD15 were set to Lipomatous frontonasal malformation; anosmia; cutis aplasia of the scalp; sparse hair; congenital heart disease
Penetrance for gene: KCTD15 were set to unknown
Mode of pathogenicity for gene: KCTD15 was set to Other
Review for gene: KCTD15 was set to AMBER
Added comment: Sources: Literature
Intellectual disability v9.128 CDK9 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. Sequencing method: WES/WGS for all studies.
CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 unrelated individuals from consanguineous families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. Sequencing method: WES/WGS for all studies.
CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.
Intellectual disability v9.128 CDK9 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. Sequencing method: WES/WGS for all studies.
CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.
Intellectual disability v9.128 CDK9 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546;29302074;30237576;33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis and Sarah Leigh, there are at least 9 individuals from x unrelated families with biallelic CDK9 variants (PMID: 26633546; 29302074; 30237576; 33640901). These patients presented with a CHARGE-like syndromic phenotype that consistently includes global developmental delay (9/9) and/or intellectual disability (1 patient with 'severe ID'; 3 patients with moderate ID: WAIS-IV IQ of 40-43). Four different missense variants have been reported - all 4 are rare in gnomAD v4, with no homozygotes reported. CDK9 is not yet associated with any phenotype in OMIM (accessed 14th Oct 2025). Based on the available evidence, CDK9 should be promoted to Green for Intellectual disability at the next GMS panel update.
Intellectual disability v9.128 CDK9 Ida Ertmanska reviewed gene: CDK9: Rating: GREEN; Mode of pathogenicity: None; Publications: 26633546, 29302074, 30237576, 33640901; Phenotypes: Global developmental delay HP:0001263, syndromic intellectual disability MONDO:0000508; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.20 XPNPEP3 Arina Puzriakova edited their review of gene: XPNPEP3: Changed rating: AMBER; Changed publications to: 38035175, 40953058; Changed phenotypes to: Nephronophthisis-like nephropathy 1, OMIM:613159, Peripheral neuropathy, MONDO:0005244, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MONDO:0859322; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare anaemia v3.10 PPOX Ida Ertmanska changed review comment from: The review by Sharon Whatley (International Porphyria Network) was resubmitted on the Rare anaemia panel with CPOX as the gene name.; to: The review by Sharon Whatley (International Porphyria Network) was resubmitted on the Rare anaemia panel with CPOX as the gene name. PPOX variants do not appear to cause anaemia.
Rare anaemia v3.10 PPOX Ida Ertmanska changed review comment from: The review by Sharon Whatley (International Porphyria Network) was resubmitted with CPOX as the gene name.; to: The review by Sharon Whatley (International Porphyria Network) was resubmitted on the Rare anaemia panel with CPOX as the gene name.
Severe microcephaly v8.15 MRPL49 Arina Puzriakova Entity copied from Intellectual disability v9.128
Severe microcephaly v8.15 MRPL49 Arina Puzriakova gene: MRPL49 was added
gene: MRPL49 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_25_ promote_green tags were added to gene: MRPL49.
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 40043708
Phenotypes for gene: MRPL49 were set to Combined oxidative phosphorylation deficiency 60, OMIM:621195; combined oxidative phosphorylation deficiency, MONDO:0000732
Rare anaemia v3.10 CPOX Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Comment on list classification: There at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance and it does not usually present with anaemia. Based on the available evidence, CPOX should be rated Green for Rare anaemia.; to: Comment on list classification: There at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance and it does not usually present with anaemia. Based on the available evidence, CPOX should be rated Green for Rare anaemia, with Mode of Inheritance set to BIALLELIC, autosomal or pseudoautosomal.
Skeletal dysplasia v8.17 PTBP1 Ronnie Wright gene: PTBP1 was added
gene: PTBP1 was added to Skeletal dysplasia. Sources: NHS GMS,Literature
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to PMID:40965981
Penetrance for gene: PTBP1 were set to unknown
Review for gene: PTBP1 was set to GREEN
Added comment: One publication (PMID: 40965981). 27 individuals from 25 families, predominantly with start loss variants (recurring de novo).

'Affected individuals presented with a syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short-limbed short stature. Intellectual functioning ranged from normal to moderately delayed'
'Additional clinical features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%)'

For the start loss variants, re-initiation of translation at p.Met31 is shown to be occurring by authors, and leads to reduced nuclear localization, enhanced cytoplasmic retention and increased protein stability.

Authors showed a recognizable methylation episignature.

Cases in CVA (incl 1 North West GLH), at least some of which share syndromic phenotypic features consistent with the literature report.
Sources: NHS GMS, Literature
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia.

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia.

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12 - transient. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Comment on list classification: There at least 2 unrelated individuals with Coproporphyria harbouring monoallelic variants in CPOX, and at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance. Based on the available evidence, CPOX should be rated Green for Rare anaemia.; to: Comment on list classification: There at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance and it does not usually present with anaemia. Based on the available evidence, CPOX should be rated Green for Rare anaemia.
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia. 2 cases of Coproporphyria with anaemia have been reported:

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia.

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia. 2 cases of Coproporphyria with anaemia have been reported:

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia. 2 cases of Coproporphyria with anaemia have been reported:

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G p.(Asp233Gly) & c.1207_1218del12, p.(Thr403_Gly406del).

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).
Retinal disorders v8.42 KIAA1549 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: KIAA1549.
Retinal disorders v8.42 KIAA1549 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic variants with retinal phenotype. However, there is no published evidence linking monoallelic variants to retinal disorder. Hence, the MOI should be updated to 'BIALLELIC, autosomal or pseudoautosomal' in the next GMS update.
Retinal disorders v8.42 KIAA1549 Achchuthan Shanmugasundram Mode of inheritance for gene: KIAA1549 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia. 2 cases of Coproporphyria with anaemia have been reported:

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with symptoms of erythropoietic harderoporphyria (photosensitivity of the skin, hemolytic anemia, and jaundice). However, the pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. We found a heterozygous, novel, four-base pair deletion in exon 7 of the CPOX gene. patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia. 2 cases of Coproporphyria with anaemia have been reported:

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with photosensitivity of the skin, hemolytic anemia, and jaundice. Became anemic on day 9, but recovered spontaneously by day 12. The pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. Heterozygous for a deletion in exon 7 of the CPOX gene. Patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Comment on list classification: There at least 17 unrelated individuals with Coproporphyria harbouring monoallelic variants in CPOX, and at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance. Based on the available evidence, CPOX should be rated Green for Rare anaemia.; to: Comment on list classification: There at least 2 unrelated individuals with Coproporphyria harbouring monoallelic variants in CPOX, and at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance. Based on the available evidence, CPOX should be rated Green for Rare anaemia.
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005).
PMID: 11309681 Lamoril et al., 2001: 17 apparently unrelated patients diagnosed with Coproporphyria, of which 15 had reported heterozygous variants in CPOX. 13 patients have experienced acute attacks (with or without skin lesions), 4 patients have had no attacks- diagnosis was established by measurement of fecal porphyrin. Missense variants are the most common.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005). The presentation does not usually include anaemia. 2 cases of Coproporphyria with anaemia have been reported:

PMID: 28349448 Hasegawa et al., 2017
Report of a neonate with symptoms of erythropoietic harderoporphyria (photosensitivity of the skin, hemolytic anemia, and jaundice). However, the pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. We found a heterozygous, novel, four-base pair deletion in exon 7 of the CPOX gene. patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).
Retinal disorders v8.41 KIAA1549 Achchuthan Shanmugasundram Phenotypes for gene: KIAA1549 were changed from No OMIM phenotype to Retinitis pigmentosa 86, OMIM:618613; retinitis pigmentosa 86, MONDO:0032834
Retinal disorders v8.40 KIAA1549 Achchuthan Shanmugasundram Publications for gene: KIAA1549 were set to 23105016; 24938718; 30120214
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005).
PMID: 11309681 Lamoril et al., 2001: 17 apparently unrelated patients diagnosed with Coproporphyria, of which 15 had reported heterozygous variants in CPOX. 13 patients have experienced acute attacks (with or without skin lesions), 4 patients have had no attacks- diagnosis was established by measurement of fecal porphyrin. Missense variants are the most common.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005).
PMID: 11309681 Lamoril et al., 2001: 17 apparently unrelated patients diagnosed with Coproporphyria, of which 15 had reported heterozygous variants in CPOX. 13 patients have experienced acute attacks (with or without skin lesions), 4 patients have had no attacks- diagnosis was established by measurement of fecal porphyrin. Missense variants are the most common.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 14th Oct 2025).
Rhabdomyolysis and metabolic muscle disorders v5.12 CASQ1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update. Phenotypes displayed by affected individuals such as muscle weakness and fatigue, exercise-induced myalgia and hyperCKaemia align with rhabdomyolysis panels. Inclusion on this panel would also ensure inclusion on the R381 super panel, as suggested by the GMS expert group.; to: Comment on list classification: There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update. This gene is currently not included on any GMS panels despite sufficient evidence to support the gene-disease association. Phenotypes displayed by affected individuals such as muscle weakness and fatigue, exercise-induced myalgia and hyperCKaemia align with rhabdomyolysis panels. Inclusion on this panel would also ensure inclusion on the R381 super panel, as suggested by the GMS expert group.
Acute rhabdomyolysis v2.6 CASQ1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update. Phenotypes displayed by affected individuals such as muscle weakness and fatigue, exercise-induced myalgia and hyperCKaemia align with rhabdomyolysis panels.; to: Comment on list classification: There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update. This gene is currently not included on any GMS panels despite sufficient evidence to support the gene-disease association. Phenotypes displayed by affected individuals such as muscle weakness and fatigue, exercise-induced myalgia and hyperCKaemia align with rhabdomyolysis panels.
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Comment on list classification: There at least 17 unrelated individuals with Coproporphyria harbouring monoallelic variants in CPOX, and at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance.
Based on the available evidence, CPOX should be rated Green for Rare anaemia.; to: Comment on list classification: There at least 17 unrelated individuals with Coproporphyria harbouring monoallelic variants in CPOX, and at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance. Based on the available evidence, CPOX should be rated Green for Rare anaemia.
Retinal disorders v8.39 KIAA1549 Achchuthan Shanmugasundram changed review comment from: PMID:23105016 (2013) reported autozygome-guided exome sequencing in a large cohort of ~150 families with retinal dystrophy, where a novel truncating variant was identified in KIAA1549 as the only variant that remained after filtering in one family.

PMID:30120214 (2018) reported the identification of a homozygous missense and a homozygous frameshift variants in KIAA1549 gene via WES in two unrelated families with retinitis pigmentosa.

There were two additional cases reported with biallelic KIAA1549 variants and retinitis pigmentosa in two different large cohort studies (PMID:31213501 (2019) & PMID:36819107 (2023)).

PMID:34027671 (2021) reported proteomics study on Pomt1 conditional knockout mouse model, which showed that KIAA1549 is a POMT1 substrate requiring O-mannosylation for proper localization and stability.

I cannot find any published evidence of patient cases of retinal disorders with monoallelic KIAA1549 variants.

Only biallelic variants in KIAA1549 gene have been associated with relevant phenotypes in OMIM (MIM #618613, accessed on 14 October 2025) and Gene2Phenotype (with 'limited' rating on the eye panel). Biallelic KIAA1549 variants have also been associated with retinitis pigmentosa 86 with 'strong' rating by the Retina expert panel on ClinGen (https://search.clinicalgenome.org/CCID:008708).; to: PMID:23105016 (2013) reported autozygome-guided exome sequencing in a large cohort of ~150 families with retinal dystrophy, where a novel truncating variant was identified in KIAA1549 as the only variant that remained after filtering in one family.

PMID:30120214 (2018) reported the identification of a homozygous missense and a homozygous frameshift variants in KIAA1549 gene via WES in two unrelated families with retinitis pigmentosa.

There were two additional cases reported with biallelic KIAA1549 variants and retinitis pigmentosa in two different large cohort studies (PMID:31213501 (2019) & PMID:36819107 (2023)).

PMID:34027671 (2021) reported proteomics study on Pomt1 conditional knockout mouse model, which showed that KIAA1549 is a POMT1 substrate requiring O-mannosylation for proper localization and stability.

I cannot find any published evidence of patient cases of retinal disorders with monoallelic KIAA1549 variants.

Only biallelic variants in KIAA1549 gene have been associated with relevant phenotypes in OMIM (MIM #618613, accessed on 14 October 2025) and Gene2Phenotype (with 'limited' rating on the eye panel). Biallelic KIAA1549 variants have also been associated with retinitis pigmentosa 86 with 'strong' rating by the Retina expert panel on ClinGen (https://search.clinicalgenome.org/CCID:008708).
Rare anaemia v3.10 CPOX Ida Ertmanska commented on gene: CPOX: Comment on list classification: There at least 17 unrelated individuals with Coproporphyria harbouring monoallelic variants in CPOX, and at least 5 unrelated families affected by Coproporphyria (AR) / Harderoporphyria (AR), with affected individuals harbouring biallelic variants in CPOX. Importantly, autosomal dominant Coproporphyria has low clinical penetrance.
Based on the available evidence, CPOX should be rated Green for Rare anaemia.
Retinal disorders v8.39 KIAA1549 Achchuthan Shanmugasundram reviewed gene: KIAA1549: Rating: GREEN; Mode of pathogenicity: None; Publications: 23105016, 30120214, 31213501, 34027671, 36819107; Phenotypes: Retinitis pigmentosa 86, OMIM:618613, retinitis pigmentosa 86, MONDO:0032834; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v5.12 CASQ1 Arina Puzriakova Classified gene: CASQ1 as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v5.12 CASQ1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update. Phenotypes displayed by affected individuals such as muscle weakness and fatigue, exercise-induced myalgia and hyperCKaemia align with rhabdomyolysis panels. Inclusion on this panel would also ensure inclusion on the R381 super panel, as suggested by the GMS expert group.
Rhabdomyolysis and metabolic muscle disorders v5.12 CASQ1 Arina Puzriakova Gene: casq1 has been classified as Amber List (Moderate Evidence).
Acute rhabdomyolysis v2.6 CASQ1 Arina Puzriakova Classified gene: CASQ1 as Amber List (moderate evidence)
Acute rhabdomyolysis v2.6 CASQ1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence available (>20 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next GMS update. Phenotypes displayed by affected individuals such as muscle weakness and fatigue, exercise-induced myalgia and hyperCKaemia align with rhabdomyolysis panels.
Acute rhabdomyolysis v2.6 CASQ1 Arina Puzriakova Gene: casq1 has been classified as Amber List (Moderate Evidence).
Rare anaemia v3.10 CPOX Ida Ertmanska changed review comment from: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005).
PMID: 11309681 Lamoril et al., 2001: 17 apparently unrelated patients diagnosed with Coproporphyria, of which 15 had reported heterozygous variants in CPOX. 13 patients have experienced acute attacks with or without skin lesions), 4 patients have had no attacks- diagnosis was established by measurement of fecal porphyrin. Missense variants are the most common.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.; to: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005).
PMID: 11309681 Lamoril et al., 2001: 17 apparently unrelated patients diagnosed with Coproporphyria, of which 15 had reported heterozygous variants in CPOX. 13 patients have experienced acute attacks (with or without skin lesions), 4 patients have had no attacks- diagnosis was established by measurement of fecal porphyrin. Missense variants are the most common.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.
Acute rhabdomyolysis v2.5 CASQ1 Arina Puzriakova gene: CASQ1 was added
gene: CASQ1 was added to Acute rhabdomyolysis. Sources: Literature
Q3_25_promote_green tags were added to gene: CASQ1.
Mode of inheritance for gene: CASQ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CASQ1 were set to 26136523; 28895244; 29039140; 30258016; 34908252; 36514469
Phenotypes for gene: CASQ1 were set to Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231
Review for gene: CASQ1 was set to GREEN
Added comment: Copied and amended relevant reviews from panel R82, where inclusion of this gene was disagreed due to lack of clinically significant variants identified in >1000 screened patients but addition to another component panel of R381 was suggested:


PMID:26136523 reported 10 cases from three families with the founder missense variant, pAsp244Gly and they all had benign vacuolar myopathy, muscle weaknesses and hyperCKaemia. All patients reported adult onset. 1 proband reported lower limb hypertrophy with normal EMG results. 6 patients had muscle biopsy, with minimal fibre size variation, and a few central nuclei.

PMID:28895244 reported the identification of three novel variants (p.Asp44Asn, p.Gly103Asp & p.Ile385Thr) in four cases with with tubular aggregate myopathy. They had fatigue and diffuse exercise-induced myalgia and the patient with p.Ile385Thr variant also had proximal muscle weakness.

PMID:29039140 reported two unrelated families with heterozygous variants (family1: p.Asn54Tyr; family 2: p.Gly103Asp). Family 1 presented between early 20s and mid-40s with a slowly progressive muscle weakness mainly involving proximal muscles in the lower limbs and family 2 presented with post-exercise myalgia in the lower limbs in early 50s.

PMID:30258016 reported 22 cases from 12 families with heterozygous variants in CASQ1. 21 of these cases shared the founder variant (p.Asp244Gly) and one had p.Gly103Asp variant. These patients usually had adult-onset exercise intolerance, elevated CK and myalgias and later developed slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Three patients presented subclinical cardiac abnormalities and four patients had pelvic girdle weakness.

PMID:34908252 reported a case with a heterozygous missense variant p.Asp44Asn, who presented with exercise‐induced muscle spasms since childhood.

PMID:36514469 reported a Chinese patient who presented with slowly progressive upper limb weakness, predominantly affecting distal muscles and was identified with heterozygous variant p.Val256Met in CASQ1.

This gene has been associated with relevant phenotypes in OMIM (MIM #616231), but not in Gene2Phenotype.
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v5.11 CASQ1 Arina Puzriakova gene: CASQ1 was added
gene: CASQ1 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Q3_25_promote_green tags were added to gene: CASQ1.
Mode of inheritance for gene: CASQ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CASQ1 were set to 26136523; 28895244; 29039140; 30258016; 34908252; 36514469
Phenotypes for gene: CASQ1 were set to Myopathy, vacuolar, with CASQ1 aggregates, OMIM:616231
Review for gene: CASQ1 was set to GREEN
Added comment: Copied and amended relevant reviews from panel R82, where inclusion of this gene was disagreed due to lack of clinically significant variants identified in >1000 screened patients but addition to another component panel of R381 was suggested:


PMID:26136523 reported 10 cases from three families with the founder missense variant, pAsp244Gly and they all had benign vacuolar myopathy, muscle weaknesses and hyperCKaemia. All patients reported adult onset. 1 proband reported lower limb hypertrophy with normal EMG results. 6 patients had muscle biopsy, with minimal fibre size variation, and a few central nuclei.

PMID:28895244 reported the identification of three novel variants (p.Asp44Asn, p.Gly103Asp & p.Ile385Thr) in four cases with with tubular aggregate myopathy. They had fatigue and diffuse exercise-induced myalgia and the patient with p.Ile385Thr variant also had proximal muscle weakness.

PMID:29039140 reported two unrelated families with heterozygous variants (family1: p.Asn54Tyr; family 2: p.Gly103Asp). Family 1 presented between early 20s and mid-40s with a slowly progressive muscle weakness mainly involving proximal muscles in the lower limbs and family 2 presented with post-exercise myalgia in the lower limbs in early 50s.

PMID:30258016 reported 22 cases from 12 families with heterozygous variants in CASQ1. 21 of these cases shared the founder variant (p.Asp244Gly) and one had p.Gly103Asp variant. These patients usually had adult-onset exercise intolerance, elevated CK and myalgias and later developed slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Three patients presented subclinical cardiac abnormalities and four patients had pelvic girdle weakness.

PMID:34908252 reported a case with a heterozygous missense variant p.Asp44Asn, who presented with exercise‐induced muscle spasms since childhood.

PMID:36514469 reported a Chinese patient who presented with slowly progressive upper limb weakness, predominantly affecting distal muscles and was identified with heterozygous variant p.Val256Met in CASQ1.

This gene has been associated with relevant phenotypes in OMIM (MIM #616231), but not in Gene2Phenotype.
Sources: Literature
Rare anaemia v3.10 CPOX Ida Ertmanska edited their review of gene: CPOX: Added comment: Coproporphyria (AD) is characterized by acute attacks of neurologic dysfunction. The attacks can be brought on by drugs, fasting, menstrual cycle, or infectious diseases. Disorder shows incomplete penetrance (PMID:16159891 Shmitt et al., 2005).
PMID: 11309681 Lamoril et al., 2001: 17 apparently unrelated patients diagnosed with Coproporphyria, of which 15 had reported heterozygous variants in CPOX. 13 patients have experienced acute attacks with or without skin lesions), 4 patients have had no attacks- diagnosis was established by measurement of fecal porphyrin. Missense variants are the most common.

Coproporphyria (AR) / Harderoporphyria (AR)
Harderoporphyria arises due to specific CPOX mutations that alter enzyme residues D400-K404; most patients described to date having at least one K404E allele.
As reviewed by Sharon Whatley, there are at least eight patients from five unrelated families with biallelic pathogenic CPOX variants, diagnosed with either Coproporphyria or Harderoporphyria (PMIDs: 9454777, 7757079, 21103937, 30828546, 40296768).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 30828546 Moghe et al., 2019
A 78-year-old man with a history of neonatal anaemia and jaundice, and life-long photosensitivity; found to have harderoporphyria: increased porphyrins in urine, plasma, erythrocytes and feces, including large amounts of harderoporphyrin in feces and erythrocytes. CPOX variants: c.698A>G ( p.Asp233Gly) & c.1207_1218del12, p.Thr403_Gly406del.

PMID: 40296768 Kelestemur et al., 2025
2 siblings with harderoporphyria, homozygous for c.83_85del, p.S28* variant (WGS). P1 had atypical genitalia and developed primary gonadal insufficiency and non-immune diabetes at ages 6 and 10, respectively. Both patients had a history of microcytic anaemia, haemolysis, cholestasis, hepatosplenomegaly in early infancy, hyperpigmentation, abdominal pain, nystagmus, optic atrophy, and mild lactic acidosis in early childhood. Primary adrenal insufficiency.; Changed publications to: 7757079, 9454777, 11309681, 16159891, 21103937, 30828546, 38940544, 40296768
Rare anaemia v3.10 PPOX Ida Ertmanska commented on gene: PPOX
Non-acute porphyrias v1.28 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata OMIM:176200; variegate porphyria MONDO:0008297 to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297
Mitochondrial disorders v9.34 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata, 176200 to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Mitochondrial disorders v9.33 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to 9540991; 9811936; 10870850; 12859407; 25778941; 30476629; 32247286; 33159949
Non-acute porphyrias v1.27 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed phenotypes to: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Non-acute porphyrias v1.27 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to 27604308; 19460837; 9811936
Non-acute porphyrias v1.26 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Rare anaemia v3.10 CPOX Ida Ertmanska gene: CPOX was added
gene: CPOX was added to Rare anaemia. Sources: Other
Mode of inheritance for gene: CPOX was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CPOX were set to 7757079; 9454777; 21103937; 30828546; 38940544; 40296768
Phenotypes for gene: CPOX were set to Coproporphyria, OMIM:121300; Harderoporphyria, OMIM:618892
Review for gene: CPOX was set to GREEN
Added comment: Review added on behalf of Sharon Whatley (International Porphyria Network):

Relevant metabolic investigation: Plasma porphyrin fluorescence emission and faecal coproporphyrin isomer (III:I) ratio (for hereditary coproporphyria) and faecal harderoporphyrin (for harderoporphyria)

PMID: 38940544 Aarsand reports that porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes. Defects in the CPOX gene cause hereditary coproporphyria.

PMID: 16159891 Schmitt reports that there are two very rare, homozygous forms of HCP one of which is characterised by the faecal excretion of harderoporphyrin. Harderoporphyria has predominantly haematological manifestations such as neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 30828546 Moghe, 9454777 Lamoril, 7757079 Lamoril, 40296768 Kelestemur, 21103937 Hasanoglu report eight patients (from five families) with biallelic pathogenic CPOX variants. They presented with neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 16159891 Schmitt reports that during childhood and adulthood, a mild residual anaemia is chronically observed in harderoporphyria patients.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Sources: Other
Childhood onset hereditary spastic paraplegia v8.20 ATL1 Achchuthan Shanmugasundram changed review comment from: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Hereditary Spastic Paraplegia - paediatric' panel from PanelApp Australia (https://panelapp-aus.org/panels/317/gene/ATL1/).; to: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. The autosomal dominant disorder is generally caused by missense variants, generating a dominant-negative effect. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. These include homozygous nonsense and missense variants. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Hereditary Spastic Paraplegia - paediatric' panel from PanelApp Australia (https://panelapp-aus.org/panels/317/gene/ATL1/).
Non-acute porphyrias v1.26 PPOX Ida Ertmanska Deleted their comment
Non-acute porphyrias v1.26 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Since biallelic variants in PPOX cause more severe symptoms, the mode of inheritance for Non-acute porphyrias should be set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood (PMIDs: 19460837, 38940544). Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms.
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on available evidence, the mode of inheritance for Non-acute porphyrias should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Non-acute porphyrias v1.26 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood (PMIDs: 19460837, 38940544). PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Non-acute porphyrias.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood (PMIDs: 19460837, 38940544). . Based on the available evidence, this gene should be rated Green for Non-acute porphyrias.
Intellectual disability v9.128 PPOX Arina Puzriakova Publications for gene: PPOX were set to 8290408; 9811936; 2004012; 35164799; 37879139; 40114189
Mitochondrial disorders v9.32 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Mitochondrial disorders.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Mitochondrial disorders.
Mitochondrial disorders v9.32 PPOX Ida Ertmanska Deleted their comment
Mitochondrial disorders v9.32 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should remain Green for Mitochondrial disorders.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).


Based on the available evidence, this gene should remain Green for Mitochondrial disorders.
Mitochondrial disorders v9.32 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Mitochondrial disorders.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189). Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Mitochondrial disorders.
Mitochondrial disorders v9.32 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed phenotypes to: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577
Childhood onset hereditary spastic paraplegia v8.20 ATL1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic ATL1 variants with early-onset spastic paraplegia, the mode of inheritance of this gene can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.20 ATL1 Achchuthan Shanmugasundram Mode of inheritance for gene: ATL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v8.19 ATL1 Achchuthan Shanmugasundram Phenotypes for gene: ATL1 were changed from Spastic paraplegia 3A, autosomal dominant,182600; Spastic Paraplegia, Dominant to Spastic paraplegia 3A, autosomal dominant, OMIM:182600; hereditary spastic paraplegia 3A, MONDO:0008437
Childhood onset hereditary spastic paraplegia v8.18 ATL1 Achchuthan Shanmugasundram Publications for gene: ATL1 were set to 11685207; 15517445; 35925862
Childhood onset hereditary spastic paraplegia v8.17 ATL1 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: ATL1.
Childhood onset hereditary spastic paraplegia v8.17 ATL1 Achchuthan Shanmugasundram changed review comment from: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Hereditary Spastic Paraplegia - paediatric' panel from PanelApp Australia (https://panelapp-aus.org/panels/317/gene/ATL1/).
Childhood onset hereditary spastic paraplegia v8.17 ATL1 Achchuthan Shanmugasundram reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18446315, 22378671, 24473461, 25193411, 26888483, 34808209, 35925862, 37927245, 39003427; Phenotypes: Spastic paraplegia 3A, autosomal dominant, OMIM:182600, hereditary spastic paraplegia 3A, MONDO:0008437; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.11 PPOX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 13 October 2025.
Cutaneous photosensitivity with a likely genetic cause v3.11 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata 176200; Variegate porphyria (Acute neuropathic porphyrias) to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Cutaneous photosensitivity with a likely genetic cause v3.10 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Possible mitochondrial disorder - nuclear genes v4.15 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata, 176200 to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Possible mitochondrial disorder - nuclear genes v4.14 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to 9540991; 10870850; 25778941; 30476629; 32247286; 33159949
Possible mitochondrial disorder - nuclear genes v4.13 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Hereditary neuropathy or pain disorder v7.20 PPOX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 13 October 2025.
Hereditary neuropathy or pain disorder v7.20 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577
Hereditary neuropathy or pain disorder v7.19 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from Porphyria variegata, OMIM:176200; Sensory neuropathy, HP:0000763 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577
Hereditary neuropathy or pain disorder v7.18 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Variegate porphyria v1.3 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Variegate porphyria v1.3 PPOX Achchuthan Shanmugasundram Publications for gene: PPOX were set to
Variegate porphyria v1.2 PPOX Achchuthan Shanmugasundram Phenotypes for gene: PPOX were changed from to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Mitochondrial disorders v9.32 PPOX Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: PPOX.
Adult onset neurodegenerative disorder v8.7 SPTLC2 Achchuthan Shanmugasundram Classified gene: SPTLC2 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v8.7 SPTLC2 Achchuthan Shanmugasundram Gene: sptlc2 has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v8.6 SPTLC2 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SPTLC2.
Adult onset neurodegenerative disorder v8.6 SPTLC1 Achchuthan Shanmugasundram Classified gene: SPTLC1 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v8.6 SPTLC1 Achchuthan Shanmugasundram Gene: sptlc1 has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v8.5 SPTLC1 Achchuthan Shanmugasundram Phenotypes for gene: SPTLC1 were changed from Juvenile ALS to Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285; amyotrophic lateral sclerosis 27, juvenile, MONDO:0859529
Adult onset neurodegenerative disorder v8.4 SPTLC1 Achchuthan Shanmugasundram Publications for gene: SPTLC1 were set to 34059824; 34459874; 35627278; 35900868
Adult onset neurodegenerative disorder v8.3 SPTLC1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SPTLC1.
Tag Q3_25_NHS_review tag was added to gene: SPTLC1.
Intellectual disability v9.127 FICD Arina Puzriakova changed review comment from: Paper by Perera et al 2022 has now been published (PMID: 36704923).

An additional 6 unrelated families have been reported with biallelic variants in this gene presenting with motor neuron disease. Unlike the cases reported by Perera et al, these individuals did not display any significant cognitive deficits (PMID: 36136088; 40062579); to: Paper by Perera et al 2022 has now been published (PMID: 36704923).

An additional 6 unrelated families have been reported with biallelic variants in this gene presenting with motor neuron disease. Unlike the cases reported by Perera et al, these individuals did not display any significant cognitive deficits (PMID: 36136088; 40062579). Therefore maintaining the Amber rating on this panel.
Intellectual disability v9.127 FICD Arina Puzriakova commented on gene: FICD
Monogenic diabetes v3.5 FICD Arina Puzriakova Classified gene: FICD as Amber List (moderate evidence)
Monogenic diabetes v3.5 FICD Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 6 families with diabetes mellitus and biallelic variants at the Arg371 or Arg374 residue of this gene (PMID: 36704923; 36136088; 40062579)
Monogenic diabetes v3.5 FICD Arina Puzriakova Gene: ficd has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.17 FICD Arina Puzriakova Tag recurrent-variant tag was added to gene: FICD.
Monogenic diabetes v3.4 FICD Arina Puzriakova Tag recurrent-variant tag was added to gene: FICD.
Monogenic diabetes v3.4 FICD Arina Puzriakova gene: FICD was added
gene: FICD was added to Monogenic diabetes. Sources: Literature
Q3_25_promote_green tags were added to gene: FICD.
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36704923; 36136088; 40062579
Phenotypes for gene: FICD were set to Spastic paraplegia 92, autosomal recessive, OMIM:620911; diabetes mellitus, MONDO:0005015; Neonatal insulin-dependent diabetes mellitus, HP:0000857
Review for gene: FICD was set to GREEN
Added comment: - PMID: 36704923 (2022) - infantile diabetes and neurodevelopmental delay associated with a single variant p.Arg371Ser, in three consanguineous families, two of which shared a common haplotype

- PMID: 36136088 (2022) - four unrelated families from different ethnic backgrounds, all harboured the same p.Arg374His variant, which was homozygous in all but one case where the variant was present in a compound heterozygous state with a frameshift variant, p.Gly370GlufsTer53. Haplotype analysis did indicate that there is a shared haplotype in all patients with the p.Arg374His variant, strongly suggesting a founder effect. Affected individuals presented with severe motor neuron disease and one patient from this cohort also had diabetes mellitus.

- PMID: 40062579 (2025) - an additional four individuals from two families with variants affecting the Arg374 residue, who presented with complicated HSP and diabetes mellitus, merging these two previously distinct presentations.
The report describes one Serbian family, comprising 2 sibs with cHSP (age of onset: 5 and 6) and diabetes mellitus (age of diagnosis: 25 and 27). The sibs had the recurrent homozygous variant p.Arg374His - however, the haplotype identified in the previous report was not found in this family, suggesting that this is an independent event.
The second was a consanguineous family from Saudi Arabia with 2 sibs affected by progressive HSP and diabetes (one prediabetic) - age of onset unclear but paediatric. This family harboured a novel homozygous variant, p.Arg374Cys. No cognitive deficits were reported in either family.

The coexistence of motor neuron disease and diabetes suggests a broader range of neurological and metabolic effects of FICD dysfunction which does warrant further investigation. It is possible that these presentations may be more related than initially thought - individuals diagnosed with infancy-onset diabetes mellitus may develop spasticity later in life, and vice versa.
Sources: Literature
Neonatal diabetes v5.4 FICD Arina Puzriakova Phenotypes for gene: FICD were changed from Spastic paraplegia 92, autosomal recessive, OMIM:620911; Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities to Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities
Neonatal diabetes v5.3 FICD Arina Puzriakova commented on gene: FICD
Childhood onset hereditary spastic paraplegia v8.17 FICD Arina Puzriakova Publications for gene: FICD were set to 36136088
Childhood onset hereditary spastic paraplegia v8.16 FICD Arina Puzriakova edited their review of gene: FICD: Added comment: This gene was reassessed in light of the amber review by John Taylor, highlighting that two distinct phenotypes linked to similar variants located in the catalytic motif of FICD have been assessed differently.

FICD was rated amber on Neonatal diabetes (293) in context of infantile diabetes and neurodevelopmental delay associated with a single variant p.Arg371Ser, in three consanguineous families, two of which shared a common haplotype (PMID: 36704923).

A separate association with severe motor neuron disease (rated green on this panel) is based on four unrelated families from different ethnic backgrounds, who all harbour the p.Arg374His variant, which was homozygous in all but one case where the variant was present in a compound heterozygous state with a frameshift variant, p.Gly370GlufsTer53. One patient from this cohort also had diabetes mellitus. Haplotype analysis did indicate that there is a shared haplotype in all patients with the p.Arg374His variant, strongly suggesting a founder effect (PMID: 36136088).

Recently, an additional four individuals from two families were reported (PMID: 40062579) with variants affecting the Arg374 residue, who presented with complicated HSP and diabetes mellitus, merging these two previously distinct presentations.
The report describes one Serbian family, comprising 2 sibs with cHSP (age of onset: 5 and 6) and diabetes mellitus (age of diagnosis: 25 and 27). The sibs had the recurrent homozygous variant p.Arg374His - however, the haplotype identified in the previous report was not found in this family, suggesting that this is an independent event.
The second was a consanguineous family from Saudi Arabia with 2 sibs affected by progressive HSP and diabetes (one prediabetic) - age of onset unclear but paediatric. This family harboured a novel homozygous variant, p.Arg374Cys. No cognitive deficits were reported in either family.

The coexistence of motor neuron disease and diabetes suggests a broader range of neurological and metabolic effects of FICD dysfunction which does warrant further investigation. It is possible that these presentations may be more related than initially thought - individuals diagnosed with infancy-onset diabetes mellitus may develop spasticity later in life, and vice versa.

Overall the recent report does lend additional support for inclusion of FICD on this panel. This gene will also be added to the Monogenic diabetes (472) panel to cover the diabetes phenotype with later onset than the initial report which was reviewed on the Neonatal diabetes (293) panel.; Changed publications to: 36704923, 36136088, 40062579; Changed phenotypes to: Spastic paraplegia 92, autosomal recessive, OMIM:620911
Possible mitochondrial disorder - nuclear genes v4.13 PPOX Ida Ertmanska commented on gene: PPOX: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Possible mitochondrial disorder - nuclear genes.
Possible mitochondrial disorder - nuclear genes v4.13 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 8290408, 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.18 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms - including neuropathy. As reported by previous reviewers, 3 individuals with biallelic variants in PPOX presented with sensory neuropathy (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift). Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Hereditary neuropathy or pain disorder.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms - including neuropathy. As reported by previous reviewers, 3 individuals with biallelic variants in PPOX presented with sensory neuropathy (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift). Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.18 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 8290408, 10870850, 11286631; Phenotypes: Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-acute porphyrias v1.26 PPOX Ida Ertmanska commented on gene: PPOX: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood (PMIDs: 19460837, 38940544). PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should be rated Green for Non-acute porphyrias.
Mitochondrial disorders v9.32 PPOX Ida Ertmanska edited their review of gene: PPOX: Added comment: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should remain Green for Mitochondrial disorders.; Changed phenotypes to: Variegate porpComment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189). PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025. Based on the available evidence, this gene should remain Green for Variegate porphyria.hyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577
Variegate porphyria v1.1 PPOX Ida Ertmanska commented on gene: PPOX: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Based on the available evidence, this gene should remain Green for Variegate porphyria.
Mitochondrial disorders v9.32 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Variegate porphyria.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Cutaneous photosensitivity with a likely genetic cause.
Neonatal diabetes v5.3 FICD Arina Puzriakova Phenotypes for gene: FICD were changed from Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities. to Spastic paraplegia 92, autosomal recessive, OMIM:620911; Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities
Cutaneous photosensitivity with a likely genetic cause v3.9 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Variegate porphyria v1.1 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' for Variegate porphyria.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' for Variegate porphyria.
Variegate porphyria v1.1 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Non-acute porphyrias v1.26 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed publications to: 9811936, 10486317, 19460837, 33159949, 35584894, 37879139, 38940544, 40114189
Non-acute porphyrias v1.26 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, variegate porphyria, MONDO:0008297; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neonatal diabetes v5.2 FICD Arina Puzriakova Publications for gene: FICD were set to
Intellectual disability v9.127 FICD Arina Puzriakova Publications for gene: FICD were set to
Variegate porphyria v1.1 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10486317, 33159949, 35584894, 37879139, 38940544, 40114189; Phenotypes: Variegate porphyria, OMIM:176200, Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, MONDO:0008297, variegate porphyria, childhood-onset, MONDO:0957577; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.3 SPTLC2 Ida Ertmanska commented on gene: SPTLC2: Comment on list classification: There are at least 10 unrelated patients reported with juvenile onset ALS with monoallelic variants in SPTLC2 (9 de novo, 1 familial case with demonstrated autosomal dominant inheritance). Based on the available evidence, this gene should be rated Green for Adult onset neurodegenerative disorder.
Adult onset neurodegenerative disorder v8.3 SPTLC2 Ida Ertmanska changed review comment from: Monoallelic variants in SPTLC2 have been associated with juvenile-onset ;amyotrophic lateral sclerosis:
PMID: 38041679 Syeda 2024 - 6 unrelated patients with a recurrent de novo variant p.Glu260Lys
PMID: 38316966 Naruse 2024 - 2 unrelated families - p.Ala71Val, p.Met68Arg
PMID: 38041684 Dohrn 2024 - 2 unrelated patients with the same de novo variant p.Met68Argetc
Sources: Literature; to: Monoallelic variants in SPTLC2 have been associated with juvenile-onset amyotrophic lateral sclerosis:

PMID: 38041679 Syeda 2024 - 6 unrelated patients with a recurrent de novo variant p.Glu260Lys - trio WES/WGS. Phenotype: early-childhood-onset spasticity, followed by rapidly progressive weakness involving upper and lower extremities, bulbar muscles, tongue fasciculations and eventual respiratory insufficiency. Onset: congenital - 4 years of age.

PMID: 38316966 Naruse 2024 - 2 unrelated Japanese families with early-onset ALS - p.Ala71Val, p.Met68Arg. Method: WES. Onset of symptoms: 22-31 years.

PMID: 38041684 Dohrn 2024 - 2 unrelated patients (one African American and one Turkish-Bulgarian) with the same de novo variant p.Met68Arg. Childhood onset. Method: WGS/WES +Sanger confirmation.

SPTLC2 is associated with Neuropathy, hereditary sensory and autonomic, type IC in OMIM (613640) - accessed 13th Oct 2025).
DDG2P v6.8 PDE6H Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Ronnie Wright, this gene does not fit into the scope of developmental disorders, particularly in the context of R27 Paediatric disorders clinical indication. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Hence, the rating with stay green, pending updates from G2P.; to: Comment on list classification: As reviewed by Ronnie Wright, this gene does not fit into the scope of developmental disorders, particularly in the context of R27 Paediatric disorders clinical indication. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Hence, the rating should stay green, pending updates from G2P.
Childhood onset hereditary spastic paraplegia v8.16 TBCB Arina Puzriakova Classified gene: TBCB as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.16 TBCB Arina Puzriakova Added comment: Comment on list classification: Rating Amber following consultation with the Genomics England Clinical Team. Some functional data that indicates disruption of the gene, however this does not provide conclusive support for pathogenicity of the founder variant. Additional functional evidence or corroborative cases would allow verification of this gene-disease association and future review of the classification on this panel.
Childhood onset hereditary spastic paraplegia v8.16 TBCB Arina Puzriakova Gene: tbcb has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v8.3 SPTLC2 Ida Ertmanska gene: SPTLC2 was added
gene: SPTLC2 was added to Adult onset neurodegenerative disorder. Sources: Literature
Mode of inheritance for gene: SPTLC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTLC2 were set to 38041684; 38041679; 38316966
Phenotypes for gene: SPTLC2 were set to Neuropathy, hereditary sensory and autonomic, type IC, OMIM:613640; amyotrophic lateral sclerosis 27, juvenile, MONDO:0859529
Review for gene: SPTLC2 was set to GREEN
Added comment: Monoallelic variants in SPTLC2 have been associated with juvenile-onset ;amyotrophic lateral sclerosis:
PMID: 38041679 Syeda 2024 - 6 unrelated patients with a recurrent de novo variant p.Glu260Lys
PMID: 38316966 Naruse 2024 - 2 unrelated families - p.Ala71Val, p.Met68Arg
PMID: 38041684 Dohrn 2024 - 2 unrelated patients with the same de novo variant p.Met68Argetc
Sources: Literature
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska edited their review of gene: SPTLC1: Changed phenotypes to: Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285, amyotrophic lateral sclerosis 27, juvenile, MONDO:0859529
Autoinflammatory disorders v2.32 ITCH Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ITCH.
Tag Q3_25_NHS_review tag was added to gene: ITCH.
Autoinflammatory disorders v2.32 ITCH Achchuthan Shanmugasundram Phenotypes for gene: ITCH were changed from Autoimmune disease, multisystem, with facial dysmorphism, 613385 to Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska commented on gene: SPTLC1: Comment on list classification: There are at least 11 unrelated cases with juvenile-onset ALS with monoallelic SPTLC1 variants (age of onset between 3-16 years). Variants were confirmed as de novo in 9/11 families. According to functional studies, ALS causing variants tend to cluster in the N-terminal transmembrane domain. Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.
Autoinflammatory disorders v2.31 ITCH Achchuthan Shanmugasundram Publications for gene: ITCH were set to PMID: 36338154
Autoinflammatory disorders v2.30 ITCH Achchuthan Shanmugasundram Classified gene: ITCH as Amber List (moderate evidence)
Autoinflammatory disorders v2.30 ITCH Achchuthan Shanmugasundram Gene: itch has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.126 PPOX Arina Puzriakova Mode of inheritance for gene: PPOX was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.125 PPOX Arina Puzriakova Phenotypes for gene: PPOX were changed from Porphyria variegata, 176200 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: LBX1.
Intellectual disability v9.124 PPOX Arina Puzriakova Publications for gene: PPOX were set to
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska changed review comment from: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4:
Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025).

Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.; to: As reviewed by James Polke, SPTLC1 variants are associated with juvenile-onset amyotrophic lateral sclerosis. There are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), none of them present in gnomAD v4. Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser (2 patients), p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1 ALS-related alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neurons. ALS causing variants tend to cluster in the N-terminal transmembrane domain (TMD); variants in the cytosolic domain are largely associated with HSAN1.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025).
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: LBX1.
Intellectual disability v9.123 PPOX Arina Puzriakova Classified gene: PPOX as Amber List (moderate evidence)
Intellectual disability v9.123 PPOX Arina Puzriakova Gene: ppox has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.122 PPOX Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PPOX.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed publications to: 18727493, 20170897, 30705142, 31091003, 33894394, 36338154
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed phenotypes to: Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385, syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed publications to: 20170897, 30705142, 31091003, 33894394, 36338154
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient-derived ITCH-deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.
Childhood onset hereditary spastic paraplegia v8.15 OGDHL Arina Puzriakova Classified gene: OGDHL as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.15 OGDHL Arina Puzriakova Gene: ogdhl has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska commented on gene: ITCH: Comment on list classification:
There are at least 14 patients from 5 unrelated families with biallelic variants in ITCH. ITCH deficiency may result in multi-systemic immune dysregulation (present in 9/14 reported patients), dysmorphic features (14/14), developmental delay (14/14), relative macrocephaly (13/14), chronic lung disease (13/14), hepatomegaly/splenomegaly (10/14), and hypotonia (8/14). Based on available evidence, ITCH should be rated Green for autoinflammatory disorders.
Childhood onset hereditary spastic paraplegia v8.14 OGDHL Arina Puzriakova Phenotypes for gene: OGDHL were changed from Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221 to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: OGDHL.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR), flux through fatty acid oxidation, and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
Hereditary neuropathy or pain disorder v7.18 XPNPEP3 Arina Puzriakova Phenotypes for gene: XPNPEP3 were changed from Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy, MONDO:0005244 to Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy, MONDO:0005244; myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MONDO:0859322
Acute rhabdomyolysis v2.4 XPNPEP3 Arina Puzriakova gene: XPNPEP3 was added
gene: XPNPEP3 was added to Acute rhabdomyolysis. Sources: Literature
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 40953058
Phenotypes for gene: XPNPEP3 were set to myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MONDO:0859322
Review for gene: XPNPEP3 was set to RED
Added comment: Biallelic variants in this gene are associated with nephronophthisis, a progressive cystic kidney disorder that leads to end-stage renal disease (OMIM:613159). Extra-renal manifestations have only been reported in a subset of cases - neurological features have been reported in at least 4 unrelated families including tremor, dystonia, rhabdomyolysis, peripheral neuropathy, sensorineural hearing loss, epilepsy and cardiomyopathy. Kidney disease was present in all (PMID: 20179356; 38035175), except one case (PMID: 40953058).

A recent report (PMID: 40953058) included the first case of mitochondrial myopathy presenting with a purely metabolic phenotype, manifesting as exertional symptoms and rhabdomyolysis associated with a homozygous XPNPEP3 variant (c.1153dup, p.(Tyr385LeufsTer13)) - however, this individual did not have any typical renal features and therefore it's worth monitoring for similar reports. In the meantime rating as Red awaiting further corroborating cases.
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v5.10 XPNPEP3 Arina Puzriakova gene: XPNPEP3 was added
gene: XPNPEP3 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 40953058
Phenotypes for gene: XPNPEP3 were set to myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MONDO:0859322
Review for gene: XPNPEP3 was set to RED
Added comment: Biallelic variants in this gene are associated with nephronophthisis, a progressive cystic kidney disorder that leads to end-stage renal disease (OMIM:613159). Extra-renal manifestations have only been reported in a subset of cases - neurological features have been reported in at least 4 unrelated families including tremor, dystonia, rhabdomyolysis, peripheral neuropathy, sensorineural hearing loss, epilepsy and cardiomyopathy. Kidney disease was present in all (PMID: 20179356; 38035175), except one case (PMID: 40953058).

A recent report (PMID: 40953058) included the first case of mitochondrial myopathy presenting with a purely metabolic phenotype, manifesting as exertional symptoms and rhabdomyolysis associated with a homozygous XPNPEP3 variant (c.1153dup, p.(Tyr385LeufsTer13)) - however, this individual did not have any typical renal features and therefore it's worth monitoring for similar reports. In the meantime rating as Red awaiting further corroborating cases.
Sources: Literature
DDG2P v6.8 PDE1B Arina Puzriakova Tag curated_removed tag was added to gene: PDE1B.
Hereditary neuropathy or pain disorder v7.17 XPNPEP3 Arina Puzriakova Phenotypes for gene: XPNPEP3 were changed from Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy to Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy, MONDO:0005244
Hereditary neuropathy or pain disorder v7.16 XPNPEP3 Arina Puzriakova Phenotypes for gene: XPNPEP3 were changed from Nephronopthisis; brain white matter lesions; sensory axonal neuropathy; recurrent rhabdomyolysis; cardiomyopathy; ataxia; hearing loss to Nephronophthisis-like nephropathy 1, OMIM:613159; Peripheral neuropathy
Hereditary neuropathy or pain disorder v7.15 XPNPEP3 Arina Puzriakova Publications for gene: XPNPEP3 were set to 40953058
Hereditary neuropathy or pain disorder v7.14 XPNPEP3 Arina Puzriakova Classified gene: XPNPEP3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.14 XPNPEP3 Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in this gene are associated with nephronophthisis, a progressive cystic kidney disorder that leads to end-stage renal disease (OMIM:613159). Extra-renal manifestations have only been reported in a subset of cases - neurological features have been reported in at least 4 unrelated families including tremor, dystonia, rhabdomyolysis, peripheral neuropathy, sensorineural hearing loss, epilepsy and cardiomyopathy. Kidney disease was present in all (PMID: 20179356; 38035175), except one case (PMID: 40953058).

In the literature, there are 2 cases with peripheral neuropathy and biallelic variants in this gene (PMID: 38035175; 40953058), however, this is not a common manifestation for this gene. One case did not have any typical renal features and therefore it's worth monitoring for similar reports. In the meantime rating as Amber awaiting further corroborating cases.
Hereditary neuropathy or pain disorder v7.14 XPNPEP3 Arina Puzriakova Gene: xpnpep3 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska edited their review of gene: ITCH: Changed publications to: 20170897, 30705142, 31091003, 36338154
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient derived ITCH deficient fibroblasts, including reduced oxygen consumption (OCR), flux through fatty acid oxidation, and a decrease in cellular ATP production.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram commented on gene: LBX1: The DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). This gene has been added with amber rating on R333 Central congenital hypoventilation panel (https://panelapp.genomicsengland.co.uk/panels/1314/gene/LBX1/) as this phenotype clearly fits into the scope of R333 clinical indication.

The 'curated_removed' tag has been added so that this gene won't be relevant on this panel until it is added to the DD panel on G2P resource.
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram Deleted their comment
DDG2P v6.8 LBX1 Achchuthan Shanmugasundram Publications for gene: LBX1 were set to PMID: 30487221
DDG2P v6.7 LBX1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 13 October 2025
DDG2P v6.7 LBX1 Achchuthan Shanmugasundram Phenotypes for gene: LBX1 were changed from to ?Central hypoventilation syndrome, congenital, 3, OMIM:619483; central hypoventilation syndrome, congenital, 3, MONDO:0030539
DDG2P v6.6 LBX1 Achchuthan Shanmugasundram Tag curated_removed tag was added to gene: LBX1.
DDG2P v6.6 LBX1 Achchuthan Shanmugasundram commented on gene: LBX1
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Classified gene: LBX1 as Amber List (moderate evidence)
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one published family and mouse model available in support of the association. Hence, this gene should be rated amber with the current evidence.
Central congenital hypoventilation v1.5 LBX1 Achchuthan Shanmugasundram Gene: lbx1 has been classified as Amber List (Moderate Evidence).
Central congenital hypoventilation v1.4 LBX1 Achchuthan Shanmugasundram Publications for gene: LBX1 were set to PMID: 30487221
Central congenital hypoventilation v1.3 LBX1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #619483). This OMIM record has been accessed on 13 October 2025.
Central congenital hypoventilation v1.3 LBX1 Achchuthan Shanmugasundram Phenotypes for gene: LBX1 were changed from to ?Central hypoventilation syndrome, congenital, 3, OMIM:619483; central hypoventilation syndrome, congenital, 3, MONDO:0030539
Central congenital hypoventilation v1.2 LBX1 Achchuthan Shanmugasundram reviewed gene: LBX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30487221; Phenotypes: ?Central hypoventilation syndrome, congenital, 3, OMIM:619483, central hypoventilation syndrome, congenital, 3, MONDO:0030539; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Central congenital hypoventilation v1.2 LBX1 Achchuthan Shanmugasundram Entity copied from DDG2P v6.6
Central congenital hypoventilation v1.2 LBX1 Achchuthan Shanmugasundram gene: LBX1 was added
gene: LBX1 was added to Central congenital hypoventilation. Sources: Expert Review
Mode of inheritance for gene: LBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LBX1 were set to PMID: 30487221
Penetrance for gene: LBX1 were set to Complete
Monogenic hearing loss v5.31 KIAA0391 Achchuthan Shanmugasundram Classified gene: KIAA0391 as Amber List (moderate evidence)
Monogenic hearing loss v5.31 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are at least four unrelated families reported with sensorineural hearing loss, this gene can be promoted to green rating in the next GMS update.
Monogenic hearing loss v5.31 KIAA0391 Achchuthan Shanmugasundram Gene: kiaa0391 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: KIAA0391.
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram commented on gene: KIAA0391: The 'new-gene-name' tag has been added as the official gene symbol for KIAA0391 is PRORP. It is also known as MRPP3.
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Monogenic hearing loss v5.30 KIAA0391 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Combined oxidative phosphorylation deficiency 54, OMIM:619737 to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Monogenic hearing loss v5.29 KIAA0391 Achchuthan Shanmugasundram gene: KIAA0391 was added
gene: KIAA0391 was added to Monogenic hearing loss. Sources: Literature
new-gene-name tags were added to gene: KIAA0391.
Mode of inheritance for gene: KIAA0391 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0391 were set to 34715011; 37558808
Phenotypes for gene: KIAA0391 were set to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Review for gene: KIAA0391 was set to GREEN
Added comment: PMID:34715011 (2021) reported four unrelated families with multisystem disease and identified with biallelic variants (either homozygous or compound heterozygous) in PRORP (KIAA0391) gene. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss (SNHL), primary ovarian insufficiency, developmental delay, and brain white matter changes. SNHL was reported in three of the four families. There is also functional evidence available from fibroblasts from affected individuals in two families.

PMID:37558808 (2023) reported three additional unrelated patients with homozygous missense PRORP variants and with pleiotropic phenotypes consistent with the previously reported cases from PMID:34715011. SNHL was reported in one these cases, while another proband did not pass neonatal hearing screening (althoughjt formal hearing test was not performed and patient died at 19 months of age).
Sources: Literature
Deafness and congenital structural abnormalities v1.34 KIAA0391 Achchuthan Shanmugasundram Classified gene: KIAA0391 as Green List (high evidence)
Deafness and congenital structural abnormalities v1.34 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are at least four unrelated families reported with sensorineural hearing loss, this gene has been promoted to green rating on this panel.
Deafness and congenital structural abnormalities v1.34 KIAA0391 Achchuthan Shanmugasundram Gene: kiaa0391 has been classified as Green List (High Evidence).
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: KIAA0391.
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram commented on gene: KIAA0391: The 'new-gene-name' tag has been added as the official gene symbol for KIAA0391 is PRORP. It is also known as MRPP3.
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Deafness and congenital structural abnormalities v1.33 KIAA0391 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Combined oxidative phosphorylation deficiency 54, OMIM:619737 to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Deafness and congenital structural abnormalities v1.32 KIAA0391 Achchuthan Shanmugasundram Phenotypes for gene: KIAA0391 were changed from Sensorineural hearing loss; primary ovarian insufficiency; leukodystrophy to Combined oxidative phosphorylation deficiency 54, OMIM:619737
Deafness and congenital structural abnormalities v1.31 KIAA0391 Achchuthan Shanmugasundram Publications for gene: KIAA0391 were set to PMID:34715011; 37558808
Deafness and congenital structural abnormalities v1.30 KIAA0391 Achchuthan Shanmugasundram reviewed gene: KIAA0391: Rating: GREEN; Mode of pathogenicity: None; Publications: 34715011, 37558808; Phenotypes: Combined oxidative phosphorylation deficiency 54, OMIM:619737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska changed review comment from: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.; to: As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a mutation in ITCH. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). No access to full article.

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Based on the available evidence, ITCH should be rated Green for Autoinflammatory disorders.
Autoinflammatory disorders v2.29 ITCH Ida Ertmanska reviewed gene: ITCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 20170897, 30705142, 31091003; Phenotypes: Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v4.7 UNC45A Ida Ertmanska changed review comment from: Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).

; to: Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM (accessed 10th Oct 2025) - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).
Cholestasis v3.10 UNC45A Ida Ertmanska changed review comment from: UNC45A has been linked to Aagenaes syndrome - a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. There are at least 28 affected individuals from 25 different families who presented with neonatal cholestasis and lymphedema (PMIDs:37328071;39887522). Based on the reported evidence, this gene should be rated Green for Cholestasis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).; to: UNC45A has been linked to Aagenaes syndrome - a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. There are at least 28 affected individuals from 25 different families who presented with neonatal cholestasis and lymphedema (PMIDs:37328071;39887522). Based on the reported evidence, this gene should be rated Green for Cholestasis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM (accessed 10th Oct 2025) - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).
Cholestasis v3.10 UNC45A Ida Ertmanska reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 37328071, 39887522; Phenotypes: Osteootohepatoenteric syndrome, OMIM:619377, Aagenaes syndrome, MONDO:0008966; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v4.7 UNC45A Ida Ertmanska commented on gene: UNC45A: Comment on list classification: UNC45A has been linked to Aagenaes syndrome - a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. There are at least 28 affected individuals from 25 different families who presented with neonatal cholestasis and lymphedema (PMIDs:37328071;39887522). Based on the reported evidence, this gene should be rated Green for Primary lymphoedema.
Primary lymphoedema v4.7 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed publications to: 37328071, 39887522
Primary lymphoedema v4.7 UNC45A Ida Ertmanska changed review comment from: PMID: 37328071 Almaas et al., 2023
Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.
26 patients from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.
Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls + CRISPR/Cas9-created cell model.; to: Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).
Primary lymphoedema v4.7 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed phenotypes to: Osteootohepatoenteric syndrome, OMIM:619377, Aagenaes syndrome, MONDO:0008966
Primary lymphoedema v4.7 UNC45A Ida Ertmanska reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 37328071; Phenotypes: Osteootohepatoenteric syndrome 619377; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
RASopathies v1.86 RREB1 Achchuthan Shanmugasundram Classified gene: RREB1 as Green List (high evidence)
RASopathies v1.86 RREB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated patients) in support of the disease association. Hence, this gene has been promoted to green rating on this panel.
RASopathies v1.86 RREB1 Achchuthan Shanmugasundram Gene: rreb1 has been classified as Green List (High Evidence).
RASopathies v1.85 RREB1 Achchuthan Shanmugasundram Phenotypes for gene: RREB1 were changed from Noonan syndrome-like disorder to RASopathy, MONDO:0021060
RASopathies v1.84 RREB1 Achchuthan Shanmugasundram Publications for gene: RREB1 were set to 32938917
RASopathies v1.83 RREB1 Achchuthan Shanmugasundram reviewed gene: RREB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38332451, 40418122; Phenotypes: RASopathy, MONDO:0021060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.39 VSX2 Ida Ertmanska edited their review of gene: VSX2: Changed publications to: 8630490, 21976963, 23028343, 24001013, 35831950, 36264558, 38994775
Retinal disorders v8.39 VSX2 Ida Ertmanska changed review comment from: Biallelic VSX2 variants often result in microphthalmia, anophthalmia, coloboma (MAC):

PMID: 21976963 Reis et al., 2011
2 unrelated consanguineous families with AR isolated bilateral microphthalmia.
Pakistani family - affected individuals homozygous for c.668G>C (p.G223A).
Iranian family - affected individuals homozygous for c.249delG (p.Leu84SerfsX57). ERG performed on 2 sisters in this family showed inner retinal dysfunction in both.

As reviewed by Beisi Xu, there are also at least three different VSX2 variants reported in three unrelated patients with retinopathy and no reported MAC phenotype.

PMID: 36264558 Smirnov et al., 2022: 3 patients from 2 unrelated non-consanguineous Turkish families, harbouring homozygous missense variants: c.595C>T, p.(Arg199Cys) and c.698C>T, p.(Pro233Leu). All 3 patients presented with infantile nystagmus, low stable visual acuity, myopia and night blindness, cause by retinopathy with lens luxation.

PMID: 24001013 Khan et al., 2013: Case study - Female, 3yo, Saudi Arabian. Phenotype: Poor vision from birth, chorioretinal atrophy, retinal dysfunction; superior lens subluxation and smooth iris. Homozygous for c.773delA; p.(Lys258Serfs*44); variant heterozygous in unaffected brother and consanguineous parents. Homozygous frameshift BCAP29 variant also identified in patient - not much known about this gene.
Functional studies in mice and human retinal organoids indicate that the reported VSX2 variants have a variable effect on VSX2’s DNA binding properties, which may explain the phenotypic heterogeneity observed in patients (PMID: 23028343; 35831950; 38994775).

This gene is not yet associated with retinal disorders in OMIM or Gene2Phenotype.; to: Biallelic VSX2 (formerly CHX10) variants often result in microphthalmia, anophthalmia, coloboma (MAC).

PMID: 21976963 Reis et al., 2011
2 unrelated consanguineous families with AR isolated bilateral microphthalmia.
Pakistani family - affected individuals homozygous for c.668G>C (p.G223A).
Iranian family - affected individuals homozygous for c.249delG (p.Leu84SerfsX57). ERG performed on 2 sisters in this family showed inner retinal dysfunction in both.

As reviewed by Beisi Xu, there are also at least three different VSX2 variants reported in three unrelated patients with retinopathy and no reported MAC phenotype:

PMID: 36264558 Smirnov et al., 2022: 3 patients from 2 unrelated non-consanguineous Turkish families, harbouring homozygous missense variants: c.595C>T, p.(Arg199Cys) and c.698C>T, p.(Pro233Leu). All 3 patients presented with infantile nystagmus, low stable visual acuity, myopia and night blindness, cause by retinopathy with lens luxation.

PMID: 24001013 Khan et al., 2013: Case study - Female, 3yo, Saudi Arabian. Phenotype: Poor vision from birth, chorioretinal atrophy, retinal dysfunction; superior lens subluxation and smooth iris. Homozygous for c.773delA; p.(Lys258Serfs*44); variant heterozygous in unaffected brother and consanguineous parents. Homozygous frameshift BCAP29 variant also identified in patient - not much known about this gene.

Functional studies in mice and human retinal organoids indicate that the reported VSX2 variants have a variable effect on VSX2’s DNA binding properties, which may explain the phenotypic heterogeneity observed in patients (PMID: 23028343; 35831950; 38994775).
PMID: 8630490 Burmeister et al., 1996: Mice homozygous for a premature stop codon in VSX2/CHX10 are blind, with obvious microphthalmia, cataractous lens, a thin retina, and no optic nerve. Study notes that loss of VSX2CHX10 leads both to reduced proliferation of retinal progenitors and to a specific absence of differentiated bipolar cells - supportive of MAC / retinal degeneration phenotype seen in patients.

This gene is not yet associated with retinal disorders in OMIM or Gene2Phenotype.
Fetal hydrops v1.91 RASA1 Achchuthan Shanmugasundram Classified gene: RASA1 as Green List (high evidence)
Fetal hydrops v1.91 RASA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (~25 unrelated cases) for the promotion of this gene to green rating on this panel.
Fetal hydrops v1.91 RASA1 Achchuthan Shanmugasundram Gene: rasa1 has been classified as Green List (High Evidence).
Fetal hydrops v1.90 RASA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 10 October 2025.
Fetal hydrops v1.90 RASA1 Achchuthan Shanmugasundram Phenotypes for gene: RASA1 were changed from capillary malformation-arteriovenous malformation-1 (CMAVM1, OMIM # 608354) to Capillary malformation-arteriovenous malformation 1, OMIM:608354; capillary malformation-arteriovenous malformation 1, MONDO:0020783
Fetal hydrops v1.89 RASA1 Achchuthan Shanmugasundram reviewed gene: RASA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36980822; Phenotypes: Capillary malformation-arteriovenous malformation 1, OMIM:608354, capillary malformation-arteriovenous malformation 1, MONDO:0020783; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v8.39 VSX2 Ida Ertmanska reviewed gene: VSX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21976963, 24001013, 36264558; Phenotypes: Microphthalmia, isolated 2, OMIM:610093, retinal disorder, MONDO:0005283; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.97 RASA1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Fetal anomalies v6.97 RASA1 Achchuthan Shanmugasundram Phenotypes for gene: RASA1 were changed from PARKES WEBER SYNDROME; CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION to Capillary malformation-arteriovenous malformation 1, OMIM:608354; capillary malformation-arteriovenous malformation 1, MONDO:0020783
Respiratory ciliopathies including non-CF bronchiectasis v4.47 DNAH9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 10 October 2025.
Respiratory ciliopathies including non-CF bronchiectasis v4.47 DNAH9 Achchuthan Shanmugasundram Phenotypes for gene: DNAH9 were changed from Primary ciliary dyskinesia to Ciliary dyskinesia, primary, 40, OMIM:618300; ciliary dyskinesia, primary, 40, MONDO:0032664
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (eight unrelated cases and functional studies) for the promotion of this gene to green rating in this panel.; to: Comment on list classification: There is sufficient evidence available (eight unrelated cases and functional studies) for the promotion of this gene to green rating on this panel.
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram Classified gene: DNAH9 as Green List (high evidence)
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight unrelated cases and functional studies) for the promotion of this gene to green rating in this panel.
Primary ciliary disorders v1.55 DNAH9 Achchuthan Shanmugasundram Gene: dnah9 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.54 DNAH9 Achchuthan Shanmugasundram Classified gene: DNAH9 as Green List (high evidence)
Primary ciliary disorders v1.54 DNAH9 Achchuthan Shanmugasundram Gene: dnah9 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.41 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Early onset or syndromic epilepsy. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes childhood-onset seizures / epilepsy.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Early onset or syndromic epilepsy. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Primary ciliary disorders v1.53 DNAH9 Achchuthan Shanmugasundram Phenotypes for gene: DNAH9 were changed from to Ciliary dyskinesia, primary, 40, OMIM:618300; ciliary dyskinesia, primary, 40, MONDO:0032664
Primary ciliary disorders v1.52 DNAH9 Achchuthan Shanmugasundram Publications for gene: DNAH9 were set to PMID: 30471717; 30471718
Primary ciliary disorders v1.51 DNAH9 Achchuthan Shanmugasundram reviewed gene: DNAH9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30471717, 30471718; Phenotypes: Ciliary dyskinesia, primary, 40, OMIM:618300, ciliary dyskinesia, primary, 40, MONDO:0032664; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.28 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Monogenic hearing loss. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes hearing loss (at least 8 cases in total).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Monogenic hearing loss. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska edited their review of gene: OGDHL: Changed publications to: 28017472, 34800363, 38031187; Changed phenotypes to: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes neurological features such as gait ataxia.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes neurological features such as ataxia (6 cases).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes neurological features such as gait ataxia.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Ataxia and cerebellar anomalies - narrow panel. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska commented on gene: OGDHL: Comment on list classification: This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly heterogeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska changed review comment from: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature; to: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a childhood-onset complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

PMIDs: 28017472; 34800363: 10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome. Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska gene: OGDHL was added
gene: OGDHL was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 28017472; 34800363; 38031187
Phenotypes for gene: OGDHL were set to Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221
Review for gene: OGDHL was set to GREEN
Added comment: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature
Primary ciliary disorders v1.51 OFD1 Achchuthan Shanmugasundram Classified gene: OFD1 as Green List (high evidence)
Primary ciliary disorders v1.51 OFD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating.
Primary ciliary disorders v1.51 OFD1 Achchuthan Shanmugasundram Gene: ofd1 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.50 OFD1 Achchuthan Shanmugasundram Mode of inheritance for gene: OFD1 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary ciliary disorders v1.49 OFD1 Achchuthan Shanmugasundram Publications for gene: OFD1 were set to
Primary ciliary disorders v1.48 OFD1 Achchuthan Shanmugasundram Phenotypes for gene: OFD1 were changed from ciliopathies to Simpson-Golabi-Behmel syndrome, type 2, OMIM:300209; ?Retinitis pigmentosa 23 , OMIM:300424; Joubert syndrome 10, OMIM:300804; Orofaciodigital syndrome I, OMIOM:311200
Primary ciliary disorders v1.47 OFD1 Achchuthan Shanmugasundram reviewed gene: OFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31366608, 31373179; Phenotypes: Simpson-Golabi-Behmel syndrome, type 2, OMIM:300209, ?Retinitis pigmentosa 23 , OMIM:300424, Joubert syndrome 10, OMIM:300804, Orofaciodigital syndrome I, OMIOM:311200; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v8.41 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28017472, 34800363, 38031187; Phenotypes: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.28 OGDHL Ida Ertmanska edited their review of gene: OGDHL: Changed rating: GREEN; Changed publications to: 28017472, 34800363, 38031187; Changed phenotypes to: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.28 OGDHL Ida Ertmanska commented on gene: OGDHL
Ataxia and cerebellar anomalies - narrow panel v8.24 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: 28017472, 34800363, 38031187; Mode of inheritance: None
Intellectual disability v9.122 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: neurodevelopmental disorder, neurodegeneration, infantile-onset epileptic encephalopathy, skeletal dysplasia, childhood-onset epilepsy, multiple congenital anomalies, dysmorphism, non-syndromic hearing loss, neuromuscular disorders, and congenital heart defects. 9/14 reported patients had developmental delay/intellectual disability. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.122 NAA60 Ida Ertmanska gene: NAA60 was added
gene: NAA60 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA60 were set to 38480682
Phenotypes for gene: NAA60 were set to Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786; basal ganglia calcification, idiopathic, 9, autosomal recessive, MONDO:0968977
Review for gene: NAA60 was set to RED
Added comment: PMID: 38480682 Chelban et al., 2024
Report of 7 unrelated families with homozygous variants in NAA60 with primary familial brain calcifications. Families originated from UK, France/Algeria, France/Morocco, UK/India, Turkey, and Saudi Arabia. 5/7 families had reported consanguinity. Sequencing method: WGS, WES.
Variants reported: c.321_327del, (p.Arg108Thrfs*3); c.338-1G>C, p.(Gly113Valfs*32); c.391C>T, (p.His131Tyr); c.130C>T, (p.Arg44Cys); c.50T>G, (p.Leu17Arg); c.428A>C, (p.Asn143Thr). No homozygotes reported in gnomAD v4.
9/10 patients had some motor features: extrapyramidal, pyramidal, cerebellar syndrome, dystonia - onset mostly in 20s-30s, one individual had symptoms from age 10 years. 3/10 individuals had mild intellectual disability, 3/10 had developmental delay from birth. 5/10 patients had some dysmorphic features. All 10 patients had some cognitive features (mostly mild): cognitive impairment (adult-onset), mild frontal syndrome, learning difficulties.
CT and brain MRI confirmed the presence of brain calcifications in all reported adult cases (9).
Phenotype and age of onset was variable, even in individuals who harboured the same variant - e.g. siblings in Family 2, homozygous for the same variant: sib II-2 had no motor features, only presented with mild frontal syndrome in her early 30s; sib II-1 presented with global developmental delay from birth, with onset of motor symptoms at age 20 - extrapyramidal and cerebellar syndrome, dystonia.

NAA60 is associated with AR Basal ganglia calcification, idiopathic, 9, autosomal recessive, 620786 in OMIM (accessed 10th Oct 2025).
In summary, while some individuals presented with intellectual disability and cognitive impairment, their symptoms were mild. Thus, these cases do not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. Based on the available evidence, this gene should be rated Red for Intellectual disability.
Sources: Literature
Skeletal dysplasia v8.17 SIK3 Sarah Graham reviewed gene: SIK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30232230, 22318228; Phenotypes: Spondyloepimetaphyseal dysplasia, Krakow type, OMIM:618162; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska changed review comment from: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4:
Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400.
Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.; to: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants:

PMID: 34059824 Mohassel et al., 2021
11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients.
Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4:
Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del.

PMID: 34459874 Johnson et al., 2021
Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals.

Functional evidence:
Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant.
Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely.

SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025).

Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.
Hereditary neuropathy or pain disorder v7.13 TDP1 Achchuthan Shanmugasundram edited their review of gene: TDP1: Added comment: As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also function evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease, This patient was identified with novel missense variant in TDP1 - p.His478Tyr. via WES and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.; Changed rating: GREEN; Changed publications to: 12244316, 15920477, 17948061, 31182267, 31723605, 39576382; Changed phenotypes to: ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, MONDO:0011801
Adult onset neurodegenerative disorder v8.3 SPTLC1 Ida Ertmanska reviewed gene: SPTLC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34059824, 34459874, 35900868, 40027730; Phenotypes: Amyotrophic lateral sclerosis 27, juvenile, 620285, amyotrophic lateral sclerosis 27, juvenile MONDO:0859529; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v6.6 PDE6H Achchuthan Shanmugasundram Classified gene: PDE6H as Green List (high evidence)
DDG2P v6.6 PDE6H Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ronnie Wright, this gene does not fit into the scope of developmental disorders, particularly in the context of R27 Paediatric disorders clinical indication. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Hence, the rating with stay green, pending updates from G2P.
DDG2P v6.6 PDE6H Achchuthan Shanmugasundram Gene: pde6h has been classified as Green List (High Evidence).
DDG2P v6.5 PDE6H Achchuthan Shanmugasundram edited their review of gene: PDE6H: Changed rating: AMBER
Tubulointerstitial kidney disease v3.6 JAG1 John Sayer gene: JAG1 was added
gene: JAG1 was added to Tubulointerstitial kidney disease. Sources: Expert list
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to PMID: 41061854
Phenotypes for gene: JAG1 were set to tubulointersitial kidney disease; kidney failure
Penetrance for gene: JAG1 were set to Incomplete
Mode of pathogenicity for gene: JAG1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: JAG1 was set to GREEN
Added comment: JAG1 causes Alagile syndrome but new evidence shows it can give renal limited phenotypes resembling ADTKD
Sources: Expert list
Adult onset neurodegenerative disorder v8.3 DNAJC7 Cassandra Smith changed review comment from: One report of biallelic inheritance

PMID:40802071 - three affected sibling with homozygous frameshift variant. Parents unaffected; to: One report of biallelic inheritance

PMID:40802071 - three affected siblings with homozygous frameshift variant. Phenotype is ALS. Parents unaffected
Adult onset neurodegenerative disorder v8.3 DNAJC7 Cassandra Smith reviewed gene: DNAJC7: Rating: ; Mode of pathogenicity: None; Publications: 40802071; Phenotypes: ; Mode of inheritance: None
Paediatric or syndromic cardiomyopathy v7.91 MT-ND5 Achchuthan Shanmugasundram changed review comment from: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the while mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.; to: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.
Hypertrophic cardiomyopathy v5.12 MT-ND5 Achchuthan Shanmugasundram changed review comment from: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the while mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.; to: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram changed review comment from: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with ncomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.; to: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with incomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram Classified gene: PDE6H as Amber List (moderate evidence)
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ronnie Wright, the rating for this gene should remain amber. This is because there is only one variant reported across multiple unrelated patients displaying phenotypic variability and without compelling functional evidence.
Retinal disorders v8.39 PDE6H Achchuthan Shanmugasundram Gene: pde6h has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.38 PDE6H Achchuthan Shanmugasundram commented on gene: PDE6H: There is only one homozygous PDE6H variant (p.Ser12Ter) reported to be identified from multiple unrelated individuals. Although this variant has been reported in three unrelated families with cone dysfunction, there are at least three other families reported with ncomplete achromatopsia, where limited clinical information was available and cone dysfunction was not reported.

The mouse model also failed to replicate the human phenotype.
Retinal disorders v8.38 PDE6H Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 09 September 2025.
Retinal disorders v8.38 PDE6H Achchuthan Shanmugasundram Phenotypes for gene: PDE6H were changed from Achromatopsia 6, OMIM:610024; achromatopsia 6, MONDO:0800197 to Achromatopsia 6, OMIM:610024; achromatopsia 6, MONDO:0800197
Retinal disorders v8.37 PDE6H Achchuthan Shanmugasundram Phenotypes for gene: PDE6H were changed from Retinal Cone Dystrophy 3, 610024; Achromatopsia 6, 610024; Eye Disorders; Achromatopsia, Cone, and Cone-rod Dystrophy to Achromatopsia 6, OMIM:610024; achromatopsia 6, MONDO:0800197
Retinal disorders v8.36 PDE6H Achchuthan Shanmugasundram Publications for gene: PDE6H were set to 15629837; 22901948; 25739440
Retinal disorders v8.35 PDE6H Achchuthan Shanmugasundram reviewed gene: PDE6H: Rating: AMBER; Mode of pathogenicity: None; Publications: 22901948, 25739440, 27472364, 35567543, 36980963; Phenotypes: Achromatopsia 6, OMIM:610024, achromatopsia 6, MONDO:0800197; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.342 FGF14 Arina Puzriakova commented on gene: FGF14
Palmoplantar keratoderma and erythrokeratodermas v1.34 FAM83G Arina Puzriakova Publications for gene: FAM83G were set to
Palmoplantar keratoderma and erythrokeratodermas v1.33 FAM83G Arina Puzriakova Classified gene: FAM83G as Amber List (moderate evidence)
Palmoplantar keratoderma and erythrokeratodermas v1.33 FAM83G Arina Puzriakova Added comment: Comment on list classification: Upgraded rating from Red to Amber inline with expert review by Tom Cullup (GOSH) to facilitate further gathering of data where appropriate which could potentially support future promotion to Green. Already Amber on GMS equivalent panels (R166 and R165)
Palmoplantar keratoderma and erythrokeratodermas v1.33 FAM83G Arina Puzriakova Gene: fam83g has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.122 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from HEREDITARY FOLATE MALABSORPTION (HFM) to Folate malabsorption, hereditary, OMIM:229050
Likely inborn error of metabolism v8.60 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary; Hereditary folate malabsorption (Disorders of folate metabolism and transport) to Folate malabsorption, hereditary, OMIM:229050; Hereditary folate malabsorption (Disorders of folate metabolism and transport)
Childhood onset dystonia, chorea or related movement disorder v7.12 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary, 229050 to Folate malabsorption, hereditary, OMIM:229050
Adult onset dystonia, chorea or related movement disorder v5.2 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary, 229050; Dystonia to Folate malabsorption, hereditary, OMIM:229050
Fetal anomalies v6.96 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from HEREDITARY FOLATE MALABSORPTION to Folate malabsorption, hereditary, OMIM:229050
Undiagnosed metabolic disorders v1.634 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Hereditary folate malabsorption (Disorders of folate metabolism and transport); Folate malabsorption, hereditary to Folate malabsorption, hereditary, OMIM:229050; Hereditary folate malabsorption (Disorders of folate metabolism and transport)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.44 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary 229050; Defects of Vitamin B12 and Folate metabolism; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Combined immunodeficiencies with associated or syndromic features to Folate malabsorption, hereditary, OMIM:229050; Defects of Vitamin B12 and Folate metabolism; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Combined immunodeficiencies with associated or syndromic features
COVID-19 research v1.145 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary 229050; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Defects of Vitamin B12 and Folate metabolism; Combined immunodeficiencies with associated or syndromic features to Folate malabsorption, hereditary, OMIM:229050; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Defects of Vitamin B12 and Folate metabolism; Combined immunodeficiencies with associated or syndromic features
Cerebral folate deficiency v1.3 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption, hereditary 229050 to Folate malabsorption, hereditary, OMIM:229050
Cytopenias and congenital anaemias v1.120 SLC46A1 Arina Puzriakova Classified gene: SLC46A1 as Green List (high evidence)
Cytopenias and congenital anaemias v1.120 SLC46A1 Arina Puzriakova Added comment: Comment on list classification: New gene added as Green. At least 5 unrelated individuals with biallelic variants in this gene and hereditary folate malabsorption which can progress to severe pancytopenia (PMID: 11807405; 17446347; 21333572; 40937236). This is a key feature of this condition and warrants inclusion on the panel.
Cytopenias and congenital anaemias v1.120 SLC46A1 Arina Puzriakova Gene: slc46a1 has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v4.24 SLC46A1 Arina Puzriakova Classified gene: SLC46A1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v4.24 SLC46A1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green. At least 5 unrelated individuals with biallelic variants in this gene and hereditary folate malabsorption which can progress to severe pancytopenia (PMID: 11807405; 17446347; 21333572; 40937236). This is a key feature of this condition and warrants inclusion on the panel.
Cytopenia - NOT Fanconi anaemia v4.24 SLC46A1 Arina Puzriakova Gene: slc46a1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v4.23 SLC46A1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SLC46A1.
Tag Q3_25_NHS_review tag was added to gene: SLC46A1.
Cytopenia - NOT Fanconi anaemia v4.23 SLC46A1 Arina Puzriakova Entity copied from Cytopenias and congenital anaemias v1.119
Cytopenia - NOT Fanconi anaemia v4.23 SLC46A1 Arina Puzriakova gene: SLC46A1 was added
gene: SLC46A1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert Review,Literature
Mode of inheritance for gene: SLC46A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC46A1 were set to 21333572; 17446347; 29390264; 11804211; 17641272
Phenotypes for gene: SLC46A1 were set to Folate malabsorption, hereditary, OMIM:229050; anemia; pancytopenia
Cytopenias and congenital anaemias v1.119 SLC46A1 Arina Puzriakova Phenotypes for gene: SLC46A1 were changed from Folate malabsorption; anemia; pancytopenia to Folate malabsorption, hereditary, OMIM:229050; anemia; pancytopenia
Publications for gene: SLC46A1 were updated from PMID: 21333572; 17446347; 29390264; 11804211; 17641272 to 21333572; 17446347; 29390264; 11804211; 17641272
Intellectual disability v9.121 SF1 Achchuthan Shanmugasundram Classified gene: SF1 as Amber List (moderate evidence)
Intellectual disability v9.121 SF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are fifteen unrelated patients reported with monoallelic SF1 variants and a neurodevelopmental disorder, of which four patients had intellectual disability of moderate severity. Hence, this gene can be promoted to green rating in the next update.
Intellectual disability v9.121 SF1 Achchuthan Shanmugasundram Gene: sf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.120 SF1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.; to: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v4.1.0 non-UK Biobank, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Intellectual disability v9.120 SF1 Achchuthan Shanmugasundram Phenotypes for gene: SF1 were changed from to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.119 SF1 Achchuthan Shanmugasundram Publications for gene: SF1 were set to PMID: 40987292
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review tag was added to gene: SF1.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: SF1.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.; to: As reviewed by Mike Spiller, PMID:40987292 reported a cohort of 15 unrelated individuals (eight males and seven females, aged from 2 to 22 years) with 15 different heterozygous variants in SF1 gene identified via exome or genome sequencing. All except two variants are absent in gnomAD v2.1.1, while two variants were identified with allele counts of 9 (intronic variant) and 1 in non-UK Biobank version of the database. 7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations were reported in addition to the one intronic variant that should be disregarded.

All these 15 patients had developmental delay during the first years of life with seven of them having global developmental delay. Intellectual disability was reported in eight patients, of which four patients had ID of moderate severity and others had either ID of mild or unknown severity.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Intellectual disability v9.118 SF1 Achchuthan Shanmugasundram reviewed gene: SF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40987292; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v7.13 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from hepatic dysfunction; sensory axonal neuropathy to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; hepatic dysfunction; sensory axonal neuropathy
Hereditary neuropathy or pain disorder v7.12 DLD Arina Puzriakova Classified gene: DLD as Red List (low evidence)
Hereditary neuropathy or pain disorder v7.12 DLD Arina Puzriakova Added comment: Comment on list classification: Several cases reported with Dihydrolipoamide dehydrogenase deficiency (OMIM:246900) but only a single report linking this to a reversible sensory neuropathy (PMID:40888368). It is worth noting that neuropathy occurred without lactic acidosis or secondary vitamin deficiencies, coupled with lipid deposition in peripheral nerve biopsies. This requires validation through additional corroborative cases and therefore rating as Red until such cases emerge.
Hereditary neuropathy or pain disorder v7.12 DLD Arina Puzriakova Gene: dld has been classified as Red List (Low Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.11 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoamide dehydrogenase deficiency, 246900 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Mitochondrial disorders v9.32 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoamide dehydrogenase deficiency, 246900; Leigh syndrome to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; Leigh syndrome
Intellectual disability v9.118 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoamide dehydrogenase deficiency, 246900; DIHYDROLIPOAMIDE DEHYDROGENASE (E3) DEFICIENCY to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Fetal anomalies v6.95 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from DIHYDROLIPOAMIDE DEHYDROGENASE (E3) DEFICIENCY; LEIGH SYNDROME to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Likely inborn error of metabolism v8.59 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Leigh syndrome; Dihydrolipoamide dehydrogenase deficiency, 246900 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Leigh syndrome
Possible mitochondrial disorder - nuclear genes v4.13 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY, 246900 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900
Undiagnosed metabolic disorders v1.633 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Dihydrolipoamide dehydrogenase deficiency, 246900; Leigh syndrome to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; Dihydrolipoyl dehydrogenase deficiency (Disorders of pyruvate metabolism); Leigh syndrome
Pyruvate dehydrogenase (PDH) deficiency v1.37 DLD Arina Puzriakova Phenotypes for gene: DLD were changed from DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY OMIM:246900; pyruvate dehydrogenase E3 deficiency MONDO:0009529 to Dihydrolipoamide dehydrogenase deficiency, OMIM:246900; pyruvate dehydrogenase E3 deficiency MONDO:0009529
Paediatric or syndromic cardiomyopathy v7.91 RPL3L Arina Puzriakova Tag Q3_24_NHS_review tag was added to gene: RPL3L.
Tag Q3_25_promote_green tag was added to gene: RPL3L.
Tag Q3_25_expert_review tag was added to gene: RPL3L.
Paediatric or syndromic cardiomyopathy v7.91 RPL3L Arina Puzriakova Publications for gene: RPL3L were set to 32514796; 32870709
Dilated and arrhythmogenic cardiomyopathy v3.9 RPL3L Arina Puzriakova Publications for gene: RPL3L were set to 32514796; 32870709
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RPL3L.
Tag Q3_25_expert_review tag was added to gene: RPL3L.
Paediatric or syndromic cardiomyopathy v7.90 RPL3L Arina Puzriakova Classified gene: RPL3L as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.90 RPL3L Arina Puzriakova Added comment: Comment on list classification: There are now at least 14 individuals from 11 families with severe early-onset dilated cardiomyopathy. Almost all attributed to compound heterozygous missense variants (also 3 frameshift and 1 splice-site) but the underlying mechanism remains poorly understood. Notably, RPL3L knockout in mice did not result in any severe heart defects. (PMID: 32514796; 32870709; 36291431; 35323613; 37308880; 39803500; 40820268)

The number of cases reported supports inclusion on this panel as Green, but given that mouse models are conflicting and this addition was rejected in a previous GMS panel release, tagging for additional GMS expert review to determine the appropriate rating.
Paediatric or syndromic cardiomyopathy v7.90 RPL3L Arina Puzriakova Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Classified gene: RPL3L as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Added comment: Comment on list classification: There are now at least 14 individuals from 11 families with severe early-onset dilated cardiomyopathy. Almost all attributed to compound heterozygous missense variants (also 3 frameshift and 1 splice-site) but the underlying mechanism remains poorly understood. Notably, RPL3L knockout in mice did not result in any severe heart defects. (PMID: 32514796; 32870709; 36291431; 35323613; 37308880; 39803500; 40820268)

The number of cases reported supports inclusion on this panel as Green, but given that mouse models are conflicting and this addition was rejected in a previous GMS panel release, tagging for additional GMS expert review to determine the appropriate rating.
Dilated and arrhythmogenic cardiomyopathy v3.8 RPL3L Arina Puzriakova Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.89 RPL3L Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype listed in OMIM: Cardiomyopathy, dilated, 2D, OMIM:619371 (accessed on 09-10-2025)
Paediatric or syndromic cardiomyopathy v7.89 RPL3L Arina Puzriakova Phenotypes for gene: RPL3L were changed from Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021 to Cardiomyopathy, dilated, 2D, OMIM:619371
Dilated and arrhythmogenic cardiomyopathy v3.7 RPL3L Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype listed in OMIM: Cardiomyopathy, dilated, 2D, OMIM:619371 (accessed on 09-10-2025)
Dilated and arrhythmogenic cardiomyopathy v3.7 RPL3L Arina Puzriakova Phenotypes for gene: RPL3L were changed from Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021 to Cardiomyopathy, dilated, 2D, OMIM:619371
Adult onset hereditary spastic paraplegia v6.3 AP5Z1 Arina Puzriakova Classified gene: AP5Z1 as Green List (high evidence)
Adult onset hereditary spastic paraplegia v6.3 AP5Z1 Arina Puzriakova Gene: ap5z1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.41 LSS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.; to: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

After seeking clinical opinion, it has been decided to recommend this gene for promotion to green rating in the next GMS update.
Skeletal dysplasia v8.17 SIK3 Eleanor Williams Classified gene: SIK3 as Amber List (moderate evidence)
Skeletal dysplasia v8.17 SIK3 Eleanor Williams Added comment: Comment on list classification: Promoted to amber since there is one published case plus a supportive mouse model. Following up with evidence from UK NHS cases and the rating maybe reviewed.
Skeletal dysplasia v8.17 SIK3 Eleanor Williams Gene: sik3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.94 SIK3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 8th October 2025
Fetal anomalies v6.94 SIK3 Eleanor Williams Phenotypes for gene: SIK3 were changed from Spondyloepimetaphyseal dysplasia, Krakow type, 618162 to ?Spondyloepimetaphyseal dysplasia, Krakow type, OMIM:618162; spondyloepimetaphyseal dysplasia, Krakow type, MONDO:0032571
Skeletal dysplasia v8.16 SIK3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 8th October 2025
Skeletal dysplasia v8.16 SIK3 Eleanor Williams Phenotypes for gene: SIK3 were changed from to ?Spondyloepimetaphyseal dysplasia, Krakow type, OMIM:618162; spondyloepimetaphyseal dysplasia, Krakow type, MONDO:0032571
Skeletal dysplasia v8.15 SIK3 Eleanor Williams Classified gene: SIK3 as Amber List (moderate evidence)
Skeletal dysplasia v8.15 SIK3 Eleanor Williams Gene: sik3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.117 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Intellectual disability.
Intellectual disability v9.117 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.117 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years; not associated with intellectual disability).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal'.
Intellectual disability v9.117 LGI1 Ida Ertmanska edited their review of gene: LGI1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.117 LGI1 Arina Puzriakova Mode of inheritance for gene: LGI1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with severe developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.116 PPOX Ida Ertmanska commented on gene: PPOX: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms. Hence, the mode of inheritance should be set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163; 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.116 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed publications to: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189
Early onset or syndromic epilepsy v8.41 LGI1 Arina Puzriakova Publications for gene: LGI1 were set to 15079010; 11810107; 22496201
Early onset or syndromic epilepsy v8.40 LGI1 Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512 to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620
Intellectual disability v9.116 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163; 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Early onset or syndromic epilepsy v8.39 LGI1 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: LGI1.
Intellectual disability v9.116 LGI1 Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512; AUTOSOMAL DOMINANT PARTIAL EPILEPSY WITH AUDITORY FEATURES to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620
Intellectual disability v9.115 PPOX Ida Ertmanska changed review comment from: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.; to: Comment on list classification: Variegate Porphyria symptoms include skin lesions, epileptic seizures, developmental delay, intellectual disability. As reviewed by Sharon Whatley, there are more than 3 unrelated individuals with Variegate Porphyria with biallelic variants in PPOX, who presented with developmental delay / childhood-onset intellectual disability, including: delayed motor skill acquisition, lack of speech acquisition, aggressivity, and other learning disabilities (PMIDs: 6143163;8290408;9811936;2004012;35164799;37879139;40114189).
Both monoallelic and biallelic variants are known to cause Variegate Porphyria; biallelic cases present with a more severe, earlier-onset phenotype than monoallelic. PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 7th October 2025.
Based on the available evidence, this gene should be rated Green for Intellectual disability.
Intellectual disability v9.115 PPOX Ida Ertmanska reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 6143163, 8290408, 9811936, 2004012, 35164799, 37879139, 40114189; Phenotypes: Variegate porphyria, childhood-onset, 620483, variegate porphyria, MONDO:0008297; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v9.115 LGI1 Arina Puzriakova Publications for gene: LGI1 were set to 0
Intellectual disability v9.114 LGI1 Arina Puzriakova Mode of inheritance for gene: LGI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Tag watchlist was removed from gene: TBX2.
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Tag microdeletion tag was added to gene: TBX2.
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Classified gene: TBX2 as Amber List (moderate evidence)
Monogenic hearing loss v5.28 TBX2 Arina Puzriakova Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.27 TBX2 Arina Puzriakova Tag watchlist tag was added to gene: TBX2.
Early onset or syndromic epilepsy v8.39 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska commented on gene: LGI1: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025).
Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - later-onset epilepsy, not associated with intellectual disability / developmental delay (PMID: 26773249). Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.
Intellectual disability v9.113 LGI1 Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in those patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients) and delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020).

Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.
Intellectual disability v9.113 LGI1 Ida Ertmanska reviewed gene: LGI1: Rating: RED; Mode of pathogenicity: None; Publications: 26773249, 40455867, 41000458; Phenotypes: developmental and epileptic encephalopathy MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.39 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.39 EMX2 Arina Puzriakova Phenotypes for gene: EMX2 were changed from Schizencephaly, 269160 to Schizencephaly, OMIM:269160
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska edited their review of gene: LGI1: Added comment: Comment on mode of inheritance: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; Changed publications to: 26773249, 40455867, 41000458
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4

Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.

Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form); to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40455867, 41000458; Phenotypes: Epilepsy, familial temporal lobe, 600512, developmental and epileptic encephalopathy MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOPI has been updated to 'BIALLELIC, autosomal or pseudoautosomal' and the rating has been changes to amber with the current evidence.; to: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOI and rating have been updated to 'BIALLELIC, autosomal or pseudoautosomal' and amber respectively.
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram Classified gene: ADCY5 as Amber List (moderate evidence)
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are patients from two different families reported with biallelic ADCY5 variants and severe intellectual disability. Hence, the MOPI has been updated to 'BIALLELIC, autosomal or pseudoautosomal' and the rating has been changes to amber with the current evidence.
Intellectual disability v9.113 ADCY5 Achchuthan Shanmugasundram Gene: adcy5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.112 ADCY5 Achchuthan Shanmugasundram Mode of inheritance for gene: ADCY5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.111 ADCY5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: ADCY5 was changed from Other - please provide details in the comments to None
Intellectual disability v9.110 ADCY5 Achchuthan Shanmugasundram Publications for gene: ADCY5 were set to 28511835
Intellectual disability v9.109 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in ADCY5 gene has been associated with 'Neurodevelopmental disorder with hyperkinetic movements and dyskinesia' phenotype in OMIM (MIM #619651, OMIM accessed on 06 October 2025).
Intellectual disability v9.109 ADCY5 Achchuthan Shanmugasundram Phenotypes for gene: ADCY5 were changed from Dyskinesia, familial, with facial myokymia, 606703 to Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651; neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211
Intellectual disability v9.108 ADCY5 Achchuthan Shanmugasundram reviewed gene: ADCY5: Rating: AMBER; Mode of pathogenicity: None; Publications: 33704598, 34631954; Phenotypes: Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.108 KCND3 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 5th October 2025
Intellectual disability v9.108 KCND3 Eleanor Williams Phenotypes for gene: KCND3 were changed from Spinocerebellar ataxia 19, 607346 to Spinocerebellar ataxia 19, OMIM: 607346; spinocerebellar ataxia type 19/22, MONDO:0011819
Intellectual disability v9.107 KCND3 Eleanor Williams Publications for gene: KCND3 were set to
Intellectual disability v9.106 KCND3 Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence)
Intellectual disability v9.106 KCND3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber as there are some cases with intellectual disability/cognitive impairment however this appears to be at the milder end of the phenotypic spectrum.
Intellectual disability v9.106 KCND3 Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Tag dd_review tag was added to gene: KCND3.
Tag Q3_25_promote_green tag was added to gene: KCND3.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.10 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least four unrelated families reported with biallelic ADCY5 variants and with childhood-onset movement disorder.

As there is sufficient evidence available for the association of both monoallelic and biallelic ADCY5 variants with the phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Childhood onset dystonia, chorea or related movement disorder v7.10 ADCY5 Achchuthan Shanmugasundram Mode of inheritance for gene: ADCY5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.9 ADCY5 Achchuthan Shanmugasundram Tag Q3_25_MOI tag was added to gene: ADCY5.
Childhood onset dystonia, chorea or related movement disorder v7.9 ADCY5 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 04 October 2025.
Childhood onset dystonia, chorea or related movement disorder v7.9 ADCY5 Achchuthan Shanmugasundram Phenotypes for gene: ADCY5 were changed from Dyskinesia, familial, with facial myokymia, 606703; dystonia; Familial dyskinesia, 606703 to Dyskinesia with orofacial involvement, autosomal dominant, OMIM:606703; dyskinesia with orofacial involvement, autosomal dominant, MONDO:0800028; Dyskinesia with orofacial involvement, autosomal recessive, OMIM:619647; dyskinesia with orofacial involvement, autosomal recessive, MONDO:0030625; Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651; neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211
Childhood onset dystonia, chorea or related movement disorder v7.8 ADCY5 Achchuthan Shanmugasundram Publications for gene: ADCY5 were set to 11310626; 24700542
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram changed review comment from: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).; to: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram edited their review of gene: ADCY5: Changed publications to: 28971144, 30975617, 33704598, 34631954
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram commented on gene: ADCY5: As previously reported, monoallelic variants in ADCY5 gene are associated with familial dyskinesia with facial myokymia (FDFM), which is an autosomal dominant movement disorder characterised by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. There are multiple families reported with this phenotype (MIM #606703).

As reviewed by Cassandra Smith, biallelic variants in ADCY5 gene are now associated with disease phenotypes (MIMs #619647 & #619651).

Autosomal recessive dyskinesia with orofacial involvement (MIM #619647) is characterised by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. Eight patients from two different families were reported with this phenotype. They were identified with either compound heterozygous (p.Gly137Cysfs*184 & p.Arg1013Cys) or homozygous variants (p.Asp588Asn) in ADCY5 gene.

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (MIM #619651) is an autosomal recessive complex neurological disorder characterised by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders. There are five patients from two different families reported with this phenotype and they were identified with homozygous variants (p.Arg1238Trp & c.897+1G>T).
Childhood onset dystonia, chorea or related movement disorder v7.7 ADCY5 Achchuthan Shanmugasundram reviewed gene: ADCY5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskinesia with orofacial involvement, autosomal dominant, OMIM:606703, dyskinesia with orofacial involvement, autosomal dominant, MONDO:0800028, Dyskinesia with orofacial involvement, autosomal recessive, OMIM:619647, dyskinesia with orofacial involvement, autosomal recessive, MONDO:0030625, Neurodevelopmental disorder with hyperkinetic movements and dyskinesia, OMIM:619651, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, MONDO:0859211; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v6.5 NRXN2 Achchuthan Shanmugasundram edited their review of gene: NRXN2: Added comment: This gene has now been downgraded to 'limited' rating on the DD panel in Gene2Phenotype resource. So, it will be demoted to red on this panel in the next GMS update.; Changed rating: RED; Changed phenotypes to: AUTISM, OMIM:209850, NRXN2-related autism
DDG2P v6.5 GSPT2 Achchuthan Shanmugasundram edited their review of gene: GSPT2: Added comment: This gene has now been downgraded to 'limited' rating on the DD panel in Gene2Phenotype resource. So, it will be demoted to red on this panel in the next GMS update.; Changed rating: RED; Changed phenotypes to: GSPT2-related intellectual disability
DDG2P v6.5 GIGYF1 Achchuthan Shanmugasundram edited their review of gene: GIGYF1: Added comment: This gene has now been downgraded to 'limited' rating on the DD panel in Gene2Phenotype resource. So, it will be demoted to red on this panel in the next GMS update.; Changed rating: RED; Changed phenotypes to: GIGYF1-related developmental disorder
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Knock-in mice (p.Phe227del equivalent) displayed defects in motor coordination and balance, and neuroinflammation. Knock-out Kcnd3 -/- mice showed no observable phenotype. Molecular evidence suggests that the misfolded protein induces a trafficking defect in the Golgi apparatus - a dominant negative effect (PMID: 39562497).
Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676, 39562497
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493; 28947073; 32823520; 32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient.
Knock-in mice (p.Phe227del equivalent) displayed defects in motor coordination and balance, and neuroinflammation. Knock-out Kcnd3 -/- mice showed no observable phenotype. Molecular evidence suggests that the misfolded protein induces a trafficking defect in the Golgi apparatus - a dominant negative effect (PMID: 39562497).
Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676, 39562497
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

Functional evidence: PMID: 39562497 Hung et al., 2025
A mouse model with a p.Phe227del-equivalent Kcnd3 knock-in displayed defects in motor coordination and balance, neuroinflammation, trafficking defect due to accumulation in the golgi apparatus, and a transcriptional effect: downregulation of genes involved in neurogenesis. Meanwhile, Kcnd3 knockout mice showed no observable phenotype. This evidence suggests a dominant negative effect of the mutation, and supports the association of KCND3 and neurodevelopmental disorders.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska commented on gene: KCND3: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.


PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.


PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska gene: KCND3 was added
gene: KCND3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCND3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND3 were set to 26189493; 28895081; 32823520; 31293010; 32921676
Phenotypes for gene: KCND3 were set to Spinocerebellar ataxia 19 (OMIM: 607346); spinocerebellar ataxia type 19/22, MONDO:0011819
Review for gene: KCND3 was set to GREEN
Added comment: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with childhood onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed phenotypes to: Spinocerebellar ataxia 19 (OMIM: 607346), spinocerebellar ataxia type 19/22, MONDO:0011819
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy.
Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy.
Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676
Intellectual disability v9.105 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 32823520 – Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. As reviewed by Nour Elkhateeb, there are reports of individuals with early onset intellectual disability / developmental delay:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.105 KCND3 Ida Ertmanska edited their review of gene: KCND3: Added comment: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; Changed publications to: 26189493, 28895081, 32823520, 32921676
Intellectual disability v9.105 KCND3 Ida Ertmanska reviewed gene: KCND3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19 (OMIM: 607346); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v8.13 TBCB Arina Puzriakova gene: TBCB was added
gene: TBCB was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
watchlist, founder-effect tags were added to gene: TBCB.
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 (2025) - 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with the same homozygous founder variant (c.589T>A, p.(Tyr197Asn)) in TBCB. Affected individuals presented during infancy with motor or speech delays and developed late-childhood-onset spastic paraparesis (onset around 9-12 years old), global developmental delay (formal assessment done in 5 individuals, indicating mild ID), and autism spectrum. Brain MRI showed corpus collosum thinning in 3, and decreased white matter in 2.

The c.589T>A (GRCh38: 19-36125492-T-A) variant has an AF of 0.006485 in the Ashkenazi Jewish population in gnomAD v4 with 0 homozygotes. Classified as VUS in ClinVar based on 1 submission.

TBCB protein levels were reduced in patient fibroblasts. Drosophila melanogaster model showed reduced survival and impaired climbing ability.
Sources: Literature
DDG2P v6.5 FGF5 Eleanor Williams Tag curated_removed tag was added to gene: FGF5.
Arthrogryposis v9.11 ERCC1 Eleanor Williams Added comment: Comment on phenotypes: Phenotype data access in OMIM on 2nd October 2025
Arthrogryposis v9.11 ERCC1 Eleanor Williams Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, OMIM:610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Deleted their comment
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams edited their review of gene: DST: Changed rating: RED
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Tag curated_removed tag was added to gene: DST.
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Classified gene: DST as No list
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Added comment: Comment on list classification: Removing from this panel. Since the presentation is syndromic it is better suited to the Paediatric or syndromic cardiomyopathy panel (panel ID 749)
Dilated and arrhythmogenic cardiomyopathy v3.6 DST Eleanor Williams Gene: dst has been removed from the panel.
Dilated and arrhythmogenic cardiomyopathy v3.5 DST Eleanor Williams Classified gene: DST as Red List (low evidence)
Dilated and arrhythmogenic cardiomyopathy v3.5 DST Eleanor Williams Gene: dst has been classified as Red List (Low Evidence).
Fetal anomalies v6.93 DST Eleanor Williams Publications for gene: DST were set to 37431644; 40497796; 35942699
Fetal anomalies v6.92 DST Eleanor Williams Phenotypes for gene: DST were changed from Arthrogryposis multiplex congenita to Arthrogryposis multiplex congenita, MONDO:0015168; arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Fetal anomalies v6.91 DST Eleanor Williams Publications for gene: DST were set to 37431644
Fetal anomalies v6.90 DST Eleanor Williams reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: None; Publications: 40497796, 35942699; Phenotypes: arthrogryposis, MONDO:0859248, cardiomyopathy, MONDO:0004994, congenital myopathy, MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams changed review comment from: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS approval.; to: Comment on list classification: Promoting to amber but checking with the clinical team whether this is the right panel for this gene.
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Tag Q3_25_promote_green was removed from gene: DST.
Paediatric or syndromic cardiomyopathy v7.88 DST Eleanor Williams Classified gene: DST as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.88 DST Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.
Paediatric or syndromic cardiomyopathy v7.88 DST Eleanor Williams Gene: dst has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.87 DST Eleanor Williams gene: DST was added
gene: DST was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Q3_25_promote_green tags were added to gene: DST.
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 40497796; 35942699
Phenotypes for gene: DST were set to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Review for gene: DST was set to GREEN
Added comment: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Created: 30 Sep 2025, 5:18 p.m. | Last Modified: 30 Sep 2025, 5:18 p.m.
Sources: Literature
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams changed review comment from: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Sources: Literature; to: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Sources: Literature
Arthrogryposis v9.10 DST Eleanor Williams changed review comment from: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.; to: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Congenital myopathy v6.38 DST Eleanor Williams changed review comment from: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.; to: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively. However, variants in the DTS-b isoform appear to result in a different phenotype.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Intellectual disability v9.105 SF1 Mike Spiller gene: SF1 was added
gene: SF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF1 were set to PMID: 40987292
Review for gene: SF1 was set to GREEN
Added comment: Gene-disease associated reported in PMID: 40987292.
15 patients with varying levels of global developmental delay and ASD. One of these is intronic with gnomad AC = 9 so can be disregarded.
Of the remaining 14 almost all are de novo. 13 absent from gnomad, 1 with AC = 1.
7 missense, 1 inframe delins, 4 NMD, 2 final exon truncations. 6/7 missenses at conserved residues within missense-constrained regions, but no hotspot cluster..

NMD variants show the most consistent phenotype of mild-moderate ID/GDD.
Of the total 14 cases ID/GDD mild in 5, moderate in 4, level not stated in 5. Language delays most consistent characteristic..

Functional studies using SF1 knockdown in neural progenitor cells show substantial effects on gene regulation and alternative splicing, consistent with SF1 loss of function. However paper does not record if this led to any effects on NPC function.

Gene constrained for LOF (gnomad v4 o/e 0.12, LOEUF 0.22).
Sources: Literature
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ERCC1.
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but this gene could be promoted to Green at the next GMS panel update.

Two unrelated individuals with biallelic ERCC1 variants have been reported who had cerebrooculofacioskeletal syndrome which includes contractures. Both died in early childhood. Cells from both individuals showed sensitivity to UV-induced DNA damage (PMID: 17273966; 23623389).

Rated Green on other GMS panels for this phenotype (Intellectual disability, Fetal anomalies) based on the same evidence. Number of cases is likely to be small due to severity of the condition.
Arthrogryposis v9.10 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.10 ERCC1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

PMID: 40684071 - liver dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome, with three children requiring liver transplants.

Progressive cholestatic liver disease was found in 3 individuals (PV50LD, PV46LD, XE28CH). Individual CA16LD also developed neonatal cholestasis which resolved, and XE1AH developed liver disease later than others in the cohort but showed signs suggestive of chronic cholestatic disease.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - liver dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome, with three children requiring liver transplants.

Progressive cholestatic liver disease was found in 3 individuals (PV50LD, PV46LD, XE28CH). Individual CA16LD also developed neonatal cholestasis which resolved, and XE1AH developed liver disease later than others in the cohort but showed signs suggestive of chronic cholestatic disease (PMID: 40684071)
Paediatric disorders - additional genes v7.10 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from hepatorenal syndrome, MONDO:0001382 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758; hepatorenal syndrome, MONDO:0001382
Renal tubulopathies v5.8 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Renal tubulopathies v5.8 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - renal dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome.

Renal involvement is variable, including tubular dysfunction (5/7) and nephrocalcinosis (2/7). The two oldest individuals progressed to end-stage renal disease in adolescence.
Renal tubulopathies v5.8 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.9 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.9 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 5 unrelated cases with a multisystem phenotype characteristic of a DNA repair disorder which is relevant for inclusion on the Paediatric disorders super panel.
Paediatric disorders - additional genes v7.9 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.10 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Cholestasis v3.10 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

PMID: 40684071 - liver dysfunction was reported in all affected individuals with ERCC1-hepatorenal syndrome, with three children requiring liver transplants.

Progressive cholestatic liver disease was found in 3 individuals (PV50LD, PV46LD, XE28CH). Individual CA16LD also developed neonatal cholestasis which resolved, and XE1AH developed liver disease later than others in the cohort but showed signs suggestive of chronic cholestatic disease.
Cholestasis v3.10 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v5.7 ERCC1 Arina Puzriakova gene: ERCC1 was added
gene: ERCC1 was added to Renal tubulopathies. Sources: Literature
Q3_25_promote_green tags were added to gene: ERCC1.
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to hepatorenal syndrome, MONDO:0001382
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 is associated with a spectrum of DNA repair disorders from severe neonatal conditions (Cerebrooculofacioskeletal syndrome 4, OMIM:610758) to multisystem disorders (Xeroderma Pigmentosum) that can extend into adolescence and early adulthood.

A recent study (PMID: 40684071) identified seven individuals from five families carrying biallelic ERCC1 variants, who exhibited a distinct clinical phenotype including growth restriction, photosensitivity, and kidney and liver dysfunction. Hepatocellular carcinoma developed in four children, resulting in death in two. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Most reported individuals have c.466 C > T (p.Arg156Trp) on at least one allele, often with a LOF variant in trans. Functional assays using patient-derived fibroblasts demonstrated significant destabilisation of the ERCC1-XPF complex and defects in NER and ICL repair.
Sources: Literature
Paediatric disorders - additional genes v7.8 ERCC1 Arina Puzriakova gene: ERCC1 was added
gene: ERCC1 was added to Paediatric disorders - additional genes. Sources: Literature
Q3_25_promote_green tags were added to gene: ERCC1.
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to hepatorenal syndrome, MONDO:0001382
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 is associated with a spectrum of DNA repair disorders from severe neonatal conditions (Cerebrooculofacioskeletal syndrome 4, OMIM:610758) to multisystem disorders (Xeroderma Pigmentosum) that can extend into adolescence and early adulthood.

A recent study (PMID: 40684071) identified seven individuals from five families carrying biallelic ERCC1 variants, who exhibited a distinct clinical phenotype including growth restriction, photosensitivity, and kidney and liver dysfunction. Hepatocellular carcinoma developed in four children, resulting in death in two. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Most reported individuals have c.466 C > T (p.Arg156Trp) on at least one allele, often with a LOF variant in trans. Functional assays using patient-derived fibroblasts demonstrated significant destabilisation of the ERCC1-XPF complex and defects in NER and ICL repair.
Sources: Literature
Cholestasis v3.9 ERCC1 Arina Puzriakova gene: ERCC1 was added
gene: ERCC1 was added to Cholestasis. Sources: Literature
Q3_25_promote_green tags were added to gene: ERCC1.
Mode of inheritance for gene: ERCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC1 were set to 40684071
Phenotypes for gene: ERCC1 were set to hepatorenal syndrome, MONDO:0001382
Review for gene: ERCC1 was set to GREEN
Added comment: ERCC1 is associated with a spectrum of DNA repair disorders from severe neonatal conditions (Cerebrooculofacioskeletal syndrome 4, OMIM:610758) to multisystem disorders (Xeroderma Pigmentosum) that can extend into adolescence and early adulthood.

A recent study (PMID: 40684071) identified seven individuals from five families carrying biallelic ERCC1 variants, who exhibited a distinct clinical phenotype including growth restriction, photosensitivity, and kidney and liver dysfunction. Hepatocellular carcinoma developed in four children, resulting in death in two. Older individuals exhibited additional features, including ataxia, basal cell carcinomas, pancreatic insufficiency, ovarian failure, hypothyroidism, and restrictive lung disease. Most reported individuals have c.466 C > T (p.Arg156Trp) on at least one allele, often with a LOF variant in trans. Functional assays using patient-derived fibroblasts demonstrated significant destabilisation of the ERCC1-XPF complex and defects in NER and ICL repair.
Sources: Literature
Childhood solid tumours v5.6 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Amber List (moderate evidence)
Childhood solid tumours v5.6 ERCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 individuals from 3 families with childhood-onset hepatocellular carcinoma due to biallelic variants in this gene. Diagnosis may have treatment implications due to heightened sensitivity of individuals with ERCC1 variants to DNA-damaging agents.
Childhood solid tumours v5.6 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v5.5 ERCC1 Arina Puzriakova Publications for gene: ERCC1 were set to
Childhood solid tumours v5.4 ERCC1 Arina Puzriakova Tag dd_review tag was added to gene: ERCC1.
Tag Q3_25_promote_green tag was added to gene: ERCC1.
Childhood solid tumours v5.4 ERCC1 Arina Puzriakova reviewed gene: ERCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40684071; Phenotypes: xeroderma pigmentosum, MONDO:0019600, hepatorenal syndrome, MONDO:0001382; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult solid tumours cancer susceptibility v2.34 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from xeroderma pigmentosum, MONDO:0019600 to hepatocellular carcinoma, MONDO:0007256
Adult solid tumours cancer susceptibility v2.33 ERCC1 Arina Puzriakova Classified gene: ERCC1 as Red List (low evidence)
Adult solid tumours cancer susceptibility v2.33 ERCC1 Arina Puzriakova Added comment: Comment on list classification: Downgraded from Amber to Red as typically childhood onset. Could only identify one report (conference abstract) describing "First Report of ERCC1-Associated Adult-Onset Hepatocellular Carcinoma, Ataxia, and Cognitive Decline" due to a homozygous variant c.466 C>T, p.(Arg156Trp) in exon 4 - https://www.mdsabstracts.org/abstract/first-report-of-ercc1-associated-adult-onset-hepatocellular-carcinoma-ataxia-and-cognitive-decline/
Adult solid tumours cancer susceptibility v2.33 ERCC1 Arina Puzriakova Gene: ercc1 has been classified as Red List (Low Evidence).
Childhood solid tumours cancer susceptibility v1.29 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from xeroderma pigmentosum, MONDO:0019600 to xeroderma pigmentosum, MONDO:0019600; hepatorenal syndrome, MONDO:0001382
Childhood solid tumours v5.4 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from xeroderma pigmentosum, MONDO:0019600 to xeroderma pigmentosum, MONDO:0019600; hepatorenal syndrome, MONDO:0001382
Adult solid tumours cancer susceptibility v2.32 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa to xeroderma pigmentosum, MONDO:0019600
Childhood solid tumours cancer susceptibility v1.28 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa to xeroderma pigmentosum, MONDO:0019600
Childhood solid tumours v5.3 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa to xeroderma pigmentosum, MONDO:0019600
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.6 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosum; ERCC1-Hepatorenal Syndrome to xeroderma pigmentosum, MONDO:0019600; hepatorenal syndrome, MONDO:0001382
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.5 ERCC1 Arina Puzriakova Added comment: Comment on publications: PMID: 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome
PMID: 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure
PMID: 40684071 - hepatorenal syndrome identified in seven individuals from five families carrying biallelic ERCC1 variants. All individuals presented with skin and/or ocular photosensitivity, among other features such as growth restriction, café-au-lait macules, kidney impairment, progressive cholestatic liver disease, and hepatocellular carcinoma.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.5 ERCC1 Arina Puzriakova Publications for gene: ERCC1 were set to 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome; 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.4 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosum to Xeroderma Pigmentosum; ERCC1-Hepatorenal Syndrome
Anophthalmia or microphthalmia v1.55 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, 610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Anophthalmia or microphthalmia v1.54 ERCC1 Arina Puzriakova Mode of inheritance for gene: ERCC1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.90 EMX2 Ida Ertmanska commented on gene: EMX2: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other schizencephaly cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Fetal anomalies.
Fetal anomalies v6.90 EMX2 Ida Ertmanska reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 8528262, 9153481, 9359037, 17506092, 18409201, 20157829; Phenotypes: Schizencephaly, OMIM:269160, schizencephaly, MONDO:0010011; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same populations.; to: The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same ethnic background.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams commented on gene: PRDX3: The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same populations.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Tag founder-effect tag was added to gene: PRDX3.
Adult onset neurodegenerative disorder v8.3 ANXA11 Eleanor Williams commented on gene: ANXA11
Adult onset neurodegenerative disorder v8.3 ANXA11 Eleanor Williams Tag founder-effect tag was added to gene: ANXA11.
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Classified gene: DST as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS approval.
Dilated and arrhythmogenic cardiomyopathy v3.4 DST Eleanor Williams Gene: dst has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v3.3 DST Eleanor Williams gene: DST was added
gene: DST was added to Dilated and arrhythmogenic cardiomyopathy. Sources: Literature
Q3_25_promote_green tags were added to gene: DST.
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 40497796; 35942699
Phenotypes for gene: DST were set to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Review for gene: DST was set to GREEN
Added comment: Associated with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency (615425) and Neuropathy, hereditary sensory and autonomic, type VI (614653) in OMIM caused by a loss of DST-e and DST-a respectively.

PMID: 40497796 (2025) - biallelic variants in the DST impacting the DST-b isoform were identified in in 19 individuals from 14 unrelated families of different ethnicities by exome or genome sequencing or Sanger sequencing of affected siblings. Other likely pathogenic variants were excluded through sequencing analysis in line with ACMG classification guidelines.

8 variants were identified in these 19 patients with variants that only affect the DST-b isoform; 4 nonsense and 4 frameshift. All variants were absent or rare in gnomad. In 13 families the variant was homozygous and in 1 it was compound heterozygous.

Prenatal abnormalities were documented in 7/15 cases (reduced fetal movements and joint contractures). Of the 16 individuals assessed post birth, all displayed contractures at birth, 10/14 (from 9 families) displayed cardiomyopathy (9 with dilated cardiomyopathy), 14/14 (from 12 families) motor delay and 15/15 (from 12 families) muscular hypotonia.

RNA sequencing from control individuals showed that transcripts encoding DST-b isoform are expressed in skeletal muscle, heart tissue, and cultured fibroblasts. RNA sequencing analysis of patient fibroblasts from 3 affected individuals showed reduced DST RNA levels, but only in one case was this statistically signficant. However, proteomic studies with fibroblasts from 2 individuals showed a significant reduction of Dystonin, and a complete loss of the DST-b isoform. The author conclude this indicates that the DST-b transcripts escape NMD but encode a protein that is instable or rapidly degraded.

In addition, biallelic variants affecting both DST-a and DST-b isoforms were identified in 4 individuals from two families by exome sequencing. All presented with severe arthrogryposis and died intrauterine or shortly after birth.

PMID: 35942699 (2022) In a Dst-b-specific mutant mouse model with a nonsense mutation, the mice exhibit late-onset protein aggregate myopathy and cardiomyopathy without neuropathy.
Sources: Literature
Arthrogryposis v9.9 DST Eleanor Williams Tag Q3_25_promote_green tag was added to gene: DST.
Congenital myopathy v6.38 DST Eleanor Williams Tag Q3_25_promote_green tag was added to gene: DST.
Arthrogryposis v9.9 DST Eleanor Williams Entity copied from Congenital myopathy v6.38
Arthrogryposis v9.9 DST Eleanor Williams gene: DST was added
gene: DST was added to Arthrogryposis. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: DST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DST were set to 40497796; 35942699
Phenotypes for gene: DST were set to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Congenital myopathy v6.38 DST Eleanor Williams Phenotypes for gene: DST were changed from to arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952
Congenital myopathy v6.37 DST Eleanor Williams Publications for gene: DST were set to 40497796
Congenital myopathy v6.36 DST Eleanor Williams Classified gene: DST as Amber List (moderate evidence)
Congenital myopathy v6.36 DST Eleanor Williams Added comment: Comment on list classification: Promoting to amber but with a recommendation for green rating following GMS review since there are sufficient cases with plausible disease causing variants and an appropriate phenotype.
Congenital myopathy v6.36 DST Eleanor Williams Gene: dst has been classified as Amber List (Moderate Evidence).
Congenital myopathy v6.35 DST Eleanor Williams reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: None; Publications: 40497796, 35942699; Phenotypes: arthrogryposis, MONDO:0859248, cardiomyopathy, MONDO:0004994, congenital myopathy, MONDO:0019952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: ANXA11.
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Classified gene: ANXA11 as Amber List (moderate evidence)
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with ANXA11 variants and white matter abnormalities - however, all three families were identified with the same variant. What matter abnormalities were not reported in successive studies. Hence, this gene should be rated amber with the current evidence.
Adult onset leukodystrophy v6.7 ANXA11 Achchuthan Shanmugasundram Gene: anxa11 has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v6.6 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619733). OMIM was accessed on 30 September 2025.
Adult onset leukodystrophy v6.6 ANXA11 Achchuthan Shanmugasundram Phenotypes for gene: ANXA11 were changed from Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514 to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Adult onset leukodystrophy v6.5 ANXA11 Achchuthan Shanmugasundram gene: ANXA11 was added
gene: ANXA11 was added to Adult onset leukodystrophy. Sources: Literature
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to 34048612
Phenotypes for gene: ANXA11 were set to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Review for gene: ANXA11 was set to AMBER
Added comment: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy. Brain imaging from patients showed white matter abnormalities using diffusion tensor imaging. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene, suggesting it could be founder variant.

Although there were patients reported with variants affecting the Asp40 amino acid residue of ANXA11 gene and presenting with myopathy phenotype in successive studies (PMIDs: 36134701; 36651622; 40730020), there were no mentions of white matter abnormalities reported for these patients in these publications.
Sources: Literature
Adult onset neurodegenerative disorder v8.3 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 30 September 2025.
Adult onset neurodegenerative disorder v8.3 ANXA11 Achchuthan Shanmugasundram Phenotypes for gene: ANXA11 were changed from Amytrophic lateral sclerosis 23, OMIM:617839 to Amyotrophic lateral sclerosis 23, OMIM:617839
Intellectual disability v9.105 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from FANCONI ANEMIA to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Fetal anomalies v6.90 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from CEREBROOCULOFACIOSKELETAL SYNDROME 4; FANCONI ANEMIA to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Structural eye disease v4.30 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4 (includes microphthalmia), 610758; Cerebrooculofacioskeletal syndrome 4, 610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Arthrogryposis v9.8 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Cerebrooculofacioskeletal syndrome 4, 610758 to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram changed review comment from: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.

The 'founder-effect' tag has been added as the same variant has been identified across populations.
Sources: Literature; to: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.

The 'founder-effect' tag has been added as the same variant has been identified in multiple families from the same populations.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram changed review comment from: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.
Sources: Literature; to: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.

The 'founder-effect' tag has been added as the same variant has been identified across populations.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: ANXA11.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Classified gene: ANXA11 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in ANXA11 gene to limb-girdle syndrome. Hence, this gene can be promoted to green rating in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.16 ANXA11 Achchuthan Shanmugasundram Gene: anxa11 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.15 ANXA11 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: ANXA11.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.15 ANXA11 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #619733). OMIM was accessed on 30 September 2025.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.15 ANXA11 Achchuthan Shanmugasundram Phenotypes for gene: ANXA11 were changed from Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514 to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Adult solid tumours cancer susceptibility v2.31 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa; Cerebrooculofacioskeletal syndrome 4, 610758 to Xeroderma Pigmentosa
Childhood solid tumours v5.2 ERCC1 Arina Puzriakova Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosa; Cerebrooculofacioskeletal syndrome 4, 610758 to Xeroderma Pigmentosa
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.14 ANXA11 Achchuthan Shanmugasundram changed review comment from: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.
Sources: Literature; to: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.

PMID:40730020 (2025) reported a 38-year-old Brazilian female patient with progressive limb weakness (more evident in proximal upper limbs and anterior compartment of the distal lower limbs), ophthalmoparesis, bilateral ptosis and bilateral scapular winging. She was identified with c.119A>T/ p.Asp40Val variant in ANXA11 gene.
Sources: Literature
Fetal anomalies v6.89 EMX2 Eleanor Williams Tag Q3_25_expert_review tag was added to gene: EMX2.
Intellectual disability v9.104 EMX2 Eleanor Williams Tag Q3_25_NHS_review tag was added to gene: EMX2.
Childhood onset dystonia, chorea or related movement disorder v7.7 CACNB4 Eleanor Williams Tag Q3_25_MOI tag was added to gene: CACNB4.
Childhood onset dystonia, chorea or related movement disorder v7.7 CACNB4 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotypes correct at 30th September 2025
Childhood onset dystonia, chorea or related movement disorder v7.7 CACNB4 Eleanor Williams Phenotypes for gene: CACNB4 were changed from ?Episodic ataxia, type 5, OMIM:613855; episodic ataxia type 5, MONDO:0013464; {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682; epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892; neurodevelopmental disorder, MONDO:0700092 to ?Episodic ataxia, type 5, OMIM:613855; episodic ataxia type 5, MONDO:0013464; {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682; epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892; neurodevelopmental disorder, MONDO:0700092
DDG2P v6.5 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: ; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
DDG2P v6.5 TSPAN7 Ida Ertmanska Deleted their review
DDG2P v6.5 TSPAN7 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated individuals reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene should be rated Amber for Intellectual disability.; to: Comment on list classification: There are at least 7 unrelated individuals reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, we decided to demote this gene to Amber for Intellectual disability.
Fetal anomalies v6.89 EMX2 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 29th September 2025
Fetal anomalies v6.89 EMX2 Eleanor Williams Phenotypes for gene: EMX2 were changed from Schizencephaly, 269160 to Schizencephaly, OMIM:269160; schizencephaly, MONDO:0010011
Fetal anomalies v6.88 EMX2 Eleanor Williams Publications for gene: EMX2 were set to
Fetal anomalies v6.87 EMX2 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: EMX2.
Early onset or syndromic epilepsy v8.37 EMX2 Eleanor Williams commented on gene: EMX2
Intellectual disability v9.104 EMX2 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 29th September 2025
Intellectual disability v9.104 EMX2 Eleanor Williams Phenotypes for gene: EMX2 were changed from Schizencephaly 269160 to Schizencephaly, OMIM:269160; schizencephaly, MONDO:0010011
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.14 ANXA11 Achchuthan Shanmugasundram gene: ANXA11 was added
gene: ANXA11 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to 34048612; 36134701; 36651622; 40730020
Phenotypes for gene: ANXA11 were set to Inclusion body myopathy and brain white matter abnormalities, OMIM:619733; inclusion body myopathy and brain white matter abnormalities, MONDO:0850514
Review for gene: ANXA11 was set to GREEN
Added comment: PMID:34048612 (2021) reported 11 patients from three different Brazilian families presenting with three different phenotypes - Amyotrophic lateral sclerosis (ALS), inclusion body myopathy (hIBM), and ALS + hIBM. All the affected probands shared the same missense variant (c.118G>T/ p.Asp40Tyr) from ANXA11 gene. The patients had proximal muscle weakness of the upper and lower limbs with walking difficulties, scapular winging, and abdominal weakness, suggestive of a limb-girdle type of myopathy.

PMID:36134701 (2022) reported the identification of the same c.118G>T/ p.Asp40Tyr variant from ANXA11 gene in seven affected individuals from four large families from a relatively isolated island of Aegan Sea from Greece. Muscle weakness was first observed in all these patients in the third to fifth decade. The symptoms later progressed to proximal upper and lower limb weakness and distal lower limb weakness, All patients also presented with scapular winging.

PMID:36651622 (2023) reported a patient of Spanish descent with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy. The patient carried a different variant affecting the same Asp40 amino acid in ANXA11 gene (c.118_119delGAinsAT/ p.Asp40Ile). Progressive ptosis was noted in middle childhood, and Opthalmoparesis and neck flexor weakness appeared later but also in the first decade of life. From the age of 14, progressive axial and facial weakness was detected, as well as scapular winging and proximal and distal weakness, more pronounced in the lower extremities.
Sources: Literature
Retinal disorders v8.35 VSX2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: VSX2.
Retinal disorders v8.35 VSX2 Arina Puzriakova Classified gene: VSX2 as Amber List (moderate evidence)
Retinal disorders v8.35 VSX2 Arina Puzriakova Gene: vsx2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.34 VSX2 Arina Puzriakova Publications for gene: VSX2 were set to
Retinal disorders v8.33 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia/coloboma 3, OMIM:610092 to retinal disorder MONDO:0005283; Microphthalmia/coloboma 3, OMIM:610092
Retinal disorders v8.32 VSX2 Arina Puzriakova Mode of inheritance for gene: VSX2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.31 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Eye Disorders to Microphthalmia/coloboma 3, OMIM:610092
Bilateral congenital or childhood onset cataracts v7.3 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia, cataracts and iris abnormalities to Microphthalmia/coloboma 3, OMIM:610092
Ocular coloboma v1.50 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia with coloboma 3, 610092 to Microphthalmia/coloboma 3, OMIM:610092
Fetal anomalies v6.87 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from MICROPHTHALMIA WITH CATARACTS AND IRIS ABNORMALITIES; MICROPHTHALMIA ISOLATED WITH COLOBOMA TYPE 3; MICROPHTHALMIA ISOLATED TYPE 2 to Microphthalmia, isolated 2, OMIM:610093; Microphthalmia/coloboma 3, OMIM:610092
Anophthalmia or microphthalmia v1.53 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia with coloboma 3 to Microphthalmia, isolated 2, OMIM:610093; Microphthalmia/coloboma 3, OMIM:610092
Structural eye disease v4.29 VSX2 Arina Puzriakova Added comment: Comment on phenotypes: This gene is associated with Microphthalmia, isolated 2, OMIM:610093 and Microphthalmia/coloboma 3, OMIM:610092 (accessed on 30-09-2025)
Structural eye disease v4.29 VSX2 Arina Puzriakova Phenotypes for gene: VSX2 were changed from Microphthalmia with coloboma 3, 610092 to Microphthalmia, isolated 2, OMIM:610093; Microphthalmia/coloboma 3, OMIM:610092
Intellectual disability v9.103 EMX2 Eleanor Williams Publications for gene: EMX2 were set to 9359037; 24975717; 27125467; 9153481
Intellectual disability v9.102 EMX2 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: EMX2.
DDG2P v6.5 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary neuropathy or pain disorder v7.11 TTC19 Achchuthan Shanmugasundram Classified gene: TTC19 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.11 TTC19 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there are three unrelated patents reported with biallelic TTC19 variants and motor neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.11 TTC19 Achchuthan Shanmugasundram Gene: ttc19 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.10 TTC19 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: TTC19.
Tag Q3_25_NHS_review tag was added to gene: TTC19.
Hereditary neuropathy or pain disorder v7.10 TTC19 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in both OMIM (MIM #615157, OMIM accessed on 30 September 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel).
Hereditary neuropathy or pain disorder v7.10 TTC19 Achchuthan Shanmugasundram Phenotypes for gene: TTC19 were changed from Ataxia; apraxia; dystonia; dysarthria; necrotic brain lesions; motor axonal neuropathy to Mitochondrial complex III deficiency, nuclear type 2, OMIM:615157; mitochondrial complex III deficiency nuclear type 2, MONDO:0014063
Hereditary neuropathy or pain disorder v7.9 TTC19 Achchuthan Shanmugasundram Publications for gene: TTC19 were set to 40946707; 37927170; 25652355
Hereditary neuropathy or pain disorder v7.8 TTC19 Achchuthan Shanmugasundram reviewed gene: TTC19: Rating: GREEN; Mode of pathogenicity: None; Publications: 25652355, 37927170, 40946707; Phenotypes: Mitochondrial complex III deficiency, nuclear type 2, OMIM:615157, mitochondrial complex III deficiency nuclear type 2, MONDO:0014063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: UGGT1.
Severe microcephaly v8.14 UGGT1 Achchuthan Shanmugasundram Classified gene: UGGT1 as Amber List (moderate evidence)
Severe microcephaly v8.14 UGGT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Severe microcephaly was only reported in five patients from four unrelated families. In addition, there is also phenotypic variability observed within the families where patients were reported with severe microcephaly. Hence, this gene should be rated amber with the current evidence.
Severe microcephaly v8.14 UGGT1 Achchuthan Shanmugasundram Gene: uggt1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.13 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: UGGT1 was set to AMBER
Added comment: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). However, severe secondary microcephaly (postnatal OFC beyond a Z-score < -3) was only reported in five patients from four families.

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with intellectual disability (six families with severe ID). Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with epilepsy (eight families and functional evidence). Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram changed review comment from: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.; to: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures (11 patients from eight unrelated families), characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.102
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: UGGT1.
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to congenital disorder of glycosylation, MONDO:0015286
Congenital disorders of glycosylation v7.8 UGGT1 Achchuthan Shanmugasundram Classified gene: UGGT1 as Amber List (moderate evidence)
Congenital disorders of glycosylation v7.8 UGGT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (10 unrelated families and functional evidence) for the promotion of this gene to green rating in this panel on the next GMS update.
Congenital disorders of glycosylation v7.8 UGGT1 Achchuthan Shanmugasundram Gene: uggt1 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v7.7 UGGT1 Achchuthan Shanmugasundram Phenotypes for gene: UGGT1 were changed from intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys to congenital disorder of glycosylation, MONDO:0015286
Congenital disorders of glycosylation v7.6 UGGT1 Achchuthan Shanmugasundram Publications for gene: UGGT1 were set to PMID: 40267907
Congenital disorders of glycosylation v7.5 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UGGT1.
Tag Q3_25_NHS_review tag was added to gene: UGGT1.
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Classified gene: UGGT1 as Amber List (moderate evidence)
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with intellectual disability (six families with severe ID). Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.102 UGGT1 Achchuthan Shanmugasundram Gene: uggt1 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: Comment on list classification: There are 5 cases with heterozygous variants in this gene and a corneal dystrophy phenotype. However, the same variant was found in all cases, and all had Spanish ancestry. WES was only performed in one family, with targetted sequencing in the others. Therefore rating Amber until a second variant is found.; to: Comment on list classification: There are 5 cases with heterozygous variants in this gene and a corneal dystrophy phenotype. However, the same variant was found in all cases, and all had Spanish ancestry. WES was only performed in one family, with targetted sequencing in the others. Therefore rating Amber until further supporting evidence is reported, such as functional data, or cases with different ethnicities.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same rare heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.

PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. No variants in the 3 genes were found in family 5. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4.
Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature; to: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same rare heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.

PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. No variants in the 3 genes were found in family 5. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4.
Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but since the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 in the proband revealed the heterozygous PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature
Congenital disorders of glycosylation v7.5 UGGT1 Achchuthan Shanmugasundram reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40267907; Phenotypes: congenital disorder of glycosylation, MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.101 UGGT1 Achchuthan Shanmugasundram Phenotypes for gene: UGGT1 were changed from intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys to congenital disorder of glycosylation, MONDO:0015286
Intellectual disability v9.100 UGGT1 Achchuthan Shanmugasundram Publications for gene: UGGT1 were set to PMID: 40267907
Intellectual disability v9.99 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UGGT1.
Tag Q3_25_NHS_review tag was added to gene: UGGT1.
Intellectual disability v9.99 UGGT1 Achchuthan Shanmugasundram reviewed gene: UGGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40267907; Phenotypes: congenital disorder of glycosylation, MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v4.6 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Ectodermal dysplasia v4.6 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Eleanor Williams, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Ectodermal dysplasia v4.6 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v4.5 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Ectodermal dysplasia v4.5 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in both OMIM (MIMs #618275 & #618840) and Gene2Phenotype (LSS-related hypotrichosis & LSS-related palmoplantar keratoderma-congenital alopecia syndrome with 'limited' rating on Skin panel).

OMIM phenotypes have been last accessed on 29 September 2025.
Ectodermal dysplasia v4.5 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Hypotrichosis 14 OMIM:618275; hypotrichosis 14 MONDO:0032649 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009; Hypotrichosis 14, OMIM:618275; hypotrichosis 14, MONDO:0032649
Ectodermal dysplasia v4.4 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alopecia-intellectual disability syndrome 4, OMIM:618840, alopecia-intellectual disability syndrome 4, MONDO:0030009, Hypotrichosis 14, OMIM:618275, hypotrichosis 14, MONDO:0032649; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia; Abnormality of the skin; Microcephaly; Cataract 44, 616509, Hypotrichosis 14, 618275; Seizures; Abnormality of the genital system; Hypotonia; Intellectual disability; Global developmental delay to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram edited their review of gene: LSS: Changed publications to: 30723320, 37157980
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 37157980; Phenotypes: Alopecia-intellectual disability syndrome 4, OMIM:618840, alopecia-intellectual disability syndrome 4, MONDO:0030009; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Corneal dystrophy v4.3 PRDX3 Eleanor Williams changed review comment from: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.


PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. Variants in the 3 genes were not found in family 4. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4. Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature; to: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same rare heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.

PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. No variants in the 3 genes were found in family 5. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4.
Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature
Ichthyosis and erythrokeratoderma v4.6 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v4.6 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least seven unrelated patients reported with ichthyosis and/ or erythroderma. Hence, this gene can be promoted to green rating in the next GMS update.
Ichthyosis and erythrokeratoderma v4.6 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v4.5 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Ichthyosis and erythrokeratoderma v4.5 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #618840) and Gene2Phenotype (LSS-related palmoplantar keratoderma-congenital alopecia syndrome with 'limited' rating on Skin panel).

The OMIM phenotype was accessed on 29 September 2025.
Ichthyosis and erythrokeratoderma v4.5 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Ichthyosis and erythrokeratoderma v4.4 LSS Achchuthan Shanmugasundram gene: LSS was added
gene: LSS was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSS were set to 30723320; 35830358
Phenotypes for gene: LSS were set to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Review for gene: LSS was set to GREEN
Added comment: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while ichthyosis and/ or erythroderma were found in eight of these individuals from six families.

PMID:35830358 (2022) reported a 4-day-old female patient who presented with alopecia and a previously unreported dermatologic manifestation of congenital localized hyperpigmentation. Examination of the patient also revealed features consistent with ichthyosis. The patient was identified with two variants in LSS gene and a de novo pathogenic variant in SPTAN1 gene. The SPTAN1 variant is associated with neurodevelopmental phenotypes including early infantile epileptic encephalopathy. There are no known cutaneous manifestations of SPTAN1 variant.
Sources: Literature
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Classified gene: PRDX3 as Amber List (moderate evidence)
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Added comment: Comment on list classification: There are 5 cases with heterozygous variants in this gene and a corneal dystrophy phenotype. However, the same variant was found in all cases, and all had Spanish ancestry. WES was only performed in one family, with targetted sequencing in the others. Therefore rating Amber until a second variant is found.
Corneal dystrophy v4.3 PRDX3 Eleanor Williams Gene: prdx3 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v4.2 PRDX3 Eleanor Williams gene: PRDX3 was added
gene: PRDX3 was added to Corneal dystrophy. Sources: Literature
Mode of inheritance for gene: PRDX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRDX3 were set to 31782998; 34369396
Phenotypes for gene: PRDX3 were set to Corneal dystrophy, punctiform and polychromatic pre-Descemet, OMIM:619871; corneal dystrophy, punctiform and polychromatic pre-descemet, MONDO:0859248
Review for gene: PRDX3 was set to AMBER
Added comment: Associated with Corneal dystrophy, punctiform and polychromatic pre-Descemet in OMIM (OMIM:619871, AD).

There are 5 cases with the same heterozygous missense variant in PRDX3 and punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) although the phenotype is variable. All cases are with Spanish ancestry and 3 of the cases were found to share the same mini-haplotype.


PMID: 31782998 (2020) - 3 previously unreported Spanish families with PPPCD were examined. Through WES and Sanger sequencing 3 heterozygous variants were found to segregate with the disease in family 1 (6 affected, 4 unaffected): PDZD8 c.872+10A>T, OR2M5 c.773T>C, and PRDX3 c.568.G>C. Sanger sequencing of the smaller families 2 and 3 found the same PDZD8 c.872+10A>T and PRDX3 c.568G>C, (p.Asp190His) variants in affected individuals but not the OR2M5 variants. PDZD8 c.872+10A>T was found to affect splicing. An additional 2 families were then examined for these variants - family 4 was found to carry the PRDX3 c.568.G>C variant. Variants in the 3 genes were not found in family 4. The same mini-haplotype was identified in the three previously unreported families (PPPCD families 1, 2, and 3) but not in PPPCD family 4, suggesting that the PRDX3 c.568G>C variant likely arose from a common ancestor in PPPCD families 1–3 and independently in PPPCD family 4. Affected individuals in families 1-4 presented with localization of opacities to the pre-Descemetic posterior stroma. In family 5, affected members presented an atypical PPPCD phenotype with opacities distributed through all levels of the corneal stroma. The authors conclude that since both PRDX3 c.568G>C and PDZD8 c.872+10A>T were identified in PPCD families 1–3 that likely share a common ancestor, but the novel PRDX3 c.568G>C variant was also found in a fourth unrelated PPPCD pedigree, PRDX3 is likely the causative gene for PPPCD.

PMID: 34369396 (2022) 38 year old Spanish woman with bilateral polychromatic deposits diffusely distributed in the posterior stroma of each cornea, just anterior to Descemet membrane, as well as beneath the anterior lens capsule in each eye. Her father was also affected. Sequencing of PRDX3 and PDZD8 identified the heterozygous in the proband revealed the PRDX3 c.568G>C variant but not the PDZD8 c.872+10A>T intronic variant.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram changed review comment from: PMID:10762541 (2000) reported the identification of two different monoallelic variants (p.Arg482Ter and p.Cys104Phe) in CACNB4 gene in three unrelated families. The p.Arg482Ter variant was reported in a patient with juvenile myoclonic epilepsy. The missense p.Cys104Phe variant was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia.

There are no other patients reported with monoallelic CACNB4 variants in published scientific literature.

Monoallelic CACNB4 variants have been associated with both episodic ataxia and epilepsy phenotypes in OMIM (MIMs #613855 & #607682, phenotypes accessed on 29 September 2025) and with CACNB4-related juvenile myoclonic epilepsy in Gene2Phenotype (with 'limited' rating on the DD panel).

PMID:32176688 (2020) reported two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. They were identified with rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. The authors identified using in silico tools, animal model, clinical, and genetic data that the p.Leu126Pro variant in CACNB4 gene to be likely pathogenic.

Biallelic CACNB4 variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:10762541 (2000) reported the identification of two different monoallelic variants (p.Arg482Ter and p.Cys104Phe) in CACNB4 gene in three unrelated families. The p.Arg482Ter variant was reported in a patient with juvenile myoclonic epilepsy. The missense p.Cys104Phe variant was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. In addition, p.Cys104Phe has been identified in over 1,000 alleles in gnomAD - https://gnomad.broadinstitute.org/variant/2-151880879-C-A?dataset=gnomad_r4.

There are no other patients reported with monoallelic CACNB4 variants in published scientific literature.

Monoallelic CACNB4 variants have been associated with both episodic ataxia and epilepsy phenotypes in OMIM (MIMs #613855 & #607682, phenotypes accessed on 29 September 2025) and with CACNB4-related juvenile myoclonic epilepsy in Gene2Phenotype (with 'limited' rating on the DD panel).

PMID:32176688 (2020) reported two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. They were identified with rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. The authors identified using in silico tools, animal model, clinical, and genetic data that the p.Leu126Pro variant in CACNB4 gene to be likely pathogenic.

Biallelic CACNB4 variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram Classified gene: CACNB4 as Green List (high evidence)
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one family reported with monoallelic CACNB4 variants and episodic ataxia. Other two families were reported with epilepsy. There is also one family reported with biallelic CACNB4 variants and a phenotype including movement disorder. Hence, this gene should be recommended for demotion from green to red in the next GMS update.

In addition, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Childhood onset dystonia, chorea or related movement disorder v7.6 CACNB4 Achchuthan Shanmugasundram Gene: cacnb4 has been classified as Green List (High Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.5 CACNB4 Achchuthan Shanmugasundram Phenotypes for gene: CACNB4 were changed from EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 9; EPISODIC ATAXIA, TYPE 5 to ?Episodic ataxia, type 5, OMIM:613855; episodic ataxia type 5, MONDO:0013464; {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682; epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892; neurodevelopmental disorder, MONDO:0700092
Childhood onset dystonia, chorea or related movement disorder v7.4 CACNB4 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: CACNB4.
Tag Q3_25_demote_red tag was added to gene: CACNB4.
Childhood onset dystonia, chorea or related movement disorder v7.4 CACNB4 Achchuthan Shanmugasundram reviewed gene: CACNB4: Rating: RED; Mode of pathogenicity: None; Publications: 10762541, 32176688; Phenotypes: ?Episodic ataxia, type 5, OMIM:613855, episodic ataxia type 5, MONDO:0013464, {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682, {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682, epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other schizencephaly cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have also been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829). No other cases with EMX2 variants were published in literature since 1997. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated and conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have also been implicated in schizencephaly. Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska changed review comment from: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly (SCH) - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the articles, published in 1996-1997, are limited by their sequencing method (EMX2 targeted gene sequencing):

PMID: 8528262 Brunelli et al., 1996
Method: SSCP analysis on PCR amplification products of 4 genes: EMX1, EMX2, OTX1, OTX2. No variants were detected in EMX1, OTX1, or OTX2. 7/8 schizencephaly patients harboured heterozygous EMX2 variants, of which 3 were de novo and predicted to be pathogenic:
c.407-4G>T – spliceAI benign, 1 allele reported in European population in gnomAD v4.1
c.407-1G>A – spliceAI splice-altering Strong, not in gnomAD v4.1
c.575_576insA p.(Ser192Argfs*41) – not in gnomAD v4.1

PMID: 9153481 Granata et al., 1997 - two brothers aged 8 and 10 with severe bilateral schizencephaly, carrying an identical point mutation in EMX2. Phenotype: severe neurologic deficits and mental retardation. No access to full article
PMID: 9359037 Faiella et al., 1997 – same two brothers? Variant c.407G>T (p.Gly136Val) – Revel score 0.46 (Uncertain); not in gnomAD v4.1

Supporting evidence: https://iamg.in/genetic_clinics/full_textdfc6.html?id=212 – Clinical Vignette, Indian Academy of Medical Genetics – NO PMID.
Case report: 7 year old boy, bilateral schizencephaly, non-consanguineous parents; heterozygous for a de novo EMX2 variant: c.473G>A, (p.Arg158Gln) – Revel score 0.63, not found in gnomAD v4.1; method: trio sequencing of EMX2 exons only.
Phenotype: Severe developmental delay noticed at age 3-4 months. At 5 years old, the developmental age was 4 months. No meaningful speech was present. History of seizures since 4 years of age. Microcornea, widely spaced teeth, severe spasticity in all limbs.

CONTRADICTING EVIDENCE:
Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations:

PMID: 17506092 Tietjen et al., 2007
EMX2 genotyping of 84 affected probands with Schizencephaly – no EMX2 mutations detected.

PMID: 18409201 Merello et al., 2008
EMX2 sequencing in 39 SCH patients detected no pathogenic mutations. Only sequenced EMX2. Authors claimed that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.

PMID: 20157829 – Hehr et al., 2010
52 patients with SCH, no EMX2 mutations detected. Sequenced EMX2 (all 52 cases) as well SHH, SIX3 and ZIC2 in some of the individuals. SIX3 and SHH variants are reported as causative instead.

EMX2 is associated with Schizencephaly in OMIM (269160, accessed 29th Sep 2025) & classified as Limited for Schizencephaly in ClinGen (Epilepsy GCEP, 2024).

No other cases with EMX2 variants were published in literature since 1997. Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.; to: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly (SCH) - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the articles, published in 1996-1997, are limited by their sequencing method (EMX2 targeted gene sequencing):

PMID: 8528262 Brunelli et al., 1996
Method: SSCP analysis on PCR amplification products of 4 genes: EMX1, EMX2, OTX1, OTX2. No variants were detected in EMX1, OTX1, or OTX2. 7/8 schizencephaly patients harboured heterozygous EMX2 variants, of which 3 were de novo and predicted to be pathogenic:
c.407-4G>T – spliceAI benign, 1 allele reported in European population in gnomAD v4.1
c.407-1G>A – spliceAI splice-altering Strong, not in gnomAD v4.1
c.575_576insA p.(Ser192Argfs*41) – not in gnomAD v4.1

PMID: 9153481 Granata et al., 1997 - two brothers aged 8 and 10 with severe bilateral schizencephaly, carrying an identical point mutation in EMX2. Phenotype: severe neurologic deficits and mental retardation. No access to full article
PMID: 9359037 Faiella et al., 1997 – same two brothers? Variant c.407G>T (p.Gly136Val) – Revel score 0.46 (Uncertain); not in gnomAD v4.1

Supporting evidence: https://iamg.in/genetic_clinics/full_textdfc6.html?id=212 – Clinical Vignette, Indian Academy of Medical Genetics – NO PMID.
Case report: 7 year old boy, bilateral schizencephaly, non-consanguineous parents; heterozygous for a de novo EMX2 variant: c.473G>A, (p.Arg158Gln) – Revel score 0.63, not found in gnomAD v4.1; method: trio sequencing of EMX2 exons only.
Phenotype: Severe developmental delay noticed at age 3-4 months. At 5 years old, the developmental age was 4 months. No meaningful speech was present. History of seizures since 4 years of age. Microcornea, widely spaced teeth, severe spasticity in all limbs.

CONTRADICTING EVIDENCE:
Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations:

PMID: 17506092 Tietjen et al., 2007
EMX2 genotyping of 84 affected probands with Schizencephaly – no EMX2 mutations detected.

PMID: 18409201 Merello et al., 2008
EMX2 sequencing in 39 SCH patients detected no pathogenic mutations. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more. Thus, authors claimed that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.

PMID: 20157829 – Hehr et al., 2010
52 patients with SCH, no EMX2 mutations detected. Sequenced EMX2 (all 52 cases) as well SHH, SIX3 and ZIC2 in some of the individuals. SIX3 and SHH variants are reported as causative instead.

EMX2 is associated with Schizencephaly in OMIM (269160, accessed 29th Sep 2025) & classified as Limited for Schizencephaly in ClinGen (Epilepsy GCEP, 2024).

No other cases with EMX2 variants were published in literature since 1997. Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska commented on gene: EMX2: Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829). No other cases with EMX2 variants were published in literature since 1997. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201 Merello et al., 2008). Due to outdated and conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Intellectual disability v9.99 EMX2 Ida Ertmanska edited their review of gene: EMX2: Changed publications to: 8528262, 9153481, 9359037, 17506092, 18409201, 20157829
Intellectual disability v9.99 EMX2 Ida Ertmanska reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Schizencephaly, OMIM:269160, schizencephaly, MONDO:0010011; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v7.7 CHAF1A Arina Puzriakova Classified gene: CHAF1A as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.7 CHAF1A Arina Puzriakova Added comment: Comment on list classification: Rating Amber as additional evidence, such as additional cases or functional data, is required to corroborate this new gene-disease association. There is also debate on whether OAVS is a monogenic condition which should be taken into account.
Paediatric disorders - additional genes v7.7 CHAF1A Arina Puzriakova Gene: chaf1a has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.6 CHAF1A Arina Puzriakova gene: CHAF1A was added
gene: CHAF1A was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: CHAF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHAF1A were set to 39333427
Phenotypes for gene: CHAF1A were set to Oculo-auriculo-vertebral spectrum
Review for gene: CHAF1A was set to AMBER
Added comment: PMID: 39333427 (2025) - 8 individuals from 5 families with Oculo-auriculo-vertebral spectrum (OAVS) and heterozygous predicted LOF variants. No functional studies. Cases were selected through Genematcher and Decipher and were sequencing by WES or WGS.

This gene-disease association is not yet represented in other resources such as PanelApp Australia, Gene2Phenotype or OMIM.
Sources: Literature
Fetal anomalies v6.86 PDE12 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: PDE12.
Tag Q3_25_expert_review was removed from gene: PDE12.
Fetal anomalies v6.86 PDE12 Arina Puzriakova commented on gene: PDE12: Maintaining Amber rating following further consultation with the expert group - The concern is that the two prenatal presentations are very different. There is no link between brain anomalies and hydrops. The panel want to see more evidence that the gene is causing a prenatal phenotype and there is not another cause of these abnormalities in these families.
Fetal anomalies v6.86 NDUFB7 Arina Puzriakova Phenotypes for gene: NDUFB7 were changed from Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135; Mitochondrial complex I deficiency, nuclear type 39 to Mitochondrial complex I deficiency, nuclear type 39, OMIM:620135
Fetal anomalies v6.85 NDUFB7 Arina Puzriakova Tag Q1_25_ expert_review was removed from gene: NDUFB7.
Tag Q3_25_NHS_review tag was added to gene: NDUFB7.
Fetal anomalies v6.85 NDUFB7 Arina Puzriakova commented on gene: NDUFB7: Following further consultation with the expert group, it was decided that this gene should be rated Green on this panel as there is sufficient evidence to support an association with a prenatal phenotype.
Fetal anomalies v6.85 FLII Arina Puzriakova Tag Q3_25_promote_green was removed from gene: FLII.
Tag Q3_25_expert_review was removed from gene: FLII.
Tag Q3_25_NHS_review was removed from gene: FLII.
Fetal anomalies v6.85 FLII Arina Puzriakova commented on gene: FLII: Maintaining as Amber following further consultation with the expert group - this gene causes isolated cardiac anomalies which is not an indication for R21 fetal anomaly testing. However, we do want to monitor in case of new reports where it is not isolated.
Intellectual disability v9.99 KCND3 Nour Elkhateeb reviewed gene: KCND3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32823520, 32921676, 26189493, 28895081, 40140957; Phenotypes: Developmental delay, intellectual disability, ataxia, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v3.2 PRDM16 Jesse Hayesmoore reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23768516, PMID: 24454898, PMID: 37395136, PMID: 33500567, PMID: 29367541, PMID: 35893073, PMID: 29447731, PMID: 30847666, PMID: 33082984, PMID: 32183154, PMID: 34540771, PMID: 34350506, PMID: 34935411, PMID: 38113297, PMID: 31965688, PMID: 40935858, PMID: 21343612, PMID: 32083975, PMID: 33086060, PMID: 34915728; Phenotypes: LVNC, DCM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Limb disorders v7.12 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from to polydactyly, MONDO:0021003
Limb disorders v7.11 NTN1 Eleanor Williams Classified gene: NTN1 as Red List (low evidence)
Limb disorders v7.11 NTN1 Eleanor Williams Gene: ntn1 has been classified as Red List (Low Evidence).
Monogenic hearing loss v5.27 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from to sensorineural hearing loss disorder, MONDO:0020678
Monogenic hearing loss v5.26 NTN1 Eleanor Williams Publications for gene: NTN1 were set to
Monogenic hearing loss v5.25 NTN1 Eleanor Williams Mode of inheritance for gene: NTN1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v5.24 NTN1 Eleanor Williams Classified gene: NTN1 as Amber List (moderate evidence)
Monogenic hearing loss v5.24 NTN1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber as there is 1 case plus some functional data supporting the association with hearing loss.
Monogenic hearing loss v5.24 NTN1 Eleanor Williams Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.99 OGDHL Ida Ertmanska changed review comment from: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly heterogeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska changed review comment from: Comment on list classifcation: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: Comment on list classification: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska commented on gene: OGDHL: Comment on list classifcation: This gene should remain Green for Intellectual disability. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly hetergoeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Intellectual disability v9.99 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28017472, 34800363, 38031187; Phenotypes: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v1.144 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Immunodeficiency 13 615518; Combined immunodeficiency; Immunodeficiency 13/ UNC119 deficiency to ?Immunodeficiency 13, OMIM:615518
Primary immunodeficiency or monogenic inflammatory bowel disease v8.43 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Immunodeficiency 13/ UNC119 deficiency; Combined immunodeficiency; Immunodeficiency 13 615518 to ?Immunodeficiency 13, OMIM:615518
Structural eye disease v4.28 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Cone-rod dystrophy; Immunodeficiency 13, 615518; Eye Disorders to Cone-rod dystrophy 24, OMIM:620342
Retinal disorders v8.30 UNC119 Arina Puzriakova Phenotypes for gene: UNC119 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Eye Disorders; Cone-Rod Dystrophy, Dominant; CD4 lymphopenia, idiopathic (Gorska (2012) Blood 119, 1399) to Cone-rod dystrophy 24, OMIM:620342; retinal disorder, MONDO:0005283
Retinal disorders v8.29 UNC119 Arina Puzriakova Publications for gene: UNC119 were set to 11006213; 23563732; 27079236
Retinal disorders v8.28 UNC119 Arina Puzriakova Tag Q3_25_demote_amber tag was added to gene: UNC119.
Ataxia and cerebellar anomalies - narrow panel v8.24 CDK5 Arina Puzriakova Publications for gene: CDK5 were set to 25560765, 15067135
Ataxia and cerebellar anomalies - narrow panel v8.23 CDK5 Arina Puzriakova Classified gene: CDK5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.23 CDK5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype comprising lissencephaly with cerebellar hypoplasia and supportive animal models. Other lissencephaly genes also included on this panel (RELN, TUBA1A)
Ataxia and cerebellar anomalies - narrow panel v8.23 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.22 CDK5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CDK5.
Ataxia and cerebellar anomalies - narrow panel v8.22 CDK5 Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25560765, 40186457, 28854363, 8855328; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.80 CDK5 Arina Puzriakova Publications for gene: CDK5 were set to 25560765, 15067135
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype comprising lissencephaly with seizures and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.
Malformations of cortical development v7.8 CDK5 Arina Puzriakova Classified gene: CDK5 as Amber List (moderate evidence)
Malformations of cortical development v7.8 CDK5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype comprising lissencephaly and supportive animal models.
Malformations of cortical development v7.8 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Cerebellar hypoplasia v1.79 CDK5 Arina Puzriakova Classified gene: CDK5 as Green List (high evidence)
Cerebellar hypoplasia v1.79 CDK5 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Green - 2 unrelated families with the same severe phenotype comprising lissencephaly and supportive animal models.
Cerebellar hypoplasia v1.79 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.78 CDK5 Arina Puzriakova reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25560765, 40186457, 28854363, 8855328; Phenotypes: Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Classified gene: CDK5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.32 CDK5 Arina Puzriakova gene: CDK5 was added
gene: CDK5 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: CDK5.
Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5 were set to 25560765; 40186457; 28854363; 8855328
Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Review for gene: CDK5 was set to GREEN
Added comment: - PMID: 25560765 (2015) - Homozygous splice site variant g.IVS8+1G>A p.V162SfsX19 segregated with a lethal form of lissencephaly with cerebellar hypoplasia in 4 patients and 25 healthy relatives from one consanguineous family. Affected newborns had dysmorphic facial features, HC in normal-low range, lymphedema, arthrogryposis multiplex, and intractable seizures. Functional studies of the variant showed loss-of-function of the gene product.

- PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.

Animal models:
Brains of Cdk5-null mice lacked cortical laminar structure and cerebellar foliation (PMID: 8855328). Cdk5 knockout in the ferret cerebral cortex also markedly impaired cortical folding (PMID: 28854363).
Sources: Literature
Malformations of cortical development v7.7 CDK5 Arina Puzriakova gene: CDK5 was added
gene: CDK5 was added to Malformations of cortical development. Sources: Literature
Q3_25_promote_green tags were added to gene: CDK5.
Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5 were set to 25560765; 40186457; 28854363; 8855328
Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Review for gene: CDK5 was set to GREEN
Added comment: - PMID: 25560765 (2015) - Homozygous splice site variant g.IVS8+1G>A p.V162SfsX19 segregated with a lethal form of lissencephaly with cerebellar hypoplasia in 4 patients and 25 healthy relatives from one consanguineous family. Affected newborns had dysmorphic facial features, HC in normal-low range, lymphedema, arthrogryposis multiplex, and intractable seizures. Functional studies of the variant showed loss-of-function of the gene product.

- PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.

Animal models:
Brains of Cdk5-null mice lacked cortical laminar structure and cerebellar foliation (PMID: 8855328). Cdk5 knockout in the ferret cerebral cortex also markedly impaired cortical folding (PMID: 28854363).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.22 RARS2 Arina Puzriakova Phenotypes for gene: RARS2 were changed from epilepsy; Pontocerebellar hypoplasia, type 6, 611523; Pontocerebellar Hypoplasia type 6; Pontocerebellar hypoplasia; Pontocerebellar Hypoplasia to Pontocerebellar hypoplasia, type 6, OMIM:611523
Monogenic hearing loss v5.23 NTN1 Ida Ertmanska commented on gene: NTN1: Comment on list classification: There is one patient reported in literature with sensorineural hearing loss, heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had hearing impairment. Morpholino gene knockdown of ntn1a in zebrafish embryos resulted in sensory hair cell defects, supporting the gene's role in hearing. Based on the available evidence, NTN1 should be rated Amber for Monogenic hearing loss.
Monogenic hearing loss v5.23 NTN1 Ida Ertmanska reviewed gene: NTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28945198, 39648562; Phenotypes: sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska changed review comment from: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset, 4-40 years old). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.; to: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset, 4-40 years old). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska changed review comment from: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.; to: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset, 4-40 years old). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska commented on gene: TBX2: Comment on list classification: There is some emerging evidence for the association of monoallelic variants in TBX2 and monogenic hearing loss. Several reported individuals with microdeletions encompassing TBX2 (among other genes) have sensorineural hearing loss. A pre-print article from 2024 reports two Chinese pedigrees with nonsense variants in TBX2, which co-segregate with hearing loss (variable onset). 10 of 25 affected individuals also had nystagmus (onset before age 10). Functional evidence in mouse models supports the role of TBX2 in inner hair cell differentiation, which is essential for hearing. Based on the available evidence, this gene should be rated Amber for monogenic hearing loss.
Monogenic hearing loss v5.23 TBX2 Ida Ertmanska gene: TBX2 was added
gene: TBX2 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX2 were set to 15459098; 20206336; 21271665; 22052739; 35508658
Phenotypes for gene: TBX2 were set to hearing loss disorder, MONDO:0005365
Review for gene: TBX2 was set to AMBER
Added comment: There is some emerging evidence for the association of TBX2 and monogenic hearing loss. Several reported individuals with de novo microdeletions encompassing TBX2 had sensorineural hearing loss as one of the symptoms (PMID: 20206336 Ballif et al., 2010; PMID: 22052739 Schönewolf-Greulich et al., 2011; PMID: 21271665 Nimmakayalu et al., 2011). TBX2 and TBX4 are suggested as strong candidate genes. However, the effect of other genes being deleted is hard to decouple.

A study by Hua et al. ( https://doi.org/10.1101/2024.07.18.24310488, pre-print, posted in July 2024) identified two Chinese families with late onset progressive sensorineural hearing loss. Affected members in each family were heterozygous for c.977delA p.(Asp326Alafs*42) and c.987delC p.(Ala330Argfs*38) respectively. Both variants are extremely rare and co-segregate with disease. Method: Linkage analysis + WGS.

Family 1: five generations, 21/102 individuals had hearing loss (AD inheritance). Age of onset 4-40 years old. Monitoring at 10 year intervals showed slowly progressive auditory decline. 9 family member also exhibited spontaneous nystagmus (onset 0-5 years). Caveat: Six other shared variants were identified in RKD3, DYNC2LI1, FAHD2A, OR5K3, TBX2, ZNF135 - autosomal dominant pattern.

Family 2: 4/14 members had hearing loss, proband had severe hearing loss with onset before 5yo; patient II.6 had late onset hearing loss (onset at 26-30yo) with nystagmus observed in childhood.

Functional data:
Tbx2 is essential for inner hair cell (IHC) differentiation in mice. Conditional Tbx2 knockout causes embryonic IHCs differentiate as outer hair cells (OHCs). Both inner and outer hair cells are required for hearing (PMID: 35508658 Garcia-Anoveros et al., 2022). Tbx2-/- knockout mouse embryos exhibit lethal cardiovascular defects (PMID: 15459098 Harrelson et a., 2004). In https://doi.org/10.1101/2024.07.18.24310488, Tbx2-/- mice were also embryonic lethal. Heterozygous Tbx2+/- mice had normal Auditory Brainstem Response thresholds at day 70. They started showing signs of hearing loss at day 100, and they exhibited severe hearing loss at day 150 – consistent with late-onset hearing loss reported in some patients. Interestingly, p.(Asp326Alafs*42) knock-in mice did not show any signs of hearing loss.

TBX2 is associated with Vertebral anomalies and variable endocrine and T-cell dysfunction (OMIM:618223, accessed 23 Sep 2025). Based on the available evidence, this gene should be rated amber for monogenic hearing loss.
Sources: Literature
Limb disorders v7.10 NTN1 Ida Ertmanska edited their review of gene: NTN1: Added comment: Comment on list classification: There is one patient reported in literature with a limb disorder (right hand polydactyly), heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had no polydcatyly. Based on the available evidence, NTN1 should be rated Red for Limb disorders.; Changed phenotypes to: polydactyly, MONDO:0021003
Limb disorders v7.10 NTN1 Ida Ertmanska gene: NTN1 was added
gene: NTN1 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to 28945198; 39648562
Review for gene: NTN1 was set to RED
Added comment: PMID: 39648562 (Toms et al., 2024) reports a patient with right hand polydactyly, heterozygous for a de novo variant in NTN1: NM_004822.3:c.1483T>A p.(Tyr495Asn). Sequencing method: WGS.The patient (Female, 30 years old, White British) also had chorioretinal coloboma and microphthalmia, and bilateral sensorineural hearing loss. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting); predicted NMD escape (https://www.deciphergenomics.org/gene/NTN1/overview/protein-genomic-info)

Confoundingly, patients with congenital mirror movements from 3 families reported in PMID: 28945198 (Meneret et al., 2017) who also harboured heterozygous NTN1 variants at the C-terminal end (p.Cys601Arg, p.Ile518del, p.Cys601Ser) had normal eyesight, no oculomotor abnormalities, and no hearing impairment.

This gene appears to be intolerant to LoF variants (NTN1 pLI score = 1). NTN1 is associated with Mirror movements 4, OMIM:618264 (OMIM entry accessed 10th Sep 2025).

Based on the available evidence, this gene can only be rated Red for Limb disorders.
Sources: Literature
Fetal anomalies v6.85 CCT6A Arina Puzriakova Tag gene-checked tag was added to gene: CCT6A.
Intellectual disability v9.99 CCT6A Arina Puzriakova Tag gene-checked tag was added to gene: CCT6A.
Intellectual disability v9.99 CCT6A Arina Puzriakova Classified gene: CCT6A as Amber List (moderate evidence)
Intellectual disability v9.99 CCT6A Arina Puzriakova Added comment: Comment on list classification: This gene can be promoted to Green at the next GMS panel update. Phenotype is quite variable and unspecific - DD/ID is the most common feature observed among affected individuals so worth adding to this panel to enable capture of variants in this gene.
Intellectual disability v9.99 CCT6A Arina Puzriakova Gene: cct6a has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.98 CCT6A Arina Puzriakova gene: CCT6A was added
gene: CCT6A was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: CCT6A.
Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CCT6A were set to 39480921
Phenotypes for gene: CCT6A were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: CCT6A was set to GREEN
Added comment: PMID: 39480921 (2024) - 5 unrelated individuals with variants in the CCT6A gene, including 4 de novo (4 LoF, 2 missense), presenting with neurodevelopmental disorders. Main clinical features include DD/ID (4/5), pyramidal/cerebellar signs (3/4), variable brain abnormalities (3/5), microcephaly (2/5 - severe only in one) seizures (2/4), visual impairment (2/5).
Sources: Literature
Neurological ciliopathies v6.3 EVC2 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: EVC2.
Fetal anomalies v6.85 EVC2 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: EVC2.
Clefting v6.11 CTGF Arina Puzriakova Classified gene: CTGF as Amber List (moderate evidence)
Clefting v6.11 CTGF Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated cases supported by a recapitulated phenotype in an animal model.
Clefting v6.11 CTGF Arina Puzriakova Gene: ctgf has been classified as Amber List (Moderate Evidence).
Clefting v6.10 CTGF Arina Puzriakova gene: CTGF was added
gene: CTGF was added to Clefting. Sources: Literature
new-gene-name, Q3_25_promote_green tags were added to gene: CTGF.
Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTGF were set to 39506047; 39414788; 12736220
Phenotypes for gene: CTGF were set to Kyphomelic dysplasia, OMIM:211350; kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Review for gene: CTGF was set to GREEN
Added comment: PMID: 39506047 (2025) reported three individuals from two unrelated families with different homozygous CCN2 variants and kyphomelic dysplasia - all had cleft palate or bifid uvula as part of their phenotype. Ccn2-deficient mice also show skeletal dysmorphisms as well as secondary cleft palate, supporting this association.

Individuals with monoallelic variants in this gene do not exhibit dysmorphic facial phenotypes such as cleft palate (PMID: 39414788).
Sources: Literature
Fetal anomalies v6.85 CTGF Arina Puzriakova Phenotypes for gene: CTGF were changed from kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510 to Kyphomelic dysplasia, OMIM:211350; kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Skeletal dysplasia v8.14 CTGF Arina Puzriakova Phenotypes for gene: CTGF were changed from kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510 to Kyphomelic dysplasia, OMIM:211350; kyphomelic dysplasia, MONDO:0008881; spondyloepimetaphyseal dysplasia, MONDO:0100510
Intellectual disability v9.97 TSPAN7 Eleanor Williams Phenotypes for gene: TSPAN7 were changed from ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58, to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, X-linked 58, MONDO:0010266
Intellectual disability v9.96 TSPAN7 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype term accessed on 22nd September 2025
Intellectual disability v9.96 TSPAN7 Eleanor Williams Phenotypes for gene: TSPAN7 were changed from Mental retardation, X-linked 58, 300210; MENTAL RETARDATION X-LINKED TYPE 58 to ntellectual developmental disorder, X-linked 58, OMIM:300210; intellectual disability, MONDO:0010266 X-linked 58,
Intellectual disability v9.95 TSPAN7 Eleanor Williams Publications for gene: TSPAN7 were set to
Intellectual disability v9.94 TSPAN7 Eleanor Williams Tag Q3_25_demote_amber tag was added to gene: TSPAN7.
Skeletal dysplasia v8.13 CTGF Arina Puzriakova Tag watchlist_moi tag was added to gene: CTGF.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Supporting evidence - variants in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.; to: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet the eligibility criteria of moderate/severe/profound global developmental delay/intellectual disability.

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska commented on gene: TSPAN7: Comment on list classification: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing: IQ<50, global developmental delay, childhood onset. There is also conflicting evidence for pathogenicity of the reported variants, including high population allele frequencies, predicted NMD escape, and sequencing method limitations. Based on the available evidence, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T, Variation ID: 3767244. Hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs), Variation ID: 1164055 – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Reported in an individual in clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961- variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska edited their review of gene: TSPAN7: Changed rating: AMBER
Intellectual disability v9.94 TSPAN7 Ida Ertmanska changed review comment from: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.; to: There are at least 7 unrelated families reported with mild to moderate intellectual disability with either LoF variants in TSPAN7, TSPAN7 duplication, or balanced translocations with a breakpoint within the TSPAN7 sequence. However, phenotype in most of the affected individuals does not meet our criteria for Intellectual Disability testing, i.e. IQ<50, global developmental delay, childhood onset:

PMID: 10655063 Zemni et al., 2000: Sequencing method: DDGE + sequencing of PCR products (TSPAN7 sequence only).
Female patient with mild MR, mild autistic features, no dysmorphic features; IQ = 64 at 10yo. Heterozygous for a [46,X,t(X;2)(p11.4;p21.3)] balanced translocation affecting within TSPAN7 in a patient with mental retardation. TSPAN7 transcripts were barely detectable by RT-PCR.

Family L28, c.652G>T, p.(Gly218Ter) – IQ 45-60 in affected individuals (no age provided); authors claim variant segregates with disease, but data is not shown; RT-PCR showed normal levels of the transcript in affected patients; variant lies in a region of predicted NMD escape. Not found in gnomAD v4.1.0.

Family T15: 4 males hemizygous for c.515C>A, p.(Pro172His). IQ = 40-45 in 3 affected individuals (age 36-40 at report), individual 16 had IQ = 70 at age 10. In addition, individual 13 had low IQ (64) but did not carry the same mutation.
Conflicting evidence:
p.(Pro172His) variant-disease association disputed in PMID: 12376945 Gomot 2002 – linkage analysis in the same family excluded the TSPAN7 variant, authors suggest it to be a rare polymorphism instead.
Subsequently in PMID: 14735593 (da Costa Maranduba et al,, 2004), authors sequenced TSPAN7 in 105 males with mental retardation and found the same variant, p.Pro172His, in another patient – 21yo at time of report, delayed developmental milestones, severe speech acquisition impairment (started talking at 3.5 years); presented with dysmorphic facial features, abnormally folded ears, hypoplastic nails and alopecia spots.
Variant’s REVEL score = 0.62 (uncertain). Highest frequency in gnomAD v4 = 0.002106 (European population) – includes 2 homozygotes and 613 hemizygotes - unlikely to be causal, frequency too high.

PMID: 12070254 Abidi et al., 2002:
2-bp deletion c.572_573del p.(Val191fs) detected in a family with intellectual disability. Method: Screening exons of TM4SF2 gene only. Variant not in gnomAD v4.1.0. Family 'MRX58': five affected males in two generations with mild to moderate mental retardation (no IQ scores or ages given); affected males live in sheltered homes, are capable of doing simple jobs, and have no dysmorphic features; carrier females in the family have normal intelligence. BsrI restriction enzyme analysis determined that the deletion segregated with the XLMR in MRX58.

PMID: 22511893 Utine et al., 2012
FAMILY 1: moderately retarded 9-year-old patient and his similarly affected 11-year-old brother had infantile hypotonia and delayed motor development; did not acquire language abilities; No dysmorphic characteristics. TSPAN7 gene was duplicated. Unaffected mother had 3 copies of the same region. Copy number variation effect not yet clear as cause of ID.

PMID: 26290131 Moyses-Oliveira et al., 2015
Patient 1 - balanced translocation X;21 disrupting the 3’ UTR of TSPAN7; no TSPAN7 expression in peripheral blood sample. Authors pose that in women with balanced X-autosome translocations, the normal X chromosome is preferentially inactivated, resulting in a lack of expression. Array CGH did not cover the area of the autosomal breakpoint – effect unknown, method limitation. Patient phenotype: ‘borderline’ ID, microsomia, microcephaly.

Other variants reported as pathogenic in databases:
c.271-1G>T in intron 2 of TSPAN7 hemizygous in proband with XLID, inherited from unaffected mother. Variant not in gnomAD v4, SpliceIAI = 1 Splice-Altering Strong. ClinVar submission by Kasturba Medical College, Manipal, India.

c.289del (p.Leu97fs) – rated Pathogenic in ClinVar for XLID58 by Pediatric Genetics Clinic, Sheba Medical Center. Collection method: clinical testing; Allele origin: inherited; Affected status: yes; Clinical Features: Neurodevelopmental delay, Attention deficit hyperactivity disorder, Abnormal cerebral white matter morphology, Short stature, Microcephaly; Test name: Whole exome sequencing; Zygosity: Hemizygote. Variant not present in gnomAD v4.

c.127dup p.(Thr43AsnfsTer42) – male patient (Patient: 318070) with intellectual disability reported in Decipher https://www.deciphergenomics.org/patient/318070/genotype/192961/browser - variant not in gnomAD v4.

The association between TSPAN7 and non-syndromic X-linked intellectual disability was classified as Moderate by ClinGen (Intellectual Disability and Autism Gene Curation Expert Panel, Dec 2020). TSPAN7 is associated with Intellectual developmental disorder, X-linked 58 in OMIM (OMIM:300210, accessed 22 Sep 2025). Due to conflicting evidence in literature, the gene can only be rated Amber for Intellectual disability.
Intellectual disability v9.94 TSPAN7 Ida Ertmanska reviewed gene: TSPAN7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10655063, 12376945, 14735593, 12070254, 22511893, 26290131; Phenotypes: Intellectual developmental disorder, X-linked 58, OMIM:300210, intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova Classified gene: BHLHE22 as Amber List (moderate evidence)
Intellectual disability v9.94 BHLHE22 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.
Intellectual disability v9.94 BHLHE22 Arina Puzriakova Gene: bhlhe22 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova Classified gene: BHLHE22 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova Gene: bhlhe22 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.3 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed in OMIM on 22nd September 2025
Neurological ciliopathies v6.3 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from Ellis-van Creveld syndrome, 225500; Weyers acrofacial dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500; Weyers acrofacial dysostosis, OMIM:193530
Neurological ciliopathies v6.2 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Skeletal ciliopathies v6.3 EVC2 Eleanor Williams Publications for gene: EVC2 were set to 38531627; 23220543; 19810119; 16404586
Skeletal ciliopathies v6.2 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed in OMIM on 22nd September 2025
Skeletal ciliopathies v6.2 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from Ellis-van Creveld syndrome, 225500; Weyers acrofacial dysostosis, 193530 to Ellis-van Creveld syndrome, OMIM:225500; Weyers acrofacial dysostosis, OMIM:193530
Skeletal ciliopathies v6.2 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Skeletal ciliopathies v6.1 EVC2 Eleanor Williams Tag Q3_25_MOI tag was added to gene: EVC2.
Fetal anomalies v6.84 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Fetal anomalies v6.83 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed in OMIM on 22nd September 2025
Fetal anomalies v6.83 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from ELLIS-VAN CREVELD SYNDROME; ACROFACIAL DYSOSTOSIS WEYERS TYPE to Ellis-van Creveld syndrome, OMIM:225500 Weyers acrofacial dysostosis, OMIM:193530
Skeletal dysplasia v8.13 EVC2 Eleanor Williams Mode of inheritance for gene: EVC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v8.12 EVC2 Eleanor Williams Added comment: Comment on phenotypes: Phenotypes accessed from OMIM 22nd September 2025.
Skeletal dysplasia v8.12 EVC2 Eleanor Williams Phenotypes for gene: EVC2 were changed from Ellis-van Creveld syndrome 225500; Weyers acrofacial dysostosis 193530 to Ellis-van Creveld syndrome, OMIM:225500; Weyers acrofacial dysostosis, OMIM:193530
Skeletal dysplasia v8.11 EVC2 Eleanor Williams Publications for gene: EVC2 were set to
Skeletal dysplasia v8.10 EVC2 Eleanor Williams Mode of inheritance for gene: EVC2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v8.9 EVC2 Eleanor Williams Tag Q3_25_MOI tag was added to gene: EVC2.
Structural eye disease v4.27 NTN1 Ida Ertmanska edited their review of gene: NTN1: Changed phenotypes to: microphthalmia, isolated, with coloboma, MONDO:0000170
Structural eye disease v4.27 NTN1 Ida Ertmanska changed review comment from: As reviewed by Hannah Knight, PMID: 39648562 (Toms et al., 2024) reports a patient with chorioretinal coloboma and microphthalmia, heterozygous for NM_004822.3:c.1483T>A p.(Tyr495Asn). The patient (Female, 30 years old, White British) also had bilateral sensorineural hearing loss and right hand polydactyly. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting); predicted NMD escape (https://www.deciphergenomics.org/gene/NTN1/overview/protein-genomic-info).

Confoundingly, patients with congenital mirror movements from 3 families reported in PMID: 28945198 (Meneret et al., 2017) who also harboured heterozygous NTN1 variants at the C-terminal end (p.Cys601Arg, p.Ile518del, p.Cys601Ser) had normal eyesight, no oculomotor abnormalities, and no hearing impairment.

Mouse, chick, and zebrafish models provide good evidence for NTN1's function in optic fissure fusion:
In PMID: 39648562, morpholino knockdown of ntn1a in zebrafish (86% gene similarity to human ortholog) had ocular coloboma and sensory hair cell defects.
PMID: 31162046 (Hardy et al.,2019): Gene knockdown in zebrafish, using sgRNA targeting the first exon of ntn1. Homozygous knockouts were phenotypic; meanwhile heterozygous fish had no ocular abnormalities. Ntn1-/- mice also displayed highly penetrant ocular coloboma (10/11). Transcriptomic profiling in chick embryos showed that NTN1 is expressed in the chick optic fissure closure.

This gene appears to be intolerant to LoF variants (NTN1 pLI score = 1). NTN1 is associated with Mirror movements 4, OMIM:618264 (OMIM entry accessed 10th Sep 2025).

Based on the available evidence, this gene can only be rated Amber for Structural eye disease.; to: As reviewed by Hannah Knight, PMID: 39648562 (Toms et al., 2024) reports a patient with chorioretinal coloboma and microphthalmia, heterozygous for a de novo variant in NTN1: NM_004822.3:c.1483T>A p.(Tyr495Asn). Sequencing method: WGS.The patient (Female, 30 years old, White British) also had bilateral sensorineural hearing loss and right hand polydactyly. The C-terminus variant is not found in gnomAD v4.1.0; in silico prediction tools: Revel score = 0.5 (Uncertain), AlphaMissense score = 0.806 (Deleterious Supporting); predicted NMD escape (https://www.deciphergenomics.org/gene/NTN1/overview/protein-genomic-info).

Confoundingly, patients with congenital mirror movements from 3 families reported in PMID: 28945198 (Meneret et al., 2017) who also harboured heterozygous NTN1 variants at the C-terminal end (p.Cys601Arg, p.Ile518del, p.Cys601Ser) had normal eyesight, no oculomotor abnormalities, and no hearing impairment.

Mouse, chick, and zebrafish models provide good evidence for NTN1's function in optic fissure fusion:
In PMID: 39648562, morpholino knockdown of ntn1a in zebrafish (86% gene similarity to human ortholog) had ocular coloboma and sensory hair cell defects.
PMID: 31162046 (Hardy et al.,2019): Gene knockdown in zebrafish, using sgRNA targeting the first exon of ntn1. Homozygous knockouts were phenotypic; meanwhile heterozygous fish had no ocular abnormalities. Ntn1-/- mice also displayed highly penetrant ocular coloboma (10/11). Transcriptomic profiling in chick embryos showed that NTN1 is expressed in the chick optic fissure closure.

This gene appears to be intolerant to LoF variants (NTN1 pLI score = 1). NTN1 is associated with Mirror movements 4, OMIM:618264 (OMIM entry accessed 10th Sep 2025).

Based on the available evidence, this gene can only be rated Amber for Structural eye disease.
Structural eye disease v4.27 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from microphthalmia, isolated, with coloboma, MONDO:0000170 to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129
Structural eye disease v4.26 NTN1 Eleanor Williams Phenotypes for gene: NTN1 were changed from Chorioretinal Coloboma; Sensorineural Hearing Loss; Polydactyly to microphthalmia, isolated, with coloboma, MONDO:0000170
Structural eye disease v4.25 NTN1 Eleanor Williams Publications for gene: NTN1 were set to PMID: 39648562
Structural eye disease v4.24 NTN1 Eleanor Williams Classified gene: NTN1 as Amber List (moderate evidence)
Structural eye disease v4.24 NTN1 Eleanor Williams Added comment: Comment on list classification: Updating the rating to amber. One case with a relevant phenotype plus some functional data from zebrafish. Note that there are cases reported with missense variants in the C-terminus of this gene, that do not exhibit the eye phenotype.
Structural eye disease v4.24 NTN1 Eleanor Williams Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.11 BHLHE22 Arina Puzriakova gene: BHLHE22 was added
gene: BHLHE22 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: BHLHE22.
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BHLHE22 was set to GREEN
Added comment: PMID: 39502664 - 11 individuals from 9 unrelated families with BHLHE22 variants, presenting with a neurodevelopmental disorder including absent or limited speech, impaired motor function, intellectual disability, involuntary movements, autistic traits, abnormal muscle tone. Most had partial or complete agenesis of the corpus callosum, and some also showed epilepsy, dysmorphic features, and eye anomalies.

Four individuals had de novo missense variants within the helix-loop-helix domain, and seven carried a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum, recapitulating the structural anomalies seen in affected humans.
Sources: Literature
Intellectual disability v9.93 BHLHE22 Arina Puzriakova gene: BHLHE22 was added
gene: BHLHE22 was added to Intellectual disability. Sources: Literature
Q3_25_promote_green tags were added to gene: BHLHE22.
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BHLHE22 was set to GREEN
Added comment: PMID: 39502664 - 11 individuals from 9 unrelated families with BHLHE22 variants, presenting with a neurodevelopmental disorder including absent or limited speech, impaired motor function, intellectual disability, involuntary movements, autistic traits, abnormal muscle tone. Most had partial or complete agenesis of the corpus callosum, and some also showed epilepsy, dysmorphic features, and eye anomalies.

Four individuals had de novo missense variants within the helix-loop-helix domain, and seven carried a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum, recapitulating the structural anomalies seen in affected humans.
Sources: Literature
Hereditary neuropathy or pain disorder v7.8 TTC19 Alexander Rossor gene: TTC19 was added
gene: TTC19 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: TTC19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC19 were set to 40946707; 37927170; 25652355
Phenotypes for gene: TTC19 were set to Ataxia; apraxia; dystonia; dysarthria; necrotic brain lesions; motor axonal neuropathy
Penetrance for gene: TTC19 were set to Complete
Review for gene: TTC19 was set to GREEN
Added comment: Evidence of motor axonal neuropathy in 3 unrelated individuals.
Sources: Expert list
Hereditary neuropathy or pain disorder v7.8 XPNPEP3 Alexander Rossor gene: XPNPEP3 was added
gene: XPNPEP3 was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 40953058
Phenotypes for gene: XPNPEP3 were set to Nephronopthisis; brain white matter lesions; sensory axonal neuropathy; recurrent rhabdomyolysis; cardiomyopathy; ataxia; hearing loss
Penetrance for gene: XPNPEP3 were set to Complete
Review for gene: XPNPEP3 was set to AMBER
Added comment: Currently sensory axonal neuropathy only reported in a single case.
Sources: Other
Hereditary neuropathy or pain disorder v7.8 TDP1 Lauren Turton reviewed gene: TDP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia with axonal neuropathy (OMIM: 607250); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
DDG2P v6.5 PDE6H Ronnie Wright reviewed gene: PDE6H: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.28 PDE6H Ronnie Wright reviewed gene: PDE6H: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 22901948; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.28 CYP2U1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: CYP2U1.
Retinal disorders v8.28 CYP2U1 Arina Puzriakova Phenotypes for gene: CYP2U1 were changed from to Spastic paraplegia 56, autosomal recessive, OMIM:615030; retinal disorder, MONDO:0005283
Retinal disorders v8.27 CYP2U1 Arina Puzriakova Publications for gene: CYP2U1 were set to 26914923; 34828401; 39605873
Retinal disorders v8.26 CYP2U1 Arina Puzriakova Classified gene: CYP2U1 as Amber List (moderate evidence)
Retinal disorders v8.26 CYP2U1 Arina Puzriakova Gene: cyp2u1 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v4.5 FLG Arina Puzriakova Classified gene: FLG as Red List (low evidence)
Rare genetic inflammatory skin disorders v4.5 FLG Arina Puzriakova Gene: flg has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v4.4 FLG Arina Puzriakova Mode of inheritance for gene: FLG was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v4.3 FLG Arina Puzriakova Publications for gene: FLG were set to 16550169
Rare genetic inflammatory skin disorders v4.2 FLG Arina Puzriakova Phenotypes for gene: FLG were changed from Eczema; Ichthyosis vulgaris 146700; Ichthyosis vulgaris to Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM:605803; hereditary palmoplantar keratoderma, MONDO:0019272
Palmoplantar keratodermas v4.3 FLG Arina Puzriakova Phenotypes for gene: FLG were changed from ICHTHYOSIS VULGARIS to Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM:605803; hereditary palmoplantar keratoderma, MONDO:0019272
Palmoplantar keratodermas v4.2 FLG Arina Puzriakova Publications for gene: FLG were set to 16444271; 16815158; 17030239; 17291859
Palmoplantar keratodermas v4.1 FLG Arina Puzriakova Tag Q3_25_MOI tag was added to gene: FLG.
Ichthyosis and erythrokeratoderma v4.3 FLG Arina Puzriakova Phenotypes for gene: FLG were changed from Ichthyosis vulgaris, OMIM:146700 to Ichthyosis vulgaris, OMIM:146700; Dermatitis, atopic, susceptibility to, 2, OMIM:605803; ichthyosis vulgaris, MONDO:0024304
Ichthyosis and erythrokeratoderma v4.2 FLG Arina Puzriakova Publications for gene: FLG were set to 16444271; 16815158; 17030239; 17291859
Ichthyosis and erythrokeratoderma v4.1 FLG Arina Puzriakova Tag Q3_25_MOI tag was added to gene: FLG.
Congenital myopathy v6.35 PNPLA2 Anna Sarkozy edited their review of gene: PNPLA2: Added comment: variants in this gene have now been reported in young individuals presenting with progressive skeletal myopathy, raised CK, and sometimes cardiomyopathy and liver dysfunction. these findings suggest that variants in this gene can be associated with an early onset form of myopathy, supporting green rating of this gene.; Changed rating: GREEN; Changed publications to: PMID: 21544567, PMID: 40919432, PMID: 37620213
Congenital myopathy v6.35 CASQ1 Anna Sarkozy commented on gene: CASQ1: Calsequestrin (CASQ) is the main Ca2+ buffer in the terminal cisternae, part of the so called Triad. Other forms of congenital myopathies are caused by genetic defects in components of the triad such as RYR1, ORAI1, STIM1 and now also CASQ1. patients with CASQ1 pathogenic variants usually present with high CK levels, mild proximal weakness, and myalgia. variable age at onset, mostly in adult life. muscle biopsy findings were typically myopathic with vacuolar inclusions strongly react with antibodies against SR calcium–machinery proteins and also tubular aggregates. These features are in part similar and overlapping what seen in association with other diseases associated with the triad.
Congenital myopathy v6.35 CASQ1 Anna Sarkozy edited their review of gene: CASQ1: Added comment: Calsequestrin (CASQ) is the main Ca2+ buffer in the terminal cisternae, part of the so called Triad. Other forms of congenital myopathies are caused by genetic defects in components of the triad such as RYR1, ORAI1, STIM1 and now also CASQ1. patients with CASQ1 pathogenic variants usually present with high CK levels, mild proximal weakness, and myalgia. variable age at onset, mostly in adult life. muscle biopsy findings were typically myopathic with vacuolar inclusions strongly react with antibodies against SR calcium–machinery proteins and also tubular aggregates. These features are in part similar and overlapping what seen in association with other diseases associated with the triad.; Changed rating: GREEN; Changed publications to: PMID: 30258016; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v6.35 VWA1 Anna Sarkozy reviewed gene: VWA1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:39502942, PMID: 33459760; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Structural eye disease v4.23 MYH10 Achchuthan Shanmugasundram Classified gene: MYH10 as Amber List (moderate evidence)
Structural eye disease v4.23 MYH10 Achchuthan Shanmugasundram Added comment: Comment on list classification: Four of six patients from three unrelated families were reported with monoallelic MYH10 variants and ocular coloboma. In addition, functional evidence from patient fibroblasts and delayed eye development in zebrafish model support the association.

However, this gene should be currently rated amber as coloboma was not consistently reported in all six patents from PMID:40044823 and was entirely absent in the previously reported cohort with neurodevelopmental phenotype (PMID:35980381).

The 'watchlist' tag has been added to review this gene for any new evidence in the future.
Structural eye disease v4.23 MYH10 Achchuthan Shanmugasundram Gene: myh10 has been classified as Amber List (Moderate Evidence).
Structural eye disease v4.22 MYH10 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: MYH10.
Structural eye disease v4.22 MYH10 Achchuthan Shanmugasundram Phenotypes for gene: MYH10 were changed from Autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features to neurodevelopmental disorder, MONDO:0700092; coloboma, MONDO:0001476
Structural eye disease v4.21 MYH10 Achchuthan Shanmugasundram edited their review of gene: MYH10: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, coloboma, MONDO:0001476
Structural eye disease v4.21 MYH10 Achchuthan Shanmugasundram Publications for gene: MYH10 were set to PMID: 40044823
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram Deleted their comment
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram changed review comment from: PMID:35980381 (2022) reported a cohort of 16 individuals with 14 unique heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders. Eye-related phenotypes were relatively minor with ptosis in 3 patients, refractive errors in four and chorioretinal lacunae in one patient.

PMID:40044823 (2025) reported six individuals from three unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features, and identified with 3 novel heterozygous variants (one of missense, splice site and one AA deletion) in the tail domain of MYH10 gene via exome or genome sequencing. However, no neurodevelopmental disorders as usually observed in this syndrome were detected. Iris and choreoretinal coloboma was reported in four of six individuals from three unrelated families (2/3 patients from family 1, 1/2 patients from family 2 and the only patient from family 3). Heterozygous variant in HOXD13 gene was identified in both mother and son from family 2, which was reported to explain their extremities anomalies. In addition, MYH10 dysfunction led to delayed development of the eye and muscular phenotype in the zebrafish model.

This gene has been currently rated Amber on Anophthalmia_Microphthalmia_Coloboma panel (https://panelapp-aus.org/panels/42/gene/MYH10/) in PanelApp Australia based on the evidence from PMID:40044823. This gene has also been rated 'moderate' on the DD panel based on the neurodevelopmental phenotype. However, it has not yet been associated with any relevant phenotypes in OMIM>; to: PMID:35980381 (2022) reported a cohort of 16 individuals with 14 unique heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders. Eye-related phenotypes were relatively minor with ptosis in 3 patients, refractive errors in four and chorioretinal lacunae in one patient.

PMID:40044823 (2025) reported six individuals from three unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features, and identified with 3 novel heterozygous variants (one of missense, splice site and one AA deletion) in the tail domain of MYH10 gene via exome or genome sequencing. However, no neurodevelopmental disorders as usually observed in this syndrome were detected. Iris and choreoretinal coloboma was reported in four of six individuals from three unrelated families (2/3 patients from family 1, 1/2 patients from family 2 and the only patient from family 3). Heterozygous variant in HOXD13 gene was identified in both mother and son from family 2, which was reported to explain their extremities anomalies. In addition, MYH10 dysfunction led to delayed development of the eye and muscular phenotype in the zebrafish model.

This gene has been currently rated Amber on Anophthalmia_Microphthalmia_Coloboma panel (https://panelapp-aus.org/panels/42/gene/MYH10/) in PanelApp Australia based on the evidence from PMID:40044823. This gene has also been rated 'moderate' on the DD panel based on the neurodevelopmental phenotype. However, it has not yet been associated with any relevant phenotypes in OMIM.
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram commented on gene: MYH10: PMID:35980381 (2022) reported a cohort of 16 individuals with 14 unique heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders. Eye-related phenotypes were relatively minor with ptosis in 3 patients, refractive errors in four and chorioretinal lacunae in one patient.

PMID:40044823 (2025) reported six individuals from three unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features, and identified with 3 novel heterozygous variants (one of missense, splice site and one AA deletion) in the tail domain of MYH10 gene via exome or genome sequencing. However, no neurodevelopmental disorders as usually observed in this syndrome were detected. Iris and choreoretinal coloboma was reported in four of six individuals from three unrelated families (2/3 patients from family 1, 1/2 patients from family 2 and the only patient from family 3). Heterozygous variant in HOXD13 gene was identified in both mother and son from family 2, which was reported to explain their extremities anomalies. In addition, MYH10 dysfunction led to delayed development of the eye and muscular phenotype in the zebrafish model.

This gene has been currently rated Amber on Anophthalmia_Microphthalmia_Coloboma panel (https://panelapp-aus.org/panels/42/gene/MYH10/) in PanelApp Australia based on the evidence from PMID:40044823. This gene has also been rated 'moderate' on the DD panel based on the neurodevelopmental phenotype. However, it has not yet been associated with any relevant phenotypes in OMIM>
Structural eye disease v4.20 MYH10 Achchuthan Shanmugasundram reviewed gene: MYH10: Rating: AMBER; Mode of pathogenicity: None; Publications: 35980381, 40044823; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).
PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).
PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska edited their review of gene: FLG: Added comment: Comment on list classification: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; Changed publications to: 16444271, 16550169, 24940654, 22409988, 33807935, 36716921, 36751330
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska commented on gene: FLG: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and symmetrical acral keratoderma, which fits into the scope of this panel.

Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022).

PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype.
c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes.
c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes.

PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes.

Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles).

PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma.

Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska changed review comment from: Comment on list classification: There are at least 17 unrelated patients with variants in FLG with palmoplantar keratoderma (PPK). PPK is frequently seen in combination with ichthyosis.
PMID:36308042 (Clabbers et al., 2022): 22 Dutch patients with palmoplantar keratoderma were found to carry mono- or bi-allelic variants in FLG. In 17/22 of the patients, variants in other known PPK genes were excluded through an exome sequencing panel. Ten patients were heterozygous, six homozygous, and six compound heterozygous, including nonsense and frameshift mutations. Phenotypes: diffuse PPK (100% of patients), palmoplantar erythema (82%), palmar hyperlinearity (91%), transgrediens (62%), and generalized xerosis cutis (100%).
Functional studies: Newborn Flg(-/-) mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).; to: Comment on list classification: There are at least 17 unrelated patients with variants in FLG with palmoplantar keratoderma (PPK). PPK is frequently seen in combination with ichthyosis.

PMID:36308042 (Clabbers et al., 2022): 22 Dutch patients with palmoplantar keratoderma were found to carry mono- or bi-allelic variants in FLG. In 17/22 of the patients, variants in other known PPK genes were excluded through an exome sequencing panel. Ten patients were heterozygous, six homozygous, and six compound heterozygous, including nonsense and frameshift mutations. Phenotypes: diffuse PPK (100% of patients), palmoplantar erythema (82%), palmar hyperlinearity (91%), transgrediens (62%), and generalized xerosis cutis (100%).

Functional studies: Newborn Flg(-/-) mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012).

Based on the available evidence, this gene should be rated Green for Palmoplantar keratodermas.
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska edited their review of gene: FLG: Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Both monoallelic and biallelic variants in FLG may cause palmoplantar keratoderma - PPK is frequently seen in combination with ichthyosis (PMID:36308042 Clabbers et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).; Changed publications to: 16444271, 16550169, 22409988, 36308042
Palmoplantar keratodermas v4.1 FLG Ida Ertmanska reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 22409988, 36308042; Phenotypes: Ichthyosis vulgaris, OMIM:146700, Dermatitis, atopic, susceptibility to, 2, OMIM: 605803, hereditary palmoplantar keratoderma, MONDO:0019272; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v4.1 FLG Ida Ertmanska reviewed gene: FLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16444271, 16550169; Phenotypes: Ichthyosis vulgaris, OMIM:146700, Dermatitis, atopic, susceptibility to, 2, OMIM: 605803, ichthyosis vulgaris, MONDO:0024304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.10 FICD John Taylor reviewed gene: FICD: Rating: AMBER; Mode of pathogenicity: None; Publications: 36136088, 36704923; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram Deleted their review
Congenital hyperinsulinism v3.5 GPC3 Achchuthan Shanmugasundram Deleted their review
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram changed review comment from: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before demoting this gene to red.; to: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before demoting this gene to amber.
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram commented on gene: AKT2
Congenital hyperinsulinism v3.5 AKT2 Achchuthan Shanmugasundram Deleted their review
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska changed review comment from: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' at the next update.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).; to: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska edited their review of gene: FLG: Added comment: Comment on mode of inheritance: MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' at the next update.

Biallelic variants are associated with severe Ichthyosis vulgaris. Monoallelic variants are associated with a mild phenotype and incomplete penetrance (PMID: 16444271 Smith et al., 2006). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006).; Changed publications to: 16444271, 16550169
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska changed review comment from: As reviewed by Ronnie Wright, FLG is associated with Ichthyosis vulgaris, which does not fit into the current scope of the Rare genetic inflammatory skin disorders panel. It should be rated Red based on the available evidence.

The gene is already rated Green on the following panels: Ichthyosis and erythrokeratoderma and Palmoplantar keratodermas.

FLG is associated with Ichthyosis vulgaris (AD &AR) OMIM:146700 and {Dermatitis, atopic, susceptibility to, 2} AD OMIM: 605803 in OMIM (accessed 18th Sep 2025).; to: Comment on list classification: As reviewed by Ronnie Wright, FLG is associated with Ichthyosis vulgaris, which does not fit into the current scope of the Rare genetic inflammatory skin disorders panel. It should be rated Red based on the available evidence.

The gene is already rated Green on the following panels: Ichthyosis and erythrokeratoderma and Palmoplantar keratodermas.

FLG is associated with Ichthyosis vulgaris (AD &AR) OMIM:146700 and {Dermatitis, atopic, susceptibility to, 2} AD OMIM: 605803 in OMIM (accessed 18th Sep 2025).
Rare genetic inflammatory skin disorders v4.1 FLG Ida Ertmanska reviewed gene: FLG: Rating: RED; Mode of pathogenicity: None; Publications: 16444271; Phenotypes: Ichthyosis vulgaris, OMIM:146700, Dermatitis, atopic, susceptibility to, 2, OMIM: 605803, ichthyosis vulgaris, MONDO:0024304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v5.12 MT-ND5 Jesse Hayesmoore reviewed gene: MT-ND5: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 14520659, PMID: 23847141, PMID: 37318682, PMID: 25681084, PMID: 12624137, PMID: 14730434, PMID: 36104228, PMID: 22759514, PMID: 30587702, PMID: 23628297, PMID: 19473338; Phenotypes: Leigh syndrome, LHON, MELAS; Mode of inheritance: MITOCHONDRIAL
Paediatric or syndromic cardiomyopathy v7.86 MT-ND5 Jesse Hayesmoore reviewed gene: MT-ND5: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 14520659, PMID: 23847141, PMID: 37318682, PMID: 25681084, PMID: 12624137, PMID: 14730434, PMID: 36104228, PMID: 22759514, PMID: 30587702, PMID: 23628297, PMID: 19473338; Phenotypes: Leigh syndrome, LHON, MELAS; Mode of inheritance: MITOCHONDRIAL
Retinal disorders v8.25 CYP2U1 Ida Ertmanska commented on gene: CYP2U1: Comment on list classification: As reviewed by Cassandra Smith, individuals with biallelic variants in CYP2U1 may present with retinal abnormalities, which fits into the scope of this panel - there at least 8 unrelated individuals reported in literature. The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases), sometimes appearing as the first symptom, before spasticity. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.
Retinal disorders v8.25 CYP2U1 Ida Ertmanska edited their review of gene: CYP2U1: Changed publications to: 23176821, 26914923, 29034544, 33107650, 34546337, 34828401, 38058766, 39605873
Retinal disorders v8.25 CYP2U1 Ida Ertmanska edited their review of gene: CYP2U1: Changed publications to: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873
Retinal disorders v8.25 CYP2U1 Ida Ertmanska Deleted their comment
Retinal disorders v8.25 CYP2U1 Ida Ertmanska commented on gene: CYP2U1: CYP2U1 is known to cause hereditary spastic paraplegia, with a variable spectrum of other symptoms being reported: intellectual disability, dystonia, pseudoxanthoma elasticum, and visual impairments (pigmentary degenerative maculopathy, loss of visual acuity, photophobia). There are at least 8 unrelated individuals with retinal abnormalities with biallelic variants in CYP2U1, harbouring missense, stop-gained, splice-altering, and frameshift variants (PMID: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873). The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases) – sometimes appearing as the first symptom, before spasticity (e.g. PMID:26914923, 39605873).

FUNCTIONAL EVIDENCE: A Cyp2u1−/− mouse model recapitulated the retinal impairments observed in patients – mice exhibited a late-onset (18 mo) ophthalmologic phenotype characterized by a cone dystrophy (PMID: 34546337 Pujol et al., 2021). Skin fibroblasts of an individual with c.61_73del, p.(Leu21Trpfs∗19) in CYP2U1 showed reduced oxygen consumption compared to controls, as well as structural abnormalities of the mitochondrial membrane (PMID: 23176821 Tesson et al., 2012). Expressing CYP2U1 with missense variants in HEK293T cells demonstrated that most missense variants were functionally inactive, due to loss of proper heme binding or destabilization of the protein structure (PMID: 29034544 Durand et al., 2018). Thus, the proposed disease mechanism is LoF leading to mitochondrial dysfunction - a common driver for degenerative retinal disease. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.

The gene is associated with Spastic paraplegia 56, autosomal recessive (OMIM:615030, accessed 17th Sep 2025). It is also Definitive for CYP2U1-related spastic paraplegia in G2P (G2P00349).
Retinal disorders v8.25 CYP2U1 Ida Ertmanska reviewed gene: CYP2U1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873; Phenotypes: Spastic paraplegia 56, autosomal recessive, OMIM:615030, retinal disorder, MONDO:0005283; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v4.1 VIPAS39 Achchuthan Shanmugasundram Tag Q1_23_promote_green was removed from gene: VIPAS39.
Tag Q3_25_promote_green tag was added to gene: VIPAS39.
Intellectual disability v9.92 UGGT1 Karen Stals gene: UGGT1 was added
gene: UGGT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to PMID: 40267907
Phenotypes for gene: UGGT1 were set to intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys
Review for gene: UGGT1 was set to GREEN
gene: UGGT1 was marked as current diagnostic
Added comment: Dardas et al report biallelic UGGT1 variants in 10 families (15 individuals), with more severe phenotypes seen with biallelic loss of function variants. UGGT1 variants were shown to impair UGGT1 glycosylation and catalytic activity.
Sources: Literature
Congenital disorders of glycosylation v7.5 UGGT1 Karen Stals gene: UGGT1 was added
gene: UGGT1 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to PMID: 40267907
Phenotypes for gene: UGGT1 were set to intellectual disability; seizures; characteristic facial features; microcephaly; congenital heart malformations, variable skeletal abnormalities; hepatic and renal involvement; polycystic kidneys
Review for gene: UGGT1 was set to GREEN
gene: UGGT1 was marked as current diagnostic
Added comment: Dardas et al report biallelic UGGT1 variants in 10 families (15 individuals), with more severe phenotypes seen with biallelic loss of function variants. UGGT1 variants were shown to impair UGGT1 glycosylation and catalytic activity.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.86 RPL3L Riyaad Aungraheeta reviewed gene: RPL3L: Rating: ; Mode of pathogenicity: Other; Publications: PMID: 40820268; Phenotypes: Neonatal dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.8 DLD Alexander Rossor gene: DLD was added
gene: DLD was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: DLD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLD were set to 40888368
Phenotypes for gene: DLD were set to hepatic dysfunction; sensory axonal neuropathy
Penetrance for gene: DLD were set to Complete
Review for gene: DLD was set to AMBER
Added comment: Single case reporting sensory axonal neuropathy therefore should be amber for now
Sources: Other
Retinal disorders v8.25 UNC119 Ida Ertmanska commented on gene: UNC119: Comment on list classification: There are three cone-rod dystrophy patients from three unrelated families reported with heterozygous UNC119 variants. However, there is conflicting evidence regarding pathogenicity of the variants. Due to conflicting evidence, this gene should be demoted to Amber for retinal disorders.
Retinal disorders v8.25 UNC119 Ida Ertmanska reviewed gene: UNC119: Rating: AMBER; Mode of pathogenicity: None; Publications: 11006213, 23563732, 35947183, 30910914; Phenotypes: retinal disorder, MONDO:0005283, Cone-rod dystrophy 24, OMIM:620342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Movement disorders
(dystonia (8/14), choreoathetosis (3/14)) were reported in several individuals with biallelic variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Movement disorders such as dystonia (8/14) and choreoathetosis (3/14) were reported in several individuals with biallelic variants in this gene.
Intellectual disability v9.92 TNR Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: TNR.
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Movement disorders
(dystonia (8/14), choreoathetosis (3/14)) were reported in several individuals with biallelic variants in this gene.
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Spastic para- or tetraparesis, apparent from infancy or early childhood, was reported in 13/15 individuals with biallelic variants in this gene.
Intellectual disability v9.92 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Impaired intellectual development noted in multiple individuals with biallelic variants in this gene, although the severity was highly variable and no formal neuropsychological testing was done. Nonetheless, cognitive developmental delay was recorded as moderate in at least 5 unrelated cases which supports inclusion on the panel.
Intellectual disability v9.92 TNR Arina Puzriakova Tag Q3_25_promote_green was removed from gene: TNR.
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova Entity copied from Intellectual disability v9.92
Childhood onset dystonia, chorea or related movement disorder v7.4 TNR Arina Puzriakova gene: TNR was added
gene: TNR was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Expert list,Expert Review Amber
Q3_25_promote_green tags were added to gene: TNR.
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 28334938; 32099069
Phenotypes for gene: TNR were set to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova Entity copied from Intellectual disability v9.92
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova gene: TNR was added
gene: TNR was added to Childhood onset hereditary spastic paraplegia. Sources: Expert list,Expert Review Amber
Q3_25_promote_green tags were added to gene: TNR.
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 28334938; 32099069
Phenotypes for gene: TNR were set to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Intellectual disability v9.92 TNR Arina Puzriakova Publications for gene: TNR were updated from 22730557; 32099069 to 28334938; 32099069
Intellectual disability v9.91 TNR Arina Puzriakova Publications for gene: TNR were set to 32099069
Intellectual disability v9.91 TNR Arina Puzriakova Phenotypes for gene: TNR were changed from Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653 to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Rare anaemia v3.10 PPOX Sharon Whatley gene: PPOX was added
gene: PPOX was added to Rare anaemia. Sources: Other
Mode of inheritance for gene: PPOX was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: PPOX were set to 38940544; 30828546; 9454777; 7757079; 40296768; 21103937
Phenotypes for gene: PPOX were set to 121300; 618892
Penetrance for gene: PPOX were set to Incomplete
Review for gene: PPOX was set to GREEN
Added comment: Relevant metabolic investigation: Plasma porphyrin fluorescence emission and faecal coproporphyrin isomer (III:I) ratio (for hereditary coproporphyria) and faecal harderoporphyrin (for harderoporphyria)

PMID: 38940544 Aarsand reports that porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes. Defects in the CPOX gene cause hereditary coproporphyria.

PMID: 16159891 Schmitt reports that there are two very rare, homozygous forms of HCP one of which is characterised by the faecal excretion of harderoporphyrin. Harderoporphyria has predominantly haematological manifestations such as neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 30828546 Moghe, 9454777 Lamoril, 7757079 Lamoril, 40296768 Kelestemur, 21103937 Hasanoglu report eight patients (from five families) with biallelic pathogenic CPOX variants. They presented with neonatal jaundice, haemolytic anaemia and hepatosplenomegaly.

PMID: 16159891 Schmitt reports that during childhood and adulthood, a mild residual anaemia is chronically observed in harderoporphyria patients.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Sources: Other
Intellectual disability v9.90 TNR Arina Puzriakova Phenotypes for gene: TNR were changed from Spastic para- or tetraparesis; Axial muscular hypotonia; Intellectual disability; Transient opisthotonus to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Intellectual disability v9.89 TNR Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: TNR.
Childhood onset dystonia, chorea or related movement disorder v7.3 CPOX Sharon Whatley reviewed gene: CPOX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 23605133, 35584894; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy v1.500 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.
PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Hereditary neuropathy v1.500 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 35584894; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v8.58 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 23236641, 11074238, 23605133, 16159891, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.632 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 11309681, 37540847, 23236641, 11074238, 23605133, 16159891, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Vascular skin disorders v2.1 CPOX Sharon Whatley reviewed gene: CPOX: Rating: RED; Mode of pathogenicity: None; Publications: 23236641; Phenotypes: ; Mode of inheritance: None
Cutaneous photosensitivity with a likely genetic cause v3.9 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 23236641, 11074238, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Non-acute porphyrias v1.26 CPOX Sharon Whatley reviewed gene: CPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 11309681, 23236641, 11074238, 16159891, 40296768, 33008663, 30828546, 21103937, 16159891, 10505225, 9454777, 7757079, 8012360, 6886003; Phenotypes: 121300, 618892; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Structural eye disease v4.20 NTN1 Ida Ertmanska commented on gene: NTN1: Comment on list classification: There is one patient reported in literature with structural eye disease (coloboma and microphthalmia), heterozygous for a C-terminus missense variant in NTN1. At least 3 other patients, heterozygous for C-terminus NTN1 variants, had no ocular abnormalities. Gene knockouts in zebrafish and mouse embryos resulted in ocular coloboma phenotype, supporting the gene's role in eye development. Based on the available evidence, NTN1 should be rated Amber for Structural eye disease.
Structural eye disease v4.20 NTN1 Ida Ertmanska reviewed gene: NTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39648562, 31162046; Phenotypes: Associated with Mirror movements 4, OMIM:618264, microphthalmia, isolated, with coloboma, MONDO:0000170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorder with complex IV deficiency v4.9 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Mitochondrial disorder with complex IV deficiency v4.9 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the promotion of this gene to green rating in the next GMS update.
Mitochondrial disorder with complex IV deficiency v4.9 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v4.8 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Mitochondrial disorder with complex IV deficiency v4.8 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from No OMIM phenotype to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Mitochondrial disorder with complex IV deficiency v4.7 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to
Mitochondrial disorder with complex IV deficiency v4.6 COX18 Achchuthan Shanmugasundram Mode of inheritance for gene: COX18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v4.5 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.31 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Mitochondrial disorders v9.31 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the promotion of this gene to green rating in the next GMS update.
Mitochondrial disorders v9.31 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.30 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from 37468577; 40830826 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Mitochondrial disorders v9.29 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from No OMIM phenotype to 37468577; 40830826
Mitochondrial disorders v9.28 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to
Mitochondrial disorders v9.27 COX18 Achchuthan Shanmugasundram Mode of inheritance for gene: COX18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.26 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Mitochondrial disorders v9.26 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.12 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v4.12 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the promotion of this gene to green rating in the next GMS update.
Possible mitochondrial disorder - nuclear genes v4.12 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v4.11 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to
Possible mitochondrial disorder - nuclear genes v4.10 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from No OMIM phenotype to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Possible mitochondrial disorder - nuclear genes v4.9 COX18 Achchuthan Shanmugasundram Mode of inheritance for gene: COX18 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.8 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Possible mitochondrial disorder - nuclear genes v4.8 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.8 COX18 Achchuthan Shanmugasundram Classified gene: COX18 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v7.8 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the association of biallelic COX18 variants with Charcot-Marie-Tooth disease. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.8 COX18 Achchuthan Shanmugasundram Gene: cox18 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v7.7 COX18 Achchuthan Shanmugasundram Phenotypes for gene: COX18 were changed from peripheral neuropathy to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626
Hereditary neuropathy or pain disorder v7.6 COX18 Achchuthan Shanmugasundram Publications for gene: COX18 were set to 40830826
Hereditary neuropathy or pain disorder v7.5 COX18 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: COX18.
Tag Q3_25_NHS_review tag was added to gene: COX18.
Hereditary neuropathy or pain disorder v7.5 COX18 Achchuthan Shanmugasundram reviewed gene: COX18: Rating: GREEN; Mode of pathogenicity: None; Publications: 37468577, 40830826; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v6.5 LBX1 Ian Berry gene: LBX1 was added
gene: LBX1 was added to DDG2P. Sources: Expert Review
Mode of inheritance for gene: LBX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LBX1 were set to PMID: 30487221
Penetrance for gene: LBX1 were set to Complete
Review for gene: LBX1 was set to GREEN
gene: LBX1 was marked as current diagnostic
Added comment: Single sib-pair in PMID: 30487221 with congenital central hypoventilation syndrome, 1bp resulting in a frameshift in the terminal exon. Mouse model of the same variant expressed a protein with an altered C-terminal and replicated the human phenotype.

Subsequent unpublished studies (in process of publication): 2 further cases in CVA/GEL dataset with comparable phenotypes, 2 further probands (with segregation) in other families via multinational collaboration.

All cases appear to have the same variant NM_006562.5: c.707del p.(Val236Alafs*59) which may be a Roma founder.
Sources: Expert Review
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic UPF1 variants with intellectual disability and/or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.89 UPF1 Achchuthan Shanmugasundram Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Classified gene: UPF1 as Amber List (moderate evidence)
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic UPF1 variants with intellectual disability and/or global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.88 UPF1 Achchuthan Shanmugasundram Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram changed review comment from: PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs).

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.; to: PMID:28135719 (2017) reported four unrelated patients with de novo heterozygous missense variants in UPF1 gene from the Deciphering Developmental Disorders Study cohort, for which no detailed phenotypic information was available in the publication. Three patients were reported with global developmental delay (mild in one) and the fourth patient was reported with neurodevelopmental delay as one of the presenting phenotypes in the Decipher database (https://www.deciphergenomics.org/gene/UPF1/patient-overlap/snvs).

PMID:28539120 (2017) reported a patient with significant intellectual disability (ID) and gross motor delay and with a heterozygous likely pathogenic variant in UPF1 gene (c.1576_1577delinsAA/ p.Ala526Asn). However, this patient also harboured a heterozygous likely pathogenic variant in SQSTM1 gene. As reviewed below by Ivone Leong, the authors suggested that it is plausible that the haploinsufficiency of SQSTM1 may have caused neurofunctional defects, which the haploinsufficiency of UPF1 may have exacerbated.

PMID:39571789 (2024) reported two unrelated paediatric patients with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. They both had language and motor delays and were identified with de novo heterozygous variants in UPF1 gene (c.949_951del/ p.Asp317del & c.1984G>A/ p.Asp662Asn). The p.Asp662Asn variant has also been previously reported in a patient from PMID:28135719.

PMID:39993774 (2025) reported a 17‐year‐old male patient with moderate intellectual disability, atypical autism, ADHD, and aggressivity. He was identified with a de novo missense variant in UPF1 gene - c.1576G>A/ p.Ala526Thr.

As reviewed by Karen Stals, there is an additional patient identified with UPF1 variant in Exeter Genomics Laboratory.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UPF1.
Tag Q3_25_NHS_review tag was added to gene: UPF1.
Intellectual disability v9.87 UPF1 Achchuthan Shanmugasundram Phenotypes for gene: UPF1 were changed from Developmental disorders to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.86 UPF1 Achchuthan Shanmugasundram Publications for gene: UPF1 were set to 33057194; 28539120
Intellectual disability v9.85 UPF1 Achchuthan Shanmugasundram edited their review of gene: UPF1: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071
Intellectual disability v9.85 UPF1 Achchuthan Shanmugasundram reviewed gene: UPF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 28539120, 39571789, 39993774; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.3 PPOX Sharon Whatley reviewed gene: PPOX: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v7.5 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 35584894, 37879139, 11286631, 10870850, 8290408; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mitochondrial disorders v9.26 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 33159949, 38940544, 10486317, 8290408, 38940544, 37879139, 40114189; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v6.82 FLII Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: FLII.
Tag Q3_25_expert_review tag was added to gene: FLII.
Tag Q3_25_NHS_review tag was added to gene: FLII.
Fetal anomalies v6.82 FLII Arina Puzriakova changed review comment from: New gene added to this panel with an Amber rating, inline with the recent review by the R21 Clinical Oversight Group.; to: New gene added to this panel with an Amber rating, inline with the recent review by the R21 Clinical Oversight Group. However, tagging for additional review as this rating contradicts the review comment "Sufficient evidence for gene-disease association and may present prenatally with structural heart defects in some cases" and this gene is tagged for promotion to Green on the R135 Paediatric or syndromic cardiomyopathy panel.
Fetal anomalies v6.82 SIRT6 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: SIRT6.
Tag Q2_25_expert_review was removed from gene: SIRT6.
Fetal anomalies v6.82 C14orf80 Arina Puzriakova commented on gene: C14orf80: Added new-gene-name tag as the latest HGNC symbol for C14orf80 is TEDC1
Fetal anomalies v6.82 C14orf80 Arina Puzriakova Tag new-gene-name tag was added to gene: C14orf80.
Fetal anomalies v6.82 PDE12 Arina Puzriakova Tag Q3_25_expert_review tag was added to gene: PDE12.
Fetal anomalies v6.82 PDE12 Arina Puzriakova changed review comment from: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; to: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group. However, tagging for additional expert review to resolve conflicting reviews - first reviewed as Green by Achchuthan Shanmugasundram but then as Amber by Alice Gardham based on the same evidence.
Fetal anomalies v6.82 NDUFB7 Arina Puzriakova edited their review of gene: NDUFB7: Changed rating: GREEN
Fetal anomalies v6.82 NDUFB7 Arina Puzriakova changed review comment from: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group.; to: Amber rating has been maintained, inline with the recent review by the R21 Clinical Oversight Group. However, tagging for additional expert review to resolve conflicting reviews - first reviewed as Green by me but then as Amber by Vicki Harrison based on the same evidence.
Fetal anomalies v6.82 ITGAV Arina Puzriakova changed review comment from: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.; to: There is sufficient evidence to promote this gene to Green at the next GMS panel update, inline with the recent review by the R21 Clinical Oversight Group.

Previously curated as Amber as only one family had fetal cases reported on; however as noted in Natalie Canham review, all affected individuals have brain anomalies which could be detected prenatally. Therefore this gene can be rated Green.
Fetal anomalies v6.82 FAAP100 Arina Puzriakova Phenotypes for gene: FAAP100 were changed from Fanconi anemia to Fanconi anemia, complementation group X, OMIM:621258
Fetal anomalies v6.81 FAAP100 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: FAAP100.
Tag Q3_25_NHS_review tag was added to gene: FAAP100.
Fetal anomalies v6.81 BORCS5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: BORCS5.
Tag Q3_25_NHS_review tag was added to gene: BORCS5.
Renal tubulopathies v5.6 MAGED2 Arina Puzriakova Phenotypes for gene: MAGED2 were changed from Bartter syndrome, type 5, antenatal, transient, 300971 to Bartter syndrome, type 5, antenatal, transient, OMIM:300971
Fetal anomalies v6.81 MAGED2 Arina Puzriakova Phenotypes for gene: MAGED2 were changed from Bartter syndrome, type 5, antenatal, transient to Bartter syndrome, type 5, antenatal, transient, OMIM:300971
Fetal anomalies v6.80 MAGED2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MAGED2.
Tag Q3_25_NHS_review tag was added to gene: MAGED2.
Fetal anomalies v6.80 ZEB1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ZEB1.
Tag Q3_25_NHS_review tag was added to gene: ZEB1.
Fetal anomalies v6.80 WDR47 Arina Puzriakova Phenotypes for gene: WDR47 were changed from Complex neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.79 WDR47 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: WDR47.
Tag Q3_25_NHS_review tag was added to gene: WDR47.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.42 UNC13D Arina Puzriakova Phenotypes for gene: UNC13D were changed from Hemophagocytic lymphohistiocytosis, familial 3, 608898; FHL3; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); HPLH3; HLH3; Fever, HSM, HLH, cytopenias,; Diseases of Immune Dysregulation to Hemophagocytic lymphohistiocytosis, familial, 3, OMIM:608898
Fetal anomalies v6.79 UNC13D Arina Puzriakova Phenotypes for gene: UNC13D were changed from Hemophagocytic lymphohistiocytosis, familial, 3, OMIM:608898; Hemophagocytic lymphohistiocytosis, familial, 3 to Hemophagocytic lymphohistiocytosis, familial, 3, OMIM:608898
Fetal anomalies v6.78 UNC13D Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: UNC13D.
Tag Q3_25_NHS_review tag was added to gene: UNC13D.
Fetal anomalies v6.78 TCP1 Arina Puzriakova Phenotypes for gene: TCP1 were changed from Intellectual developmental disorder with polymicrogyria and seizures to Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021
Fetal anomalies v6.77 TCP1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: TCP1.
Tag Q3_25_NHS_review tag was added to gene: TCP1.
Fetal anomalies v6.77 STX5 Arina Puzriakova Phenotypes for gene: STX5 were changed from ?Congenital disorder of glycosylation, type IIaa, OMIM:620454; Congenital disorder of glycosylation, type IIaa to Congenital disorder of glycosylation, type IIaa, OMIM:620454
Fetal anomalies v6.76 STX5 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: STX5.
Tag Q3_25_NHS_review tag was added to gene: STX5.
Fetal anomalies v6.76 SRPK3 Arina Puzriakova Phenotypes for gene: SRPK3 were changed from X-linked intellectual developmental disorder-114 to Intellectual developmental disorder, X-linked 114, OMIM:301134
Fetal anomalies v6.75 SRPK3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SRPK3.
Tag Q3_25_NHS_review tag was added to gene: SRPK3.
Fetal anomalies v6.75 SPTA1 Arina Puzriakova Tag watchlist was removed from gene: SPTA1.
Tag Q3_25_promote_green tag was added to gene: SPTA1.
Tag Q3_25_NHS_review tag was added to gene: SPTA1.
Intellectual disability v9.85 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Monogenic short stature v1.23 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Early onset or syndromic epilepsy v8.31 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Severe microcephaly v8.12 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Fetal anomalies v6.75 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Fetal anomalies v6.74 SPOUT1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SPOUT1.
Tag Q3_25_NHS_review tag was added to gene: SPOUT1.
Intellectual disability v9.84 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Early onset or syndromic epilepsy v8.30 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Intellectual disability v9.84 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures (MIM 615553) to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Early onset or syndromic epilepsy v8.29 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures (MIM 615553); Early onset epileptic encephalopathy with skeletal defects to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Likely inborn error of metabolism v8.58 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Congenital disorders of glycosylation v7.5 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures 615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Fetal anomalies v6.74 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Fetal anomalies v6.73 SLC35A3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SLC35A3.
Tag Q3_25_NHS_review tag was added to gene: SLC35A3.
Fetal anomalies v6.73 SLC12A9 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SLC12A9.
Tag Q3_25_NHS_review tag was added to gene: SLC12A9.
Fetal anomalies v6.73 SENP7 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: SENP7.
Tag Q3_25_NHS_review tag was added to gene: SENP7.
Fetal anomalies v6.73 RPL26 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RPL26.
Tag Q3_25_NHS_review tag was added to gene: RPL26.
Fetal anomalies v6.73 RNU5B-1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RNU5B-1.
Tag Q3_25_NHS_review tag was added to gene: RNU5B-1.
Fetal anomalies v6.73 RIPPLY2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RIPPLY2.
Tag Q3_25_NHS_review tag was added to gene: RIPPLY2.
Fetal anomalies v6.73 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter; Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Fetal anomalies v6.72 RAB11B Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: RAB11B.
Tag Q3_25_NHS_review tag was added to gene: RAB11B.
Intellectual disability v9.83 PUS3 Arina Puzriakova Phenotypes for gene: PUS3 were changed from Global developmental delay; Microcephaly; Mental retardation, autosomal recessive 55, 617051; Intellectual disability to Neurodevelopmental disorder with microcephaly and gray sclerae, OMIM:617051
Fetal anomalies v6.72 PUS3 Arina Puzriakova Phenotypes for gene: PUS3 were changed from Neurodevelopmental disorder with microcephaly and gray sclerae to Neurodevelopmental disorder with microcephaly and gray sclerae, OMIM:617051
Fetal anomalies v6.71 PUS3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PUS3.
Tag Q3_25_NHS_review tag was added to gene: PUS3.
Fetal anomalies v6.71 PTEN Arina Puzriakova Phenotypes for gene: PTEN were changed from COWDEN DISEASE; Cowden syndrome 1; LHERMITTE-DUCLOS DISEASE; PROTEUS SYNDROME; MACROCEPHALY/AUTISM SYNDROME; BANNAYAN-ZONANA SYNDROME; VACTERL ASSOCIATION WITH HYDROCEPHALUS to Cowden syndrome 1, OMIM:158350
Fetal anomalies v6.70 PTEN Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PTEN.
Tag Q3_25_NHS_review tag was added to gene: PTEN.
Renal ciliopathies v4.3 PSKH1 Arina Puzriakova Phenotypes for gene: PSKH1 were changed from hepatorenal syndrome, MONDO:0001382 to Cholestasis, progressive familial intrahepatic, 13, OMIM:620962
Cholestasis v3.8 PSKH1 Arina Puzriakova Phenotypes for gene: PSKH1 were changed from hepatorenal syndrome, MONDO:0001382 to Cholestasis, progressive familial intrahepatic, 13, OMIM:620962
Fetal anomalies v6.70 PSKH1 Arina Puzriakova Phenotypes for gene: PSKH1 were changed from hepatorenal syndrome, MONDO:0001382 to Cholestasis, progressive familial intrahepatic, 13, OMIM:620962
Fetal anomalies v6.69 PSKH1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PSKH1.
Tag Q3_25_NHS_review tag was added to gene: PSKH1.
Fetal anomalies v6.69 PPFIBP1 Arina Puzriakova Phenotypes for gene: PPFIBP1 were changed from Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024
Fetal anomalies v6.68 PPFIBP1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PPFIBP1.
Tag Q3_25_NHS_review tag was added to gene: PPFIBP1.
Fetal anomalies v6.68 PPFIA3 Arina Puzriakova Phenotypes for gene: PPFIA3 were changed from Paul-Chao neurodevelopmental syndrome to Paul-Chao neurodevelopmental syndrome, OMIM:621122
Fetal anomalies v6.67 PPFIA3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PPFIA3.
Tag Q3_25_NHS_review tag was added to gene: PPFIA3.
Fetal anomalies v6.67 PLAA Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PLAA.
Tag Q3_25_NHS_review tag was added to gene: PLAA.
Fetal anomalies v6.67 PIGW Arina Puzriakova Phenotypes for gene: PIGW were changed from Glycosylphosphatidylinositol biosynthesis defect 11 to Glycosylphosphatidylinositol biosynthesis defect 11, OMIM:616025
Fetal anomalies v6.66 PIGW Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PIGW.
Tag Q3_25_NHS_review tag was added to gene: PIGW.
Fetal anomalies v6.66 PIGP Arina Puzriakova Phenotypes for gene: PIGP were changed from Developmental and epileptic encephalopathy 55 to Developmental and epileptic encephalopathy 55, OMIM:617599
Fetal anomalies v6.65 PIGP Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PIGP.
Tag Q3_25_NHS_review tag was added to gene: PIGP.
Intellectual disability v9.82 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from MRT53; Mental retardation, autosomal recessive 53, 616917; # 616917 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 53 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Early onset or syndromic epilepsy v8.28 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from Mental retardation, autosomal recessive 53 616917 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Fetal anomalies v6.65 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from Intellectual Disability with Seizures and Hypotonia; Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917; Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Fetal anomalies v6.64 PIGG Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PIGG.
Tag Q3_25_NHS_review tag was added to gene: PIGG.
Fetal anomalies v6.64 PI4KA Arina Puzriakova Phenotypes for gene: PI4KA were changed from Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531; Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis MONDO:0014679; Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Fetal anomalies v6.63 PI4KA Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PI4KA.
Tag Q3_25_NHS_review tag was added to gene: PI4KA.
Fetal anomalies v6.63 PHF5A Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PHF5A.
Tag Q3_25_NHS_review tag was added to gene: PHF5A.
Fetal anomalies v6.63 PAK2 Arina Puzriakova Phenotypes for gene: PAK2 were changed from Knobloch syndrome 2 to Knobloch syndrome 2, OMIM:618458
Fetal anomalies v6.62 PAK2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PAK2.
Tag Q3_25_NHS_review tag was added to gene: PAK2.
Fetal anomalies v6.62 PAICS Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: PAICS.
Tag Q3_25_NHS_review tag was added to gene: PAICS.
Intellectual disability v9.81 ODC1 Arina Puzriakova Phenotypes for gene: ODC1 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Alopecia; Ectodermal dysplasia to Bachmann-Bupp syndrome, OMIM:619075
Fetal anomalies v6.62 ODC1 Arina Puzriakova Phenotypes for gene: ODC1 were changed from Bachmann-Bupp syndrome to Bachmann-Bupp syndrome, OMIM:619075
Fetal anomalies v6.61 ODC1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ODC1.
Tag Q3_25_NHS_review tag was added to gene: ODC1.
Intellectual disability v9.80 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from BOSCH-BOONSTRA OPTIC ATROPHY SYNDROME to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Retinal disorders v8.25 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from Bosch-Boonstra-Schaaf optic atrophy syndrome, 615722 to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Optic neuropathy v5.24 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from Bosch-Boonstra-Schaaf optic atrophy syndrome, 615722 to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Fetal anomalies v6.61 NR2F1 Arina Puzriakova Phenotypes for gene: NR2F1 were changed from BOSCH-BOONSTRA OPTIC ATROPHY SYNDROME; Bosch-Boonstra-Schaaf optic atrophy syndrome to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722
Fetal anomalies v6.60 NR2F1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: NR2F1.
Tag Q3_25_NHS_review tag was added to gene: NR2F1.
Fetal anomalies v6.60 NEXN Arina Puzriakova Tag watchlist was removed from gene: NEXN.
Tag Q3_25_promote_green tag was added to gene: NEXN.
Tag Q3_25_NHS_review tag was added to gene: NEXN.
Fetal anomalies v6.60 NEPRO Arina Puzriakova commented on gene: NEPRO: The 'new-gene-name' tag has been added to this gene as the latest HGNC gene symbol for NEPRO is RMP64.
Fetal anomalies v6.60 NEPRO Arina Puzriakova Tag new-gene-name tag was added to gene: NEPRO.
Tag Q3_25_promote_green tag was added to gene: NEPRO.
Tag Q3_25_NHS_review tag was added to gene: NEPRO.
Fetal anomalies v6.60 MSL2 Arina Puzriakova Phenotypes for gene: MSL2 were changed from Karayol-Borroto-Haghshenas neurodevelopmental syndrome to Karayol-Borroto-Haghshenas neurodevelopmental syndrome, OMIM:620985
Fetal anomalies v6.59 MIA3 Arina Puzriakova Tag Q3_25_NHS_review tag was added to gene: MIA3.
Fetal anomalies v6.59 MSL2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MSL2.
Tag Q3_25_NHS_review tag was added to gene: MSL2.
Skeletal dysplasia v8.9 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from short stature; skeletal dysplasia; amelogenesis; dentinogenesis imperfecta; short stature; brachydactyly; Platyspondyly; insulin-dependent diabetes mellitus; sensorineural hearing loss; mild intellectual disability to Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.59 MIA3 Arina Puzriakova Phenotypes for gene: MIA3 were changed from Odontochondrodysplasia-2 with hearing loss and diabetes to Ondontochondrodysplasia 2 with hearing loss and diabetes, OMIM:619269
Fetal anomalies v6.58 MIA3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MIA3.
Fetal anomalies v6.58 MED11 Arina Puzriakova Phenotypes for gene: MED11 were changed from Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, OMIM:620327
Fetal anomalies v6.57 MED11 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MED11.
Tag Q3_25_NHS_review tag was added to gene: MED11.
Intellectual disability v9.79 MAPK1 Arina Puzriakova Phenotypes for gene: MAPK1 were changed from Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin to Noonan syndrome 13, OMIM:619087
Fetal anomalies v6.57 MAPK1 Arina Puzriakova Phenotypes for gene: MAPK1 were changed from Noonan syndrome 13; Noonan syndrome 13, OMIM:619087 to Noonan syndrome 13, OMIM:619087
Fetal anomalies v6.56 MAPK1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: MAPK1.
Tag Q3_25_NHS_review tag was added to gene: MAPK1.
Fetal anomalies v6.56 LSS Arina Puzriakova Phenotypes for gene: LSS were changed from Cataract 44; Alopecia-intellectual disability syndrome 4 to Alopecia-intellectual disability syndrome 4, OMIM:618840; Cataract 44, OMIM:616509
Fetal anomalies v6.55 LSS Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LSS.
Tag Q3_25_NHS_review tag was added to gene: LSS.
Fetal anomalies v6.55 LGI3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LGI3.
Tag Q3_25_NHS_review tag was added to gene: LGI3.
Fetal anomalies v6.55 LDB1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LDB1.
Tag Q3_25_NHS_review tag was added to gene: LDB1.
Proteinuric renal disease v5.2 LAGE3 Arina Puzriakova Phenotypes for gene: LAGE3 were changed from Galloway-Mowat syndrome 2, X-linked #301006 to Galloway-Mowat syndrome 2, X-linked, OMIM:301006
Fetal anomalies v6.55 LAGE3 Arina Puzriakova Phenotypes for gene: LAGE3 were changed from Galloway-Mowat syndrome 2, X-linked; Galloway-Mowat syndrome 2, X-linked, OMIM:301006 to Galloway-Mowat syndrome 2, X-linked, OMIM:301006
Fetal anomalies v6.54 LAGE3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: LAGE3.
Tag Q3_25_NHS_review tag was added to gene: LAGE3.
Fetal anomalies v6.54 C12orf66 Arina Puzriakova commented on gene: C12orf66: Added new-gene-name tag, new approved HGNC gene symbol for C12orf66 is KICS2
Fetal anomalies v6.54 C12orf66 Arina Puzriakova Tag new-gene-name tag was added to gene: C12orf66.
Tag Q3_25_promote_green tag was added to gene: C12orf66.
Tag Q3_25_NHS_review tag was added to gene: C12orf66.
Fetal anomalies v6.54 C12orf66 Arina Puzriakova Phenotypes for gene: C12orf66 were changed from Intellectual developmental disorder, autosomal recessive 83 to Intellectual developmental disorder, autosomal recessive 83, OMIM:621100
Fetal anomalies v6.53 ITGAV Arina Puzriakova Phenotypes for gene: ITGAV were changed from syndromic disease, MONDO:0002254; Syndromic disease, MONDO:0002254 to Syndromic disease, MONDO:0002254
Fetal anomalies v6.52 ITGAV Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: ITGAV.
Tag Q3_25_NHS_review tag was added to gene: ITGAV.
Renal ciliopathies v4.2 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, OMIM:615996 to Bardet-Biedl syndrome 19, OMIM:615996
Ophthalmological ciliopathies v5.4 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, 615996 to Bardet-Biedl syndrome 19, OMIM:615996
Fetal anomalies v6.52 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from Bardet-Biedl syndrome 19, OMIM:615996; Bardet-Biedl syndrome 19 to Bardet-Biedl syndrome 19, OMIM:615996
Intellectual disability v9.78 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from Bardet-Biedl syndrome 19, MIM#615996 to Bardet-Biedl syndrome 19, OMIM:615996
Rare multisystem ciliopathy disorders v1.175 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, 615996 to Bardet-Biedl syndrome 19, OMIM:615996
Retinal disorders v8.24 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, OMIM:615996 to Bardet-Biedl syndrome 19, OMIM:615996
Bardet Biedl syndrome v2.8 IFT27 Arina Puzriakova Phenotypes for gene: IFT27 were changed from ?Bardet-Biedl syndrome 19, 615996 to Bardet-Biedl syndrome 19, OMIM:615996
Fetal anomalies v6.51 IFT27 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: IFT27.
Tag Q3_25_NHS_review tag was added to gene: IFT27.
Fetal anomalies v6.51 HNRNPU Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: HNRNPU.
Tag Q3_25_NHS_review tag was added to gene: HNRNPU.
Intellectual disability v9.77 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy, early infantile, 54, 617391; intellectual disability to Developmental and epileptic encephalopathy 54, OMIM:617391
Early onset or syndromic epilepsy v8.27 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 54, 617391 to Developmental and epileptic encephalopathy 54, OMIM:617391
Fetal anomalies v6.51 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from EPILEPTIC ENCEPHALOPATHY; Developmental and epileptic encephalopathy 54 to Developmental and epileptic encephalopathy 54, OMIM:617391
Fetal anomalies v6.50 HDAC3 Arina Puzriakova Phenotypes for gene: HDAC3 were changed from HDAC3-related neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.49 HDAC3 Arina Puzriakova Tag gene-checked tag was added to gene: HDAC3.
Fetal anomalies v6.49 HDAC3 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: HDAC3.
Tag Q3_25_NHS_review tag was added to gene: HDAC3.
Fetal anomalies v6.49 GNAI2 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GNAI2.
Tag Q3_25_NHS_review tag was added to gene: GNAI2.
Intellectual disability v9.76 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Galactosemia, 230400; GALACTOSEMIA (GALCT) to Galactosemia, OMIM:230400
Fetal anomalies v6.49 GEMIN4 Arina Puzriakova Phenotypes for gene: GEMIN4 were changed from Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities to Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, OMIM:617913
Fetal anomalies v6.48 GEMIN4 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GEMIN4.
Tag Q3_25_NHS_review tag was added to gene: GEMIN4.
Likely inborn error of metabolism v8.57 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Intellectual disability; Classical galactosaemia (Disorders of galactose metabolism); Galactosemia; Cataracts to Galactosemia, OMIM:230400
Undiagnosed metabolic disorders v1.632 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Classical galactosaemia (Disorders of galactose metabolism); Cataracts; Intellectual disability; Galactosemia 230400 to Galactosemia, OMIM:230400
Bilateral congenital or childhood onset cataracts v7.2 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Confirmed DD gene for galactosemia to Galactosemia, OMIM:230400
Fetal anomalies v6.48 GALT Arina Puzriakova Phenotypes for gene: GALT were changed from Galactosemia; GALACTOSEMIA to Galactosemia, OMIM:230400
Fetal anomalies v6.47 GALT Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: GALT.
Tag Q3_25_NHS_review tag was added to gene: GALT.
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova changed review comment from: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the complex infantile-onset disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber but this gene should be promoted to Green at the next GMS panel update on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v8.21
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova gene: EXOSC8 was added
gene: EXOSC8 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review Amber
Q3_25_promote_green tags were added to gene: EXOSC8.
Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC8 were set to 24989451; 38017281; 34210538
Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Cerebellar hypoplasia v1.78 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Green List (high evidence)
Cerebellar hypoplasia v1.78 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.
Cerebellar hypoplasia v1.78 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.77 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to
Cerebellar hypoplasia v1.76 EXOSC8 Arina Puzriakova Mode of inheritance for gene: EXOSC8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.75 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451, 38017281, 34210538; Phenotypes: Pontocerebellar hypoplasia, type 1C, OMIM:616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v8.10 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Green List (high evidence)
Hereditary ataxia with onset in adulthood v8.10 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red on this panel.

There are currently five reported families with biallelic variants in this gene, all presenting with an infantile-onset disorder (latest reported age of onset is 6 months) (PMIDs: 24989451; 38017281; 34210538). Motor dysfunction is a prominent feature, although it does not overtly manifest as ataxia. Nevertheless, this gene has been added to the 'Ataxia and cerebellar anomalies - narrow panel' due to the presence of cerebellar hypoplasia in affected individuals, and because the early age of onset aligns more closely with that panel.
Hereditary ataxia with onset in adulthood v8.10 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Green List (High Evidence).
Hereditary ataxia with onset in adulthood v8.9 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to
Hereditary ataxia with onset in adulthood v8.8 EXOSC8 Arina Puzriakova Tag Q3_25_demote_red tag was added to gene: EXOSC8.
Ataxia and cerebellar anomalies - narrow panel v8.21 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.21 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but this gene should be promoted to Green at the next GMS panel update on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.
Ataxia and cerebellar anomalies - narrow panel v8.21 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.20 EXOSC8 Arina Puzriakova Mode of inheritance for gene: EXOSC8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.19 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to
Ataxia and cerebellar anomalies - narrow panel v8.18 EXOSC8 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: EXOSC8.
Ataxia and cerebellar anomalies - narrow panel v8.18 EXOSC8 Arina Puzriakova reviewed gene: EXOSC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 24989451, 38017281, 34210538; Phenotypes: Pontocerebellar hypoplasia, type 1C, OMIM:616081; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.75 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to 24989451; 38017281; 34210538
Intellectual disability v9.74 EXOSC8 Arina Puzriakova Publications for gene: EXOSC8 were set to 24989451; 29656927
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Classified gene: EXOSC8 as Amber List (moderate evidence)
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel update - 5 unrelated families with pontocerebellar hypoplasia due to biallelic variants in this gene. Almost all described patients exhibited psychomotor retardation (PMIDs: 24989451; 38017281; 34210538)
Intellectual disability v9.73 EXOSC8 Arina Puzriakova Gene: exosc8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Tag founder-effect tag was added to gene: EXOSC8.
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Tag watchlist was removed from gene: EXOSC8.
Tag founder-effect was removed from gene: EXOSC8.
Tag Q3_25_promote_green tag was added to gene: EXOSC8.
Intellectual disability v9.72 EXOSC8 Arina Puzriakova edited their review of gene: EXOSC8: Added comment: PMID: 34210538 (2021) - 16-year-old Spanish boy with cerebellar and spinal muscular atrophy, spasticity, psychomotor retardation, nystagmus, ophthalmoparesis, epilepsy, and mitochondrial respiratory chain (MRC) deficiency. The phenotype was described as milder compared to previous cases. WES revealed three variants in the EXOSC8 gene (c.[390+1delG];[628C>T;815G>C]) which lead to reduced mRNA expression and protein levels.

PMID: 38017281 (2024) - Homozygous missense variant c.238G>A;p.Val80Ile causing exon skipping in a patient with psychomotor retardation, spasticity, spinal muscle atrophy, respiratory problems, diaphragmatic hernia, dilated lateral ventricles, hypoplastic temporal lobes, thinning of the brain stem, dysmorphic facies, nystagmus, congenital esotropia and contractures.; Changed rating: GREEN; Changed publications to: 24989451, 38017281, 34210538
Intellectual disability v9.72 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 37879139,40114189, 33159949, 35164799, 9811936, 8290408, 2004012, 6143163; Phenotypes: 620483; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.72 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Intellectual disability v9.71 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, OMIM:616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Hereditary neuropathy v1.500 PPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP).
PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy.
PMID:11286631 Kauppinen reports a patient who following birth presented with severe bullous skin disease followed by increased fragility and keloid-like scarring. His fingers were shortened. Mental status, EEG, and CT of the head were normal, but sensory polyneuropathy was shown in especially in the upper extremities. Fine motor coordination disturbances were accompanied by minor verbal and visuospatial deficiencies. DNA from the patient showed that he is compound heterozygous for PPOX: c.35T>C, p.(Ile12Thr) and c.767C>G, p.(Pro256Arg).
PMID:10870850 Corrigall reports a 10-month-old child with fragile skin with blisters, scars, and milia most marked in sun-exposed areas. She had brachydactyly, photo-onycholysis, myopia, nystagmus, a sensory neuropathy and problems with concentration. She never had a typical acute attack. Genetic analysis showed that this patient was compound heterozygous for PPOX c.175C>T, p.(Arg59Trp) and c.1043A>G, p.(Tyr348Cys).
PMID: 8290408 Hift reports child who within days of birth developed severe blistering of the face and hands. She had brachydactyly, severe myopia and a pendular nystagmus. Neurological development was delayed with normal intelligence. She had gross sensory neuropathy of the hands and feet but no acute attacks.
Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.; to: Relevant metabolic investigation: urine porphobilinogen (to be completed before genetic testing for diagnosis of an acute porphyric attack) plasma porphyrin fluorescence emission (homozygous VP).
PMID: 38940544 Aarsand reports that variegate porphyria (VP) is an autosomal dominant disorder and estimates that individuals with a predisposition for VP in the general population is 1/3,000 (except where founder effects occur e.g. South Africa). A rough estimate of the penetrance of pathogenic variants in this gene is given as 1%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that VP is diagnosed using biochemical tests (urine porphobilinogen during an acute attack followed by plasma fluorescence emission or if the patient only has cutaneous symptoms plasma porphyrin fluorescence) as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.
PMID: 37879139 Assaleh reports that biallelic VP is rare. To the best of our knowledge there are 25 patients (in 21 families) reported with homozygous VP (40114189 Kaiser 37879139 Assaleh, 33159949 Cho and references therein). It usually presents in infancy with severe cutaneous manifestations. Three of these patients (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift) had sensory neuropathy, as reported by the previous reviewer.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the PPOX gene, due to its low clinical penetrance.
Hereditary neuropathy v1.500 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38940544, 35584894, 37879139, 11286631, 10870850, 8290408; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.8 PPOX Sharon Whatley reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 33159949, 38940544, 10486317, 8290408, 37879139, 40114189; Phenotypes: 176200, 620483; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v9.70 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia, type 1C, MIM#616081 to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Hereditary ataxia with onset in adulthood v8.8 EXOSC8 Arina Puzriakova Phenotypes for gene: EXOSC8 were changed from Pontocerebellar hypoplasia type 1C to Pontocerebellar hypoplasia, type 1C, OMIM:616081