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Tubulointerstitial kidney disease v3.33 MT-TV Una Conka-Priedeslaipa gene: MT-TV was added
gene: MT-TV was added to Tubulointerstitial kidney disease. Sources: Literature
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Publications for gene: MT-TV were set to https://www.sciencedirect.com/science/article/pii/S246802492602810X
Added comment: In 27,747 participants from the Mount Sinai Million Health Discoveries Program, an ancestrally diverse biobank with whole-exome sequencing and linked electronic health records, the MT-TV m.1630A>G variant was observed in 4 individuals with kidney disease and 6 without kidney disease and was significantly associated with kidney disease risk (OR = 5.63, 95% CI: 1.28–22.89, P = 0.016).
Sources: Literature
Familial melanoma v2.5 CHEK2 Riyaad Aungraheeta gene: CHEK2 was added
gene: CHEK2 was added to Familial melanoma. Sources: Literature
Mode of inheritance for gene: CHEK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CHEK2 were set to PMID: 42177185
Phenotypes for gene: CHEK2 were set to Mucosal melanoma
Review for gene: CHEK2 was set to AMBER
Added comment: The CHEK2 c.1100delC variant was enriched in this retrospective cohort of mucosal melanoma patients compared to population controls (OR 6.7; 95% CI 1.8–17.5).
Sources: Literature
Familial melanoma v2.5 MITF Riyaad Aungraheeta gene: MITF was added
gene: MITF was added to Familial melanoma. Sources: Literature
Mode of inheritance for gene: MITF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MITF were set to PMID: 42177185
Phenotypes for gene: MITF were set to Mucosal melanoma
Review for gene: MITF was set to AMBER
Added comment: The MITF E318K variant was enriched in this retrospective cohort of mucosal melanoma patients compared to population controls (OR 6.0; 95% CI 2.2–13.2).
Sources: Literature
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram changed review comment from: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).; to: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia. The siblings died after 3 and 5 days after birth.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram Classified gene: CNTN1 as Amber List (moderate evidence)
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are two unrelated families reported with biallelic CNTN1 variants, myopathy was only reported in one. The siblings from the second family died after 3 and 5 days after birth. Both families were reported with fetal akinesia. There is also functional evidence available from cntn1 null mouse which showed progressive muscle weakness. Hence, this gene can only be rated amber on this panel with current evidence (one family and functional evidence).
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.35 CNTN1 Achchuthan Shanmugasundram Phenotypes for gene: CNTN1 were changed from Myopathy, congenital, Compton-North, OMIM:612540 to Congenital myopathy 12, OMIM:612540
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram edited their review of gene: CNTN1: Changed publications to: 19026398, 32779773; Changed phenotypes to: Congenital myopathy 12, OMIM:612540
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram changed review comment from: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).; to: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram edited their review of gene: CNTN1: Changed rating: AMBER
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram Deleted their comment
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram commented on gene: CNTN1: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram reviewed gene: CNTN1: Rating: GREEN; Mode of pathogenicity: None; Publications: Congenital myopathy 12, OMIM:612540; Phenotypes: 19026398, 32779773; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.13 HMGCS1 Achchuthan Shanmugasundram Classified gene: HMGCS1 as Amber List (moderate evidence)
Skeletal dysplasia v9.13 HMGCS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with biallelic HMGCS1 variants and with congenital myopathy with rigid spine. All cases also had scoliosis. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Skeletal dysplasia v9.13 HMGCS1 Achchuthan Shanmugasundram Gene: hmgcs1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.12 HMGCS1 Achchuthan Shanmugasundram gene: HMGCS1 was added
gene: HMGCS1 was added to Skeletal dysplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: HMGCS1.
Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCS1 were set to 39531736
Phenotypes for gene: HMGCS1 were set to Congenital myopathy 28 with rigid spine, OMIM:621433; congenital myopathy 28 with rigid spine, MONDO:0980756
Review for gene: HMGCS1 was set to GREEN
Added comment: PMID:39531736 (2025) reported biallelic variants in HMGCS1 gene identified via whole exome and genome sequencing in five patients from four unrelated families with rigid spine syndrome. The identified variants included 6 missense variants and one 2-basepair deletion resulting in a frameshift and early termination. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated and muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.

Three of the four functionally analysed variants exhibited reduced thermal stability, and two of them showed subtle changes in enzymatic activity compared to the wildtype. Hmgcs1 mutant zebrafish displayed severe early defects and the four variants tested have reduced function compared to wild-type HMGCS1 in zebrafish rescue assays. In addition, potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish was also demonstrated.

This gene has been associated with relevant phenotype in OMIM (MIM #62143) and the OMIM record was last accessed on 28 May 2026.
Sources: Literature
Clefting v7.5 JPH1 Achchuthan Shanmugasundram Classified gene: JPH1 as Amber List (moderate evidence)
Clefting v7.5 JPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are four unrelated patients reported with congenital myopathy and biallelic JPH1 variants, only two of them were reported with cleft palate as one of the phenotypes. Hence, this gene can only be rated amber with the current evidence.
Clefting v7.5 JPH1 Achchuthan Shanmugasundram Gene: jph1 has been classified as Amber List (Moderate Evidence).
Clefting v7.4 JPH1 Achchuthan Shanmugasundram gene: JPH1 was added
gene: JPH1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy 25, OMIM:620964; congenital myopathy 25, MONDO:0975808
Review for gene: JPH1 was set to AMBER
Added comment: PMID:39209426 (2024) reported four unrelated patients with congenital myopathy and they had similar clinical presentation with prominent facial, ocular and bulbar features. The disease onset was in neonatal period and had hypotonia, poor feeding, cleft palate and talipes. Four different homozygous loss-of-function variants were reported in these patients either by whole-exome or whole-genome sequencing. Cleft palate was reported in two of these patients and arched palate in one.

This gene has been associated with relevant phenotypes in OMIM (MIM #620964, last accessed 28 May 2026) and in Gene2Phenotype (with 'moderate' confidence rating on the DD panel).
Sources: Literature
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: JPH1.
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Classified gene: JPH1 as Amber List (moderate evidence)
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with congenital myopathy and biallelic JPH1 variants. All patients had spine involvement (kyphoscoliosis, scoliosis or lumbar lordosis). Hence, this gene can be promoted to green rating on Skeletal dysplasia panel in the next GMS update.
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Gene: jph1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.10 JPH1 Achchuthan Shanmugasundram edited their review of gene: JPH1: Changed rating: GREEN
Skeletal dysplasia v9.10 JPH1 Achchuthan Shanmugasundram gene: JPH1 was added
gene: JPH1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy 25, OMIM:620964; congenital myopathy 25, MONDO:0975808
Review for gene: JPH1 was set to AMBER
Added comment: PMID:39209426 (2024) reported four unrelated patients with congenital myopathy and they had similar clinical presentation with prominent facial, ocular and bulbar features. The disease onset was in neonatal period and had hypotonia, poor feeding, cleft palate and talipes. Four different homozygous loss-of-function variants were reported in these patients either by whole-exome or whole-genome sequencing. Kyphoscoliosis and rigid spine was reported in patient 1, dorsal scoliosis, lumbar lordosis and winged scapulae in patient 2, mild lumbar lordosis in patient 3 and mild scoliosis in patient 4.

This gene has been associated with relevant phenotypes in OMIM (MIM #620964, last accessed 28 May 2026) and in Gene2Phenotype (with 'moderate' confidence rating on the DD panel).
Sources: Literature
Congenital myopathy v7.34 JPH1 Achchuthan Shanmugasundram Classified gene: JPH1 as Amber List (moderate evidence)
Congenital myopathy v7.34 JPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated individuals with Congenital myopathy 25 and with biallelic JPH1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Congenital myopathy v7.34 JPH1 Achchuthan Shanmugasundram Gene: jph1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.33 JPH1 Achchuthan Shanmugasundram Phenotypes for gene: JPH1 were changed from to Congenital myopathy 25, OMIM:620964; congenital myopathy 25, MONDO:0975808
Congenital myopathy v7.32 JPH1 Achchuthan Shanmugasundram Publications for gene: JPH1 were set to
Congenital myopathy v7.31 JPH1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: JPH1.
Tag Q2_26_NHS_review tag was added to gene: JPH1.
Congenital myopathy v7.31 JPH1 Achchuthan Shanmugasundram reviewed gene: JPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39209426; Phenotypes: Congenital myopathy 25, OMIM:620964, congenital myopathy 25, MONDO:0975808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.31 HMGCS1 Achchuthan Shanmugasundram Classified gene: HMGCS1 as Amber List (moderate evidence)
Congenital myopathy v7.31 HMGCS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Anna Sarkozy, there is sufficient evidence available (four unrelated families and functional evidence) for the association of biallelic HMGCS1 variants with congenital myopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Congenital myopathy v7.31 HMGCS1 Achchuthan Shanmugasundram Gene: hmgcs1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.30 HMGCS1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: HMGCS1.
Tag Q2_26_NHS_review tag was added to gene: HMGCS1.
Congenital myopathy v7.30 HMGCS1 Achchuthan Shanmugasundram Phenotypes for gene: HMGCS1 were changed from to Congenital myopathy 28 with rigid spine, OMIM:621433; congenital myopathy 28 with rigid spine, MONDO:0980756
Congenital myopathy v7.29 HMGCS1 Achchuthan Shanmugasundram Publications for gene: HMGCS1 were set to
Congenital myopathy v7.28 HMGCS1 Achchuthan Shanmugasundram reviewed gene: HMGCS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39531736; Phenotypes: Congenital myopathy 28 with rigid spine, OMIM:621433, congenital myopathy 28 with rigid spine, MONDO:0980756; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.28 CACNA1H Achchuthan Shanmugasundram Classified gene: CACNA1H as Amber List (moderate evidence)
Congenital myopathy v7.28 CACNA1H Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are three unrelated individuals reported with biallelic CACNA1H variants so far, only one of them was reported with congenital amyotrophy/ myopathy. There is also functional evidence available in support of the association. Hence, this gene can only be rated amber with current evidence on this panel.
Congenital myopathy v7.28 CACNA1H Achchuthan Shanmugasundram Gene: cacna1h has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.27 CACNA1H Achchuthan Shanmugasundram Publications for gene: CACNA1H were set to
Congenital myopathy v7.26 CACNA1H Achchuthan Shanmugasundram Mode of inheritance for gene: CACNA1H was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 CACNA1H Achchuthan Shanmugasundram reviewed gene: CACNA1H: Rating: AMBER; Mode of pathogenicity: None; Publications: 25773295, 31070086, 41272325; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska changed review comment from: PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025
Lit review of 322 cases with non-syndromic dentinogenesis imperfecta (DI - characterized clinically by amber or gray-yellow opalescent tooth discoloration, obliteration of pulp chambers and root canals, and attrition. Both deciduous and permanent teeth are affected (PMID: 18456718 Song et al., 2008).
DSPP mutations were the most frequent, with with 59 documented variants from 37 publications. 34/59 variants were in exon 5 of DSPP.
Sources: Literature; to: PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025
Lit review of 322 cases with non-syndromic dentinogenesis imperfecta (DI - characterized clinically by amber or gray-yellow opalescent tooth discoloration, obliteration of pulp chambers and root canals, and attrition. Both deciduous and permanent teeth are affected (PMID: 18456718 Song et al., 2008)).
DSPP mutations were the most frequent, with 59 documented variants from 37 publications. 34/59 variants were in exon 5 of DSPP.
Sources: Literature
Optic neuropathy v6.42 MT-ATP6 Achchuthan Shanmugasundram Tag Q2_26_expert_review tag was added to gene: MT-ATP6.
Optic neuropathy v6.42 MT-ATP6 Achchuthan Shanmugasundram Phenotypes for gene: MT-ATP6 were changed from Leber optic atrophy; 535000; neurogenic weakness, ataxia, and retinitis pigmentosa; retinopathy; NARP syndrome, MONDO:0010794 to NARP syndrome, MONDO:0010794
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska changed review comment from: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are common and homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.; to: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are common and homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska changed review comment from: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.; to: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are common and homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska changed review comment from: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes. Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.; to: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska commented on gene: MT-ATP6: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes. Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska Phenotypes for gene: MT-ATP6 were changed from Leber optic atrophy; 535000; neurogenic weakness, ataxia, and retinitis pigmentosa; retinopathy to Leber optic atrophy; 535000; neurogenic weakness, ataxia, and retinitis pigmentosa; retinopathy; NARP syndrome, MONDO:0010794
Optic neuropathy v6.40 MT-ATP6 Ida Ertmanska Publications for gene: MT-ATP6 were set to 7726182; 10676807; 26448634; 26252090; 24118886 (functional evidence); 23266623
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska Tag Q2_26_demote_red tag was added to gene: MT-ATP6.
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska edited their review of gene: MT-ATP6: Changed phenotypes to: NARP syndrome, MONDO:0010794
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska edited their review of gene: MT-ATP6: Changed rating: RED; Changed publications to: 7726182, 24986921, 26252090, 26448634, 41234160; Changed mode of inheritance: MITOCHONDRIAL
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 26252090 Gao et al., 2015
Report of two Chinese families with Leber's hereditary optic neuropathy, with penetrance of 12.5% and 30.0% in the two families. Only mitochondrial genome was sequenced - this detected homoplasmic T8821G mutation in MT-ATP6, and distinct sets of polymorphisms belonging to haplogroups M10a.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.; to: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 26448634 Widgren et al., 2015
Nine rare mutations in MT-ATP6 were identified in seven patients, of whom four manifested with retinopathy and three had clusters of MT-ATP6 mutations.
Variant m.8842A>G (MT-ATP6) found in an optic neuropathy patient (haplogroup H2). 2 other MT-ATP6 variants found in nystagmus cohort, and 4 other variants were unique to the retinal degeneration group. The m.8842A>G was not predicted to affect protein function. 128/56430 individuals are homoplasmic in gnomAD v3.1.2 (most in haplogroup H) - B/LB in ClinVar.

PMID: 26252090 Gao et al., 2015
Report of two Chinese families with Leber's hereditary optic neuropathy, with penetrance of 12.5% and 30.0% in the two families. Only mitochondrial genome was sequenced - this detected homoplasmic T8821G mutation in MT-ATP6, and distinct sets of polymorphisms belonging to haplogroups M10a.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.; to: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 26252090 Gao et al., 2015
Report of two Chinese families with Leber's hereditary optic neuropathy, with penetrance of 12.5% and 30.0% in the two families. Only mitochondrial genome was sequenced - this detected homoplasmic T8821G mutation in MT-ATP6, and distinct sets of polymorphisms belonging to haplogroups M10a.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska commented on gene: MT-ATP6
Optic neuropathy v6.39 NDUFS1 Ida Ertmanska Publications for gene: NDUFS1 were set to
Optic neuropathy v6.38 NDUFS1 Ida Ertmanska Phenotypes for gene: NDUFS1 were changed from Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226 to Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226
Optic neuropathy v6.37 NDUFS1 Ida Ertmanska Classified gene: NDUFS1 as Amber List (moderate evidence)
Optic neuropathy v6.37 NDUFS1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases reported with biallelic NDUFS1 variants and optic neuropathy (LHON-like or syndromic CI-deficiency presentation). Hence, this gene should be promoted to Green at the next update.
Optic neuropathy v6.37 NDUFS1 Ida Ertmanska Gene: ndufs1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.36 NDUFS1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFS1.
Optic neuropathy v6.36 NDUFS1 Ida Ertmanska reviewed gene: NDUFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11349233, 39423307; Phenotypes: Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska changed review comment from: Saada et al., 2012 PMID: 21607760
P1 - Male, Ashkenazi Jewish ancestry - diagnosed with Leigh syndrome, optic atrophy noted at 26 months. Homozygous for NDUFAF5:c.749G>T, p.Gly250Val.

Simon et al., 2020, PMID: 30473481
P2 - Female, Taiwanese descent - presented at twenty-seven months of age with strabismus, followed by ptosis and vomiting during an intercurrent illness. Ophthalmological testing at 7yrs old revealed nystagmus as well as optic neuritis.

Mansukhani et al. 2021, PMID: 32918965
Proband with LHONplus phenotype, compound het for nonsense & missense variants.

Chen et al. 2024, PMID: 36580434
Proband with LHON-like phenotype with cognitive impairment, hom for frameshift NDUFAF5 variant c.1004_1007del, p.N335Tfs*37 (asymptomatic parents both het).
Sources: Literature; to: Saada et al., 2012 PMID: 21607760
P1 - Male, Ashkenazi Jewish ancestry - diagnosed with Leigh syndrome, optic atrophy noted at 26 months. Homozygous for NDUFAF5:c.749G>T, p.Gly250Val.

Simon et al., 2020, PMID: 30473481
P2 - Female, Taiwanese descent - presented at twenty-seven months of age with strabismus, followed by ptosis and vomiting during an intercurrent illness. Ophthalmological testing at 7yrs old revealed nystagmus as well as optic neuritis.

Mansukhani et al. 2021, PMID: 32918965
Proband with LHONplus phenotype, compound het for nonsense & missense variants in NDUFAF5: c.24G>A, p.(Trp8*) and c.827G>A, p.(Arg276Gln),

Chen et al. 2024, PMID: 36580434
Proband with LHON-like phenotype with cognitive impairment, hom for frameshift NDUFAF5 variant c.1004_1007del, p.N335Tfs*37 (asymptomatic parents both het).

NDUFAF5 is associated with AR Mitochondrial complex I deficiency, nuclear type 16, OMIM:618238 (accessed 27th May 2026).
Sources: Literature
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska Classified gene: NDUFAF5 as Amber List (moderate evidence)
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska Added comment: Comment on list classification: There are at least 4 unrelated probands reported in literature with biallelic NDUFAF5 variants and optic neuropathy (LHON-like or (Leigh-like presentation). Hence, this gene should be promoted to Green on Optic neuropathy.
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska Gene: ndufaf5 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.35 NDUFAF5 Ida Ertmanska gene: NDUFAF5 was added
gene: NDUFAF5 was added to Optic neuropathy. Sources: Literature
Q2_26_promote_green tags were added to gene: NDUFAF5.
Mode of inheritance for gene: NDUFAF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF5 were set to 21607760; 30473481; 32918965; 36580434
Phenotypes for gene: NDUFAF5 were set to Mitochondrial complex I deficiency, nuclear type 16, OMIM:618238
Review for gene: NDUFAF5 was set to GREEN
Added comment: Saada et al., 2012 PMID: 21607760
P1 - Male, Ashkenazi Jewish ancestry - diagnosed with Leigh syndrome, optic atrophy noted at 26 months. Homozygous for NDUFAF5:c.749G>T, p.Gly250Val.

Simon et al., 2020, PMID: 30473481
P2 - Female, Taiwanese descent - presented at twenty-seven months of age with strabismus, followed by ptosis and vomiting during an intercurrent illness. Ophthalmological testing at 7yrs old revealed nystagmus as well as optic neuritis.

Mansukhani et al. 2021, PMID: 32918965
Proband with LHONplus phenotype, compound het for nonsense & missense variants.

Chen et al. 2024, PMID: 36580434
Proband with LHON-like phenotype with cognitive impairment, hom for frameshift NDUFAF5 variant c.1004_1007del, p.N335Tfs*37 (asymptomatic parents both het).
Sources: Literature
Optic neuropathy v6.34 NDUFB11 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is associated with AR ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is associated with XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).
Optic neuropathy v6.34 NDUFS2 Ida Ertmanska Phenotypes for gene: NDUFS2 were changed from Mitochondrial complex I deficiency, nuclear type 6, 618228 to Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228; ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569
Optic neuropathy v6.33 NDUFS2 Ida Ertmanska Publications for gene: NDUFS2 were set to 28031252
Optic neuropathy v6.32 NDUFS2 Ida Ertmanska Classified gene: NDUFS2 as Amber List (moderate evidence)
Optic neuropathy v6.32 NDUFS2 Ida Ertmanska Added comment: Comment on list classification: There are at least 5 unrelated families with biallelic NDUFS2 variants and optic atrophy (LHON-like or Leigh-like presentation). Hence, this gene should be promoted to Green at the next update.
Optic neuropathy v6.32 NDUFS2 Ida Ertmanska Gene: ndufs2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.31 NDUFS2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFS2.
Optic neuropathy v6.31 NDUFS2 Ida Ertmanska changed review comment from: Loeffen et al. 2001, PMID: 11220739: 3 families with AR NDUFS2-related CI deficiency; in 2 of these families, symptoms included OA.

Gerber et al. 2017, PMID: 28031252: one family with 3 affected siblings with LHON-like phenotype, compound het for missense variants.

Fiorini et al. 2023, PMID: 36913248: listed in table (1 French family), but likely corresponds Gerber et al. 2017.

NDUFS2 is associated with AR Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228 and AR ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569 in OMIM (accessed 27th May 2026).; to: Loeffen et al. 2001, PMID: 11220739: 3 families with AR NDUFS2-related CI deficiency; in 2 of these families, symptoms included OA, third proband died shortly after birth.
Family A: hom c.683G>A, p.Arg228Gln - fine horizontal nystagmus and bilateral OA
Family C: hom c.1237T>C, p.Ser413Pro - horizontal nystagmus, pallor of the optic discs

Tuppen et al., 2010 PMID: 20819849: recurrent p.Met292Th NDUFS2 mutation causes Leigh syndrome in multiple families.
Patient 22 - Female patient with psychomotor delay, learning difficulties and episodes of tonic upward eye deviation were noted from infancy. She subsequently developed progressive dystonia affecting all four limbs, optic nerve hypoplasia, dysarthria and dysphagia.
Patient 35 - Male patient, presented at 34 months of age with developmental delay, ataxia, nystagmus, optic atrophy and a mild, persistent metabolic acidosis (Patient 17 in Salemi R et al).
Caveat: 2 homozygotes reported in gnomAD v4, AF = 0.004563 - VUS in ClinVar.

Gerber et al. 2017, PMID: 28031252: one family with 3 affected siblings with LHON-like phenotype, compound het for missense variants p.Tyr53Cys; p.Tyr308Cys.

NDUFS2 is associated with AR Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228 and AR ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569 in OMIM (accessed 27th May 2026).
Optic neuropathy v6.31 NDUFS2 Ida Ertmanska reviewed gene: NDUFS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11220739, 28031252, 36913248; Phenotypes: Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228, ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.31 NSUN3 Ida Ertmanska Phenotypes for gene: NSUN3 were changed from optic neuropathy; optic atrophy; LHON; LHON-like to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Optic neuropathy v6.30 NSUN3 Ida Ertmanska Publications for gene: NSUN3 were set to PMID: 38790159; PMID: 40465263
Optic neuropathy v6.29 NSUN3 Ida Ertmanska Classified gene: NSUN3 as Amber List (moderate evidence)
Optic neuropathy v6.29 NSUN3 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Neringa Jurkute, there are at least 6 unrelated families reported in literature with optic neuropathy (isolated or syndromic) and biallelic NSUN3 variants. Hence, this gene can be promoted to Green on Optic neuropathy at the next update.
Optic neuropathy v6.29 NSUN3 Ida Ertmanska Gene: nsun3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.28 NSUN3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NSUN3.
Tag Q2_26_NHS_review tag was added to gene: NSUN3.
Optic neuropathy v6.28 NSUN3 Ida Ertmanska reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38790159, 40465263; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM:619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.28 NDUFV2 Ida Ertmanska Phenotypes for gene: NDUFV2 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 7, OMIM:618229
Optic neuropathy v6.27 NDUFV2 Ida Ertmanska Publications for gene: NDUFV2 were set to PMID: 41234160
Optic neuropathy v6.26 NDUFV2 Ida Ertmanska Classified gene: NDUFV2 as Red List (low evidence)
Optic neuropathy v6.26 NDUFV2 Ida Ertmanska Gene: ndufv2 has been classified as Red List (Low Evidence).
Optic neuropathy v6.25 NDUFV2 Ida Ertmanska commented on gene: NDUFV2: Comment on list classification: As there is only one proband reported to date with biallelic NDUFV2 variants and isolated optic atrophy, this gene can only be rated Red on this panel.
Optic neuropathy v6.25 NDUFV2 Ida Ertmanska reviewed gene: NDUFV2: Rating: RED; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 7, OMIM:618229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).
Congenital myopathy v7.25 TRIM32 Anna Sarkozy reviewed gene: TRIM32: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.9 TRAPPC2L Anna Sarkozy reviewed gene: TRAPPC2L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 TNPO3 Anna Sarkozy reviewed gene: TNPO3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital muscular dystrophy v7.9 TCAP Anna Sarkozy reviewed gene: TCAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 FOXK2 Anna Sarkozy reviewed gene: FOXK2: Rating: GREEN; Mode of pathogenicity: ; Publications: 40410591; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v7.25 PACSIN3 Anna Sarkozy reviewed gene: PACSIN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 38637313; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 TUBA4A Anna Sarkozy reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: ; Publications: 38413182; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 unrelated individuals reported in literature with NDUFV1 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: There are at least 3 unrelated individuals reported in literature with biallelic NDUFV1 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFV1.
Tag Q2_26_NHS_review tag was added to gene: NDUFV1.
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska Publications for gene: NDUFV1 were set to 41234160
Optic neuropathy v6.24 NDUFV1 Ida Ertmanska Classified gene: NDUFV1 as Amber List (moderate evidence)
Optic neuropathy v6.24 NDUFV1 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated individuals reported in literature with NDUFV1 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.24 NDUFV1 Ida Ertmanska Gene: ndufv1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska edited their review of gene: NDUFV1: Changed rating: GREEN
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska edited their review of gene: NDUFV1: Changed publications to: 29976978, 34807224, 41234160
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).
Congenital muscular dystrophy v7.8 TRAPPC2L Arina Puzriakova Classified gene: TRAPPC2L as No list
Congenital muscular dystrophy v7.8 TRAPPC2L Arina Puzriakova Gene: trappc2l has been removed from the panel.
Congenital muscular dystrophy v7.7 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.24 TRIM32 Arina Puzriakova Classified gene: TRIM32 as No list
Congenital myopathy v7.24 TRIM32 Arina Puzriakova Gene: trim32 has been removed from the panel.
Congenital myopathy v7.23 TRIM32 Arina Puzriakova gene: TRIM32 was added
gene: TRIM32 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TRIM32 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.22 TNPO3 Arina Puzriakova Classified gene: TNPO3 as No list
Congenital myopathy v7.22 TNPO3 Arina Puzriakova Gene: tnpo3 has been removed from the panel.
Congenital myopathy v7.21 TNPO3 Arina Puzriakova gene: TNPO3 was added
gene: TNPO3 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TNPO3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.20 FOXK2 Arina Puzriakova Classified gene: FOXK2 as No list
Congenital myopathy v7.20 FOXK2 Arina Puzriakova Gene: foxk2 has been removed from the panel.
Congenital myopathy v7.19 FOXK2 Arina Puzriakova gene: FOXK2 was added
gene: FOXK2 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: FOXK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v7.18 PACSIN3 Arina Puzriakova Classified gene: PACSIN3 as No list
Congenital myopathy v7.18 PACSIN3 Arina Puzriakova Gene: pacsin3 has been removed from the panel.
Congenital myopathy v7.17 PACSIN3 Arina Puzriakova gene: PACSIN3 was added
gene: PACSIN3 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: PACSIN3 was set to BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska Phenotypes for gene: NDUFV1 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225
Optic neuropathy v6.22 NDUFV1 Ida Ertmanska Publications for gene: NDUFV1 were set to PMID: 41234160
Optic neuropathy v6.21 NDUFV1 Ida Ertmanska Classified gene: NDUFV1 as Amber List (moderate evidence)
Optic neuropathy v6.21 NDUFV1 Ida Ertmanska Gene: ndufv1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.20 NDUFV1 Ida Ertmanska reviewed gene: NDUFV1: Rating: AMBER; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.16 TUBA4A Arina Puzriakova Classified gene: TUBA4A as No list
Congenital myopathy v7.16 TUBA4A Arina Puzriakova Gene: tuba4a has been removed from the panel.
Congenital myopathy v7.15 TUBA4A Arina Puzriakova gene: TUBA4A was added
gene: TUBA4A was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v6.20 NDUFS7 Ida Ertmanska Phenotypes for gene: NDUFS7 were changed from Optic neuropathy; optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 3, OMIM:618224
Optic neuropathy v6.19 NDUFS7 Ida Ertmanska Publications for gene: NDUFS7 were set to PMID: 41234160
Optic neuropathy v6.18 NDUFS7 Ida Ertmanska Classified gene: NDUFS7 as Amber List (moderate evidence)
Optic neuropathy v6.18 NDUFS7 Ida Ertmanska Added comment: Comment on list classification: There are now 5 unrelated probands reported in literature with biallelic NDUFS7 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green on Optic neuropathy at the next update.
Optic neuropathy v6.18 NDUFS7 Ida Ertmanska Gene: ndufs7 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.17 NDUFS7 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFS7.
Tag Q2_26_NHS_review tag was added to gene: NDUFS7.
Optic neuropathy v6.17 NDUFS7 Ida Ertmanska reviewed gene: NDUFS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3, OMIM:618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.17 NDUFB11 Ida Ertmanska Phenotypes for gene: NDUFB11 were changed from Optic neuropathy, optic atrophy; LHON-like to ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021
Optic neuropathy v6.16 NDUFB11 Ida Ertmanska Publications for gene: NDUFB11 were set to PMID: 41234160
Optic neuropathy v6.15 NDUFB11 Ida Ertmanska Classified gene: NDUFB11 as Amber List (moderate evidence)
Optic neuropathy v6.15 NDUFB11 Ida Ertmanska Added comment: Comment on list classification: There are now 3 male individuals from 2 families reported with hemizygous NDUFB11 variants and optic atrophy. Hence, this gene can only be rated Amber with the current evidence.
Optic neuropathy v6.15 NDUFB11 Ida Ertmanska Gene: ndufb11 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.14 NDUFB11 Ida Ertmanska edited their review of gene: NDUFB11: Changed publications to: 27488349, 41234160
Optic neuropathy v6.14 NDUFB11 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

This gene is associated with AR ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is associated with AR ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).
Rare anaemia v4.6 NDUFB11 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 27th May 2026.
Rare anaemia v4.6 NDUFB11 Ida Ertmanska Phenotypes for gene: NDUFB11 were changed from sideroblastic anaemia to ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021; Linear skin defects with multiple congenital anomalies 3, OMIM:300952; sideroblastic anemia, MONDO:0015194
Rare anaemia v4.5 NDUFB11 Ida Ertmanska Publications for gene: NDUFB11 were set to 27488349
Rare anaemia v4.4 NDUFB11 Ida Ertmanska commented on gene: NDUFB11: Comment on list classification: There are 4 unrelated male probands reported with a recurrent hemizygous p.Phe93del variant in NDUFB11 and sideroblastic anemia. In addition, 2 unrelated male probands have been reported with mild microcytic / normocytic anemia with different NDUFB11 missense variants. The female heterozygous carriers were unaffected. Hence, this gene should be promoted to Green for Rare anaemia, with MOI set to X-LINKED: hemizygous mutation in males, biallelic mutations in females.
Rare anaemia v4.4 NDUFB11 Ida Ertmanska changed review comment from: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

PMID: 30423443 Reinson et al., 2019
Report of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286C>T and c.328C>T) in NDUFB11.
P2 had persistent mild leukopenia and microcytic anemia, P1 had transient normocytic anemia at 2 months, which he recovered from after iron administration.

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).; to: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

PMID: 30423443 Reinson et al., 2019
Report of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286T>C, p.(Ser96Pro) and c.328C>T, p.Pro110Ser) in NDUFB11.
P2 had persistent mild leukopenia and microcytic anemia, P1 had transient normocytic anemia at 2 months, which he recovered from after iron administration.

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).
Rare anaemia v4.4 NDUFB11 Ida Ertmanska edited their review of gene: NDUFB11: Changed phenotypes to: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021, Linear skin defects with multiple congenital anomalies 3, OMIM:300952, sideroblastic anemia, MONDO:0015194
Rare anaemia v4.4 NDUFB11 Ida Ertmanska edited their review of gene: NDUFB11: Changed publications to: 27488349, 30423443
Rare anaemia v4.4 NDUFB11 Ida Ertmanska changed review comment from: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).; to: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

PMID: 30423443 Reinson et al., 2019
Report of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286C>T and c.328C>T) in NDUFB11.
P2 had persistent mild leukopenia and microcytic anemia, P1 had transient normocytic anemia at 2 months, which he recovered from after iron administration.

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).
Rare anaemia v4.4 NDUFB11 Ida Ertmanska Publications for gene: NDUFB11 were set to
Rare anaemia v4.3 NDUFB11 Ida Ertmanska Mode of inheritance for gene: NDUFB11 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare anaemia v4.2 NDUFB11 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFB11.
Rare anaemia v4.2 NDUFB11 Ida Ertmanska reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 27488349; Phenotypes: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021, Linear skin defects with multiple congenital anomalies 3, OMIM:300952; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pigmentary skin disorders v5.2 NDUFB11 Ida Ertmanska reviewed gene: NDUFB11: Rating: AMBER; Mode of pathogenicity: None; Publications: 27488349, 41234160; Phenotypes: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Optic neuropathy v6.14 NDUFAF8 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 6 individuals from 3 unrelated individuals reported in literature with biallelic NDUFAF8 variants and optic atrophy - isolated or syndromic. Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: There are at least 6 individuals from 3 unrelated families reported in literature with biallelic NDUFAF8 variants and optic atrophy - isolated or syndromic. Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.14 NDUFAF8 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

5/6 patients reported with NDUFAF8 variants had isolated optic atrophy; the sixth proband had OA plus nystagmus and cerebellar ataxia.
Family U - 2 sibs hom for c.44T>G p.(L15R) - isolated OA, MRI normal
Families W & V (4 individuals from 2 families)- hom for c.195+271C>T p.? deep intronic variant - insidious isolated OA in family W, individuals in Family V had LHON-like presentation of OA + strabismus, hyperopia, non-specific white matter lesions on MRI (3/3), also mild DD, nystagmus, and unsteady gate in 1/3.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

5/6 patients reported with NDUFAF8 variants had isolated optic atrophy; the sixth proband had OA plus nystagmus and cerebellar ataxia.
Family U - 2 sibs hom for c.44T>G p.(L15R) - isolated OA, MRI normal
Families W & V (4 individuals from 2 families)- hom for c.195+271C>T p.? deep intronic variant - insidious isolated OA in family W, individuals in Family V had LHON-like presentation of OA + strabismus, hyperopia, non-specific white matter lesions on MRI (3/3), also mild DD, nystagmus, and unsteady gate in 1/3.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776 (accessed 26th May 2026).
Optic neuropathy v6.14 NDUFAF4 Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: NDUFAF4.
Optic neuropathy v6.14 NDUFAF8 Achchuthan Shanmugasundram Tag Q2_26_NHS_review tag was added to gene: NDUFAF8.
Optic neuropathy v6.14 NDUFB11 Ida Ertmanska reviewed gene: NDUFB11: Rating: AMBER; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Optic neuropathy v6.14 NDUFAF8 Ida Ertmanska Phenotypes for gene: NDUFAF8 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776
Optic neuropathy v6.13 NDUFAF8 Ida Ertmanska Publications for gene: NDUFAF8 were set to PMID: 41234160
Optic neuropathy v6.12 NDUFAF8 Ida Ertmanska Classified gene: NDUFAF8 as Amber List (moderate evidence)
Optic neuropathy v6.12 NDUFAF8 Ida Ertmanska Added comment: Comment on list classification: There are at least 6 individuals from 3 unrelated individuals reported in literature with biallelic NDUFAF8 variants and optic atrophy - isolated or syndromic. Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.12 NDUFAF8 Ida Ertmanska Gene: ndufaf8 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.11 NDUFAF8 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFAF8.
Optic neuropathy v6.11 NDUFAF8 Ida Ertmanska reviewed gene: NDUFAF8: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.11 NDUFAF4 Ida Ertmanska Phenotypes for gene: NDUFAF4 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237
Optic neuropathy v6.10 NDUFAF4 Ida Ertmanska Publications for gene: NDUFAF4 were set to PMID: 41234160
Optic neuropathy v6.9 NDUFAF4 Ida Ertmanska Classified gene: NDUFAF4 as Amber List (moderate evidence)
Optic neuropathy v6.9 NDUFAF4 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic NDUFAF4 variants and isolated optic atrophy. Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.9 NDUFAF4 Ida Ertmanska Gene: ndufaf4 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFAF4.
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska edited their review of gene: NDUFAF4: Changed publications to: 38381526, 41234160
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF4 variants:
Family S - proband with NDUFAF4 comp het variants c.224del p.(P75Lfs*7) and c.413T>C p.(I138T), with isolated optic atrophy
Family T - 2 sibs homozygous for c.413T>C p.(I138T) variant in NDUFAF4 with isolated optic atrophy

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF4 variants:
Family S - proband with NDUFAF4 comp het variants c.224del p.(P75Lfs*7) and c.413T>C p.(I138T), with isolated optic atrophy
Family T - 2 sibs homozygous for c.413T>C p.(I138T) variant in NDUFAF4 with isolated optic atrophy

PMID: 38381526 Barboni et al., 2025
Report of a 17yo boy with subacute bilateral visual loss with no pain - atypical LHON diagnosis. He was comp het for NDUFAF4: c.413T>C, p.Ile138Thr and c.224del, p.Pro75LeufsTer7. Temporal pallor of both the optic discs, optic disc microangiopathy, and temporal retinal nerve fiber layer (RNFL) thinning noted at 12 yrs old.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237 (accessed 26th May 2026).
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska reviewed gene: NDUFAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.8 NDUFAF3 Ida Ertmanska Phenotypes for gene: NDUFAF3 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240
Optic neuropathy v6.7 NDUFAF3 Ida Ertmanska Publications for gene: NDUFAF3 were set to PMID: 41234160
Optic neuropathy v6.6 NDUFAF3 Ida Ertmanska Classified gene: NDUFAF3 as Amber List (moderate evidence)
Optic neuropathy v6.6 NDUFAF3 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic NDUFAF3 variants and Leigh syndrome spectrum, including optic atrophy. An additional case was reported with neonatal mitochondrial disease and pallor of the optic disc, with another homozygous NDUFAF3 variants. Based on available evidence, this gene should remain Amber on optic neuropathy, until more evidence emerges.
Optic neuropathy v6.6 NDUFAF3 Ida Ertmanska Gene: ndufaf3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.5 NDUFAF3 Ida Ertmanska edited their review of gene: NDUFAF3: Changed publications to: 19463981, 27986404, 41234160
Optic neuropathy v6.5 NDUFAF3 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family R - proband with LSS, presented with Motor delay, Abnormal basal ganglia MRI signal intensity, optic atrophy with insidious onset at 0-3 years of age; harboured NDUFAF3 c.5C>A, p.(A2D) and c.489_490del, p.(G164Sfs*29) comp het variants

PMID: 27986404 Baertling et al., 2017
Female Indian patient with Leigh syndrome diagnosis, bilateral optic atrophy was noted at 15 months. WES revealed a homozygous NDUFAF3 variant c.494C>T, p.Ala165Val.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family R - proband with LSS, presented with Motor delay, Abnormal basal ganglia MRI signal intensity, optic atrophy with insidious onset at 0-3 years of age; harboured NDUFAF3 c.5C>A, p.(A2D) and c.489_490del, p.(G164Sfs*29) comp het variants

PMID: 27986404 Baertling et al., 2017
Female Indian patient with Leigh syndrome diagnosis, bilateral optic atrophy was noted at 15 months. WES revealed a homozygous NDUFAF3 variant c.494C>T, p.Ala165Val.

PMID: 19463981 Saada et al. 2009
Male proband II-1 of Arab descent with neonatal mitochondrial disease diagnosis, including bilateral pallor of the optic disc seen on fundoscopy (no MRI done). He was homozygous for c.365G>C, p. R122P in NDUFAF3.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240 (accessed 26th May 2026).
Optic neuropathy v6.5 NDUFAF3 Ida Ertmanska reviewed gene: NDUFAF3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27986404, 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF2 variants:
Two sibs from family P - carrying variants in NDUFAF2: c.95A>G p.(Y32C) and c.148del p.(R50Efs*3), showed OA and peripheral axonal neuropathy - "OA-Plus"
Proband from family Q - homozygous for NDUFAF2 c.114C>G, p.(Y38*), showed OA and peripheral axonal neuropathy - "OA-Plus"

PMID: 37938061 Chen et al., 2024
Report of a 35yo patient with AR LHON - isolated optic atrophy, no Leigh-like encephalopathy. He reported vision problems starting at age 15yrs. Brain MRI showed bilateral thin optic nerve. WES detected comp het variants in NDUFAF2: c.139C>T, p.Arg47*, and c.148del, p.Arg50Glufs*3 - confirmed in trans.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233 (accessed 26th May 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF2 variants:
Two sibs from family P - carrying variants in NDUFAF2: c.95A>G p.(Y32C) and c.148del p.(R50Efs*3), showed OA and peripheral axonal neuropathy - "OA-Plus"
Proband from family Q - homozygous for NDUFAF2 c.114C>G, p.(Y38*), showed OA and peripheral axonal neuropathy - "OA-Plus"

PMID: 37938061 Chen et al., 2024
Report of a 35yo patient with AR LHON - isolated optic atrophy, no Leigh-like encephalopathy. He reported vision problems starting at age 15yrs. Brain MRI showed bilateral thin optic nerve. WES detected comp het variants in NDUFAF2: c.139C>T, p.Arg47*, and c.148del, p.Arg50Glufs*3 - confirmed in trans.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233 (accessed 26th May 2026).
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska Classified gene: NDUFAF2 as Amber List (moderate evidence)
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated cases reported in literature with biallelic NDUFAF2 variants and optic neuropathy (either isolated OA or syndromic). Based on available evidence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska Gene: ndufaf2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.4 NDUFAF2 Ida Ertmanska Phenotypes for gene: NDUFAF2 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233
Optic neuropathy v6.3 NDUFAF2 Ida Ertmanska Publications for gene: NDUFAF2 were set to PMID: 41234160
Optic neuropathy v6.2 NDUFAF2 Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: NDUFAF2.
Optic neuropathy v6.2 NDUFAF2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFAF2.
Optic neuropathy v6.2 NDUFAF2 Ida Ertmanska reviewed gene: NDUFAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37938061, 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.8 SHROOM4 Ida Ertmanska Tag watchlist tag was added to gene: SHROOM4.
Early onset or syndromic epilepsy v9.8 SHROOM4 Ida Ertmanska commented on gene: SHROOM4: Comment on list classification: While there are 6 cases with seizures reported in literature, it is from a single publication and two of the variants are present in hemizygous state in GnomAD. There are several other SHROOM4 gene-phenotype associations reported with limited case numbers. Hence, on advice of Genomics England's Clinical Team, this gene should be rated Amber with a 'watchlist' tag, until more evidence emerges.
Limb disorders v8.7 IFT57 Ida Ertmanska Publications for gene: IFT57 were set to 27060890; 40273360
Limb disorders v8.6 IFT57 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: IFT57.
Limb disorders v8.6 IFT57 Ida Ertmanska commented on gene: IFT57: Comment on list classification: There are 2 unrelated individuals reported in literature with bialellic IFT57 variants and polydactyly. Functional evidence from a knockout mouse model supports this gene-phenotype association. Hence, this gene should be promoted to Green on Limb disorders at the next update.
Limb disorders v8.6 IFT57 Ida Ertmanska edited their review of gene: IFT57: Changed publications to: 17027958, 27060890, 40273360
Limb disorders v8.6 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia, polydactyly, and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia, polydactyly, and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

PMID: 17027958 Houde et al., 2006
IFT57-/- knockout mouse (old gene name Hippi) only survived roughly until E9.5. One embryo survived until E13.5, and showed exencephaly, hypotelorism, and polydactyly on both fore and hind limbs.

Sources: Literature
Limb disorders v8.6 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia, polydactyly, and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature
Monogenic hearing loss v6.15 DSPP Ida Ertmanska commented on gene: DSPP: Comment on list classification: There is limited and conflicting evidence regarding the association between DSPP variants and dominant hearing loss. There are 3 Chinese families reported with DSPP missense variants and hearing loss, including one pedigree with a common likely benign variant. The other two families had both dentinogenesis imperfecta and hearing loss, and harboured the same DSPP variant detected by linkage analysis/targeted DSPP seq - another gene likely responsible for hearing loss. In addition, numerous other cases with 59+ different DSPP variants have been reported in literature with isolated dentinogenesis imperfecta.
Monogenic hearing loss v6.15 DSPP Ida Ertmanska Phenotypes for gene: DSPP were changed from Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500 to Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500
Monogenic hearing loss v6.15 DSPP Ida Ertmanska Phenotypes for gene: DSPP were changed from hearing loss; Dentinogenesis imperfecta, Shields type II, 125490; Deafness, autosomal dominant 36, with dentinogenesis, 605594; Dentinogenesis imperfecta, Shields type III, 125500; Dentin dysplasia, type II, 125420; Dentin dysplasia, type II,1254203 to Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500
Monogenic hearing loss v6.14 DSPP Ida Ertmanska Publications for gene: DSPP were set to PMID:10706475; 11116156; 11175770; 11175779; 11175790; 12354781; 12721295; 14758537; 15592686; 15954904; 17210923; 18456718; 22392858; 22582013; 2433419; 2462619; 7573043; 8995371; 9533027
Monogenic hearing loss v6.13 DSPP Ida Ertmanska Tag Q2_26_demote_red tag was added to gene: DSPP.
Monogenic hearing loss v6.13 DSPP Ida Ertmanska edited their review of gene: DSPP: Changed publications to: 11175790, 17686168, 29741433, 33229591, 39806231
Monogenic hearing loss v6.13 DSPP Ida Ertmanska changed review comment from: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li ey al., 2018
Proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).; to: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li et al., 2018
Chinese proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).
Monogenic hearing loss v6.13 DSPP Ida Ertmanska changed review comment from: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI).

Hearing loss has not been reported in any other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025); to: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li ey al., 2018
Proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska edited their review of gene: DSPP: Changed publications to: 18456718, 39806231
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska Classified gene: DSPP as Amber List (moderate evidence)
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska Gene: dspp has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.32 DSPP Ida Ertmanska Publications for gene: DSPP were set to 1845671839806231
Amelogenesis imperfecta v4.31 DSPP Ida Ertmanska gene: DSPP was added
gene: DSPP was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: DSPP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DSPP were set to 1845671839806231
Phenotypes for gene: DSPP were set to Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500
Review for gene: DSPP was set to GREEN
Added comment: PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025
Lit review of 322 cases with non-syndromic dentinogenesis imperfecta (DI - characterized clinically by amber or gray-yellow opalescent tooth discoloration, obliteration of pulp chambers and root canals, and attrition. Both deciduous and permanent teeth are affected (PMID: 18456718 Song et al., 2008).
DSPP mutations were the most frequent, with with 59 documented variants from 37 publications. 34/59 variants were in exon 5 of DSPP.
Sources: Literature
Monogenic hearing loss v6.13 DSPP Ida Ertmanska reviewed gene: DSPP: Rating: RED; Mode of pathogenicity: None; Publications: 11175790, 39806231; Phenotypes: Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594, Dentin dysplasia, type II, OMIM:125420, Dentinogenesis imperfecta, Shields type II, OMIM:125490, Dentinogenesis imperfecta, Shields type III, OMIM:125500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v6.13 PLCG1 Ida Ertmanska commented on gene: PLCG1: Comment on list classification: There are now 3 unrelated individuals with heterozygous PLCG1 variants and hearing loss. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v10.18 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Intellectual disability v10.17 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Intellectual disability v10.17 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and ID/DD. Hence, this gene should be promoted to Green at the next update.; Changed publications to: 27435318, 40385417, 40621786, 42012897
Intellectual disability v10.17 BORCS5 Ida Ertmanska commented on gene: BORCS5: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."
Childhood onset hereditary spastic paraplegia v9.2 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Childhood onset hereditary spastic paraplegia v9.1 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Childhood onset hereditary spastic paraplegia v9.1 BORCS5 Ida Ertmanska commented on gene: BORCS5: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and childhood-onset HSP. Hence, this gene should be promoted to Green at the next update.
Childhood onset hereditary spastic paraplegia v9.1 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."; Changed publications to: 27435318, 40385417, 40621786, 42012897
Optic neuropathy v6.2 BORCS5 Ida Ertmanska commented on gene: BORCS5: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and optic neuropathy. Hence, this gene should be promoted to Green at the next update.
Optic neuropathy v6.2 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."; Changed publications to: 27435318, 40385417, 40621786, 42012897
Optic neuropathy v6.2 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Early onset or syndromic epilepsy v9.8 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Optic neuropathy v6.1 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Arthrogryposis v10.6 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Arthrogryposis v10.5 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Arthrogryposis v10.5 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and lethal arthrogryposis. Hence, this gene should be promoted to Green at the next update.; Changed publications to: 27435318, 40385417, 40621786, 42012897
Arthrogryposis v10.5 BORCS5 Ida Ertmanska commented on gene: BORCS5: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."
Early onset or syndromic epilepsy v9.7 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Early onset or syndromic epilepsy v9.7 BORCS5 Ida Ertmanska commented on gene: BORCS5: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.7 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."; Changed publications to: 27435318, 40385417, 40621786, 42012897
Structural eye disease v5.6 FBN1 Ida Ertmanska Publications for gene: FBN1 were set to 1301946, 8136837
Structural eye disease v5.5 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Structural eye disease v5.5 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Ectopia lentis (displacement or malposition of the eye’s natural lens) is a very common feature in individuals with Marfan Syndrome. Hence, 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.
Structural eye disease v5.5 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Pneumothorax - familial v3.6 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Ehlers Danlos syndrome with a likely monogenic cause v4.11 FBN1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Thoracic aortic aneurysm or dissection (GMS) 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: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Ehlers Danlos syndrome with a likely monogenic cause 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.
Pneumothorax - familial v3.6 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. As stated by previous reviewers, pneumothorax is a common feature of Marfan Syndrome. Hence, the MOI on Pneumothorax - familial 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.
Pneumothorax - familial v3.6 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v4.11 FBN1 Ida Ertmanska Phenotypes for gene: FBN1 were changed from Marfan syndrome, OMIM:154700 to Marfan syndrome, OMIM:154700; Marfan syndrome, MONDO:0007947
Ehlers Danlos syndrome with a likely monogenic cause v4.10 FBN1 Ida Ertmanska Publications for gene: FBN1 were set to
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Thoracic aortic aneurysm or dissection (GMS) 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.
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska edited their review of gene: FBN1: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v5.4 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Thoracic aortic aneurysm or dissection (GMS) 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.
Thoracic aortic aneurysm or dissection (GMS) v5.4 FBN1 Ida Ertmanska Publications for gene: FBN1 were set to 26888179; 20082464; 7762551
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska changed review comment from: PMID: 23278365 Hogue et al., 2013
Report of a proband (Mexican-American woman, consanguineous parents) + literature review of 4 additional unrelated families with biallelic FBN1 variants and severe Marfan syndrome - heterozygous parents were either asymptomatic or had a milder form of Marfan syndrome. Mostly biallelic missense, one instance of missense + deletion in 2 sibs. Proband presented with scoliosis, arachnodactyly, dislocated lenses, mitral valve prolapse, aortic dilatation, dural ectasias.

PMID: 27582083 Arnaud et al., 2017
In a large cohort of Marfan syndrome patients, 4 probands were homozygous and 22 potentially comp het for FBN1 variants (5 confirmed to be in trans). All 4 homozygous individuals harboured missense variants; comp het cases either had biallelic missense FBN1 variants, or missense + nonsense. Heterozygous carriers usually also diagnosed with MFS, sometimes very mild e.g., isolated mild skeletal features in women. The severity of symptoms and age of onset varied a lot, both between biallelic and among monoallelic cases.

PMID: 31950671 McInerney-Leo et al., 2020
Report of a pedigree with Marfan syndrome (ectopia lentis, though the skeletal phenotype is variable, and not all have aortic dilatation) - some individuals with monoallelic and some with biallelic FBN1 variants.
All subjects with Marfan syndrome harboured p.Tyr754Cys in FBN1. An additional variant (p.Met2273Thr), previously associated with 'incomplete' MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years.
The heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.; to: PMID: 23278365 Hogue et al., 2013
Report of a proband (Mexican-American woman, consanguineous parents) + literature review of 4 additional unrelated families with biallelic FBN1 variants and severe Marfan syndrome - heterozygous parents were either asymptomatic or had a milder form of Marfan syndrome. Mostly biallelic missense, one instance of missense + deletion in 2 sibs. Proband presented with scoliosis, arachnodactyly, dislocated lenses, mitral valve prolapse, aortic dilatation, dural ectasias.

PMID: 27582083 Arnaud et al., 2017
In a large cohort of Marfan syndrome patients, 4 probands were homozygous and 22 potentially comp het for FBN1 variants (5 confirmed to be in trans). All 4 homozygous individuals harboured missense variants; comp het cases either had biallelic missense FBN1 variants, or missense + nonsense. Heterozygous carriers usually also diagnosed with MFS, sometimes very mild e.g., isolated mild skeletal features in women. The severity of symptoms and age of onset varied a lot, both between biallelic and among monoallelic cases.

PMID: 31950671 McInerney-Leo et al., 2020
Report of a pedigree with Marfan syndrome (ectopia lentis, though the skeletal phenotype is variable, and not all have aortic dilatation) - some individuals with monoallelic and some with biallelic FBN1 variants.
All subjects with Marfan syndrome harboured p.Tyr754Cys in FBN1. An additional variant (p.Met2273Thr), previously associated with 'incomplete' MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years.
The heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.

The association between FBN1 and Marfan syndrome is rated as Definitive in Gene2Phenotype, both for the AD and AR inheritance patterns.
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myopathy v7.14 DST Anna Sarkozy reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: 40497796; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.6 HMGCR Anna Sarkozy reviewed gene: HMGCR: Rating: GREEN; Mode of pathogenicity: ; Publications: 37167966, 36745799; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 CASQ1 Anna Sarkozy edited their review of gene: CASQ1: Added comment: vacuolar myopathy with aggregates, in absence of biopsy this condition could be in strong differential with CM; Changed publications to: 26136523, PMID: 30258016, 25116801
Congenital myopathy v7.14 SPTAN1 Anna Sarkozy reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40999194, 40023774; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 SPTBN4 Anna Sarkozy reviewed gene: SPTBN4: Rating: GREEN; Mode of pathogenicity: ; Publications: 33772159, 28540413; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.6 TK2 Anna Sarkozy reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 TK2 Anna Sarkozy reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.6 MCOLN1 Anna Sarkozy reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 33454187; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 MCOLN1 Anna Sarkozy reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 33454187; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 JPH1 Anna Sarkozy reviewed gene: JPH1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39209426; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 HRAS Anna Sarkozy edited their review of gene: HRAS: Added comment: congenital myopathy with excess muscle spindles; congenital weakness, hypotonia, arthrogryposis, atrial tachycardia, hypertrophic cardiomyopathy, and marked excess of muscle spindles on biopsy.; Changed rating: GREEN; Changed publications to: 17412879, 11150980; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 HNRNPA1 Anna Sarkozy edited their review of gene: HNRNPA1: Added comment: amber in distal myopathy , green in ALS panel, now reported in families with childhood onset myopathy; Changed rating: GREEN; Changed publications to: 39121134; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 HMGCS1 Anna Sarkozy reviewed gene: HMGCS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39531736; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 CNTN1 Anna Sarkozy edited their review of gene: CNTN1: Added comment: 2 families reported with variants in this gene; severe phenotype with fetal akinesia and nonspecific myopathic features on skeletal muscle biopsy.; Changed rating: GREEN; Changed publications to: 32779773, 19026398
Congenital myopathy v7.14 CCDC78 Anna Sarkozy edited their review of gene: CCDC78: Added comment: 2 families reported. Recent paper supporting functional role; Changed publications to: 22818856, 39273074; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 CACNA1H Anna Sarkozy reviewed gene: CACNA1H: Rating: GREEN; Mode of pathogenicity: ; Publications: 31070086; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.5 HMGCR Arina Puzriakova Classified gene: HMGCR as No list
Congenital muscular dystrophy v7.5 HMGCR Arina Puzriakova Gene: hmgcr has been removed from the panel.
Congenital muscular dystrophy v7.4 HMGCR Arina Puzriakova gene: HMGCR was added
gene: HMGCR was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: HMGCR was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.13 SPTAN1 Arina Puzriakova Classified gene: SPTAN1 as No list
Congenital myopathy v7.13 SPTAN1 Arina Puzriakova Gene: sptan1 has been removed from the panel.
Adult onset neurodegenerative disorder v9.1 LRSAM1 Oliver Ziff gene: LRSAM1 was added
gene: LRSAM1 was added to Adult onset neurodegenerative disorder. Sources: Literature,Expert Review
Mode of inheritance for gene: LRSAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRSAM1 were set to 22781092; 28335037
Phenotypes for gene: LRSAM1 were set to Charcot Marie Toothe disease, axonal, type 2P, 614436
Penetrance for gene: LRSAM1 were set to Complete
Mode of pathogenicity for gene: LRSAM1 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: LRSAM1 was set to GREEN
gene: LRSAM1 was marked as current diagnostic
Added comment: Causes CMT2P with marked motor features out of proportion to sensory loss, presenting as an PMA mimic. Needs inclusion in R460.1 to avoid R78 reanalysis.
Sources: Literature, Expert Review
Congenital myopathy v7.12 SPTAN1 Arina Puzriakova gene: SPTAN1 was added
gene: SPTAN1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.11 TK2 Arina Puzriakova Classified gene: TK2 as No list
Congenital myopathy v7.11 TK2 Arina Puzriakova Gene: tk2 has been removed from the panel.
Congenital myopathy v7.10 TK2 Arina Puzriakova gene: TK2 was added
gene: TK2 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TK2 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.3 MCOLN1 Arina Puzriakova Classified gene: MCOLN1 as No list
Congenital muscular dystrophy v7.3 MCOLN1 Arina Puzriakova Gene: mcoln1 has been removed from the panel.
Congenital myopathy v7.9 MCOLN1 Arina Puzriakova Classified gene: MCOLN1 as No list
Congenital myopathy v7.9 MCOLN1 Arina Puzriakova Gene: mcoln1 has been removed from the panel.
Adult onset neurodegenerative disorder v9.1 MORC2 Oliver Ziff gene: MORC2 was added
gene: MORC2 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MORC2 were set to 26497905; 26659848
Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Penetrance for gene: MORC2 were set to Complete
Mode of pathogenicity for gene: MORC2 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: MORC2 was set to GREEN
gene: MORC2 was marked as current diagnostic
Added comment: Causes CMT2Z. Presents with prominent SMA-like proximal and distal weakness in adults, mimicking PMA. Needs inclusion in R460.1 to avoid R78 reanalysis.
Sources: Expert Review, Literature
Congenital muscular dystrophy v7.2 MCOLN1 Arina Puzriakova gene: MCOLN1 was added
gene: MCOLN1 was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: MCOLN1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.8 MCOLN1 Arina Puzriakova gene: MCOLN1 was added
gene: MCOLN1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: MCOLN1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.7 JPH1 Arina Puzriakova Classified gene: JPH1 as No list
Congenital myopathy v7.7 JPH1 Arina Puzriakova Gene: jph1 has been removed from the panel.
Congenital myopathy v7.6 JPH1 Arina Puzriakova gene: JPH1 was added
gene: JPH1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.5 HMGCS1 Arina Puzriakova Classified gene: HMGCS1 as No list
Congenital myopathy v7.5 HMGCS1 Arina Puzriakova Gene: hmgcs1 has been removed from the panel.
Adult onset neurodegenerative disorder v9.1 MME Oliver Ziff gene: MME was added
gene: MME was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: MME was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: MME were set to 26924531
Phenotypes for gene: MME were set to Charcot-Marie-Tooth disease, axonal, type 2T, OMIM:617017
Penetrance for gene: MME were set to Complete
Mode of pathogenicity for gene: MME 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: MME was set to GREEN
gene: MME was marked as current diagnostic
Added comment: MME variants frequently present as a late-onset >40 years motor-predominant axonal polyneuropathy. Because the clinical presentation features progressive distal lower motor neuron weakness and wasting in adulthood, it mimics Progressive Muscular Atrophy and LMN-variant MND. Adding it to the R460.1 panel is necessary to capture these mimics upfront and prevent sequential R78 WGS reanalysis for patients on the MND diagnostic pathway.
Sources: Expert Review, Literature
Congenital myopathy v7.4 HMGCS1 Arina Puzriakova gene: HMGCS1 was added
gene: HMGCS1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.3 CACNA1H Arina Puzriakova Classified gene: CACNA1H as No list
Congenital myopathy v7.3 CACNA1H Arina Puzriakova Gene: cacna1h has been removed from the panel.
Congenital myopathy v7.2 CACNA1H Arina Puzriakova gene: CACNA1H was added
gene: CACNA1H was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: CACNA1H was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset neurodegenerative disorder v9.1 UBA1 Oliver Ziff gene: UBA1 was added
gene: UBA1 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: UBA1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: UBA1 were set to 18179898; 31932168; 26456228; 27797960; 35919735; 33108101
Phenotypes for gene: UBA1 were set to Spinal muscular atrophy, X-linked 2, OMIM:301830
Penetrance for gene: UBA1 were set to Complete
Mode of pathogenicity for gene: UBA1 was set to Other
Review for gene: UBA1 was set to GREEN
gene: UBA1 was marked as current diagnostic
Added comment: Germline UBA1 variants cause SMAX2, an anterior horn cell disorder that presents with progressive lower motor neuron degeneration. It is a direct clinical and biological mimic of PMA/LMN-variant ALS and should be included on the MND panel to prevent diagnostic misses. Needs inclusion in R460.1
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 NEFH Oliver Ziff reviewed gene: NEFH: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2CC, 616924; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset neurodegenerative disorder v9.1 ATP7A Oliver Ziff gene: ATP7A was added
gene: ATP7A was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: ATP7A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATP7A were set to 20170900
Phenotypes for gene: ATP7A were set to Spinal muscular atrophy, X-linked 3, distal, OMIM:300489
Penetrance for gene: ATP7A were set to Complete
Mode of pathogenicity for gene: ATP7A was set to Other
Review for gene: ATP7A was set to GREEN
gene: ATP7A was marked as current diagnostic
Added comment: Specific missense variants cause X-linked distal motor neuropathy (SMAX3), mimicking adult LMN disease without systemic Menkes features. Needs inclusion in R460.1 to prevent R78 reanalysis.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 DYNC1H1 Oliver Ziff reviewed gene: DYNC1H1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 21820100, 26392352; Phenotypes: Charcot Marie Tooth disease, axonal, type 20, 614228, Mental retardation, autosomal dominant 13, 614563, Spinal muscular atrophy, lower extremity predominant, AD, 158600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset neurodegenerative disorder v9.1 IGHMBP2 Oliver Ziff gene: IGHMBP2 was added
gene: IGHMBP2 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: IGHMBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IGHMBP2 were set to 26392352; 34726235
Phenotypes for gene: IGHMBP2 were set to Charcot-Marie-Tooth disease, axonal, type 2S 616155; Neuronopathy, distal hereditary motor, type VI, 604320
Penetrance for gene: IGHMBP2 were set to Incomplete
Mode of pathogenicity for gene: IGHMBP2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Causes a slowly progressive adult-onset distal SMA. Phenotypically overlaps with LMN-variant MND. Needs inclusion in R460.1 ALS panel to avoid R78 reanalysis.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SORD Oliver Ziff gene: SORD was added
gene: SORD was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to 323670585; 33314640; 33397963
Phenotypes for gene: SORD were set to Sorbitol dehydrogenase deficiency with peripheral neuropathy OMIM:618912; Neuropathy, distal hereditary motor, OMIM:158590
Penetrance for gene: SORD were set to Complete
Mode of pathogenicity for gene: SORD 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: SORD was set to GREEN
gene: SORD was marked as current diagnostic
Added comment: Prevalent cause of recessive dHMN/CMT2. It frequently presents as progressive LMN weakness in adulthood, making it a critical, potentially treatable ALS mimic. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SYT2 Oliver Ziff gene: SYT2 was added
gene: SYT2 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: SYT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYT2 were set to 26519543; 30533528
Phenotypes for gene: SYT2 were set to Neuropathy, distal hereditary motor, OMIM:158590; Progressive muscular atrophy, OMIM:105400
Penetrance for gene: SYT2 were set to Complete
Mode of pathogenicity for gene: SYT2 was set to Other
Added comment: Presents as a slowly progressive distal motor neuropathy and LMN syndrome mimicking PMA. mimics LMN-predominant MND, necessitating upfront R460.1 screening.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SLC5A7 Oliver Ziff gene: SLC5A7 was added
gene: SLC5A7 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: SLC5A7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC5A7 were set to 29782645; 23141292
Phenotypes for gene: SLC5A7 were set to Neuronopathy, distal hereditary motor, type VIIA
Penetrance for gene: SLC5A7 were set to Complete
Mode of pathogenicity for gene: SLC5A7 was set to Other
Review for gene: SLC5A7 was set to GREEN
gene: SLC5A7 was marked as current diagnostic
Added comment: Dominant negative variants cause a distal hereditary motor neuropathy (dHMN7A) mimicking progressive isolated LMN degeneration. mimics LMN-predominant MND, necessitating upfront screening. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 TRPV4 Oliver Ziff gene: TRPV4 was added
gene: TRPV4 was added to Adult onset neurodegenerative disorder. Sources: Literature,Expert Review
Mode of inheritance for gene: TRPV4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPV4 were set to 20037586
Phenotypes for gene: TRPV4 were set to Hereditary motor and sensory neuropathy, type IIc, 606071
Penetrance for gene: TRPV4 were set to Complete
Mode of pathogenicity for gene: TRPV4 was set to Other
Review for gene: TRPV4 was set to GREEN
gene: TRPV4 was marked as current diagnostic
Added comment: Causes scapuloperoneal SMA and dHMN. The progressive motor weakness frequently mimics LMN-predominant MND, necessitating upfront R460.1 screening. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Literature, Expert Review
Autoinflammatory disorders v3.9 OTULIN Ida Ertmanska changed review comment from: PMID: 38630025 Davidson et al., 2024
Report of 2 patients (unrelated, 1 Caucasian and 1 Saudi family) with het p.Cys129Ser (stemming from c.385T>A or c.386G>C) change in OTULIN and a presentation consistent with OTULIN-related autoinflammatory syndrome. Authors observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. Patients presented with very early onset chronic inflammation, sterlie pustulosis, wound dehiscence. Variant is posed to have a dominant-negative effect.

PMID: 38914362 Caballero-Oteyza et al., 2024
Novel homozygous missense mutation OTULIN c.595T>A; p.(Trp199Arg) detected in a Moroccan infant with an ORAS phenotype of severe, sterile systemic inflammation, panniculitis. Method: WES + Sanger. Literature review in the paper includes 9 AR ORAS, 17 OTULIN Haploinsufficiency (AR Immunodeficiency) and 3 Dominant negative ORAS cases (including one from this study).; to: PMID: 38630025 Davidson et al., 2024
Report of 2 patients (unrelated, 1 Caucasian and 1 Saudi family) with het p.Cys129Ser (stemming from c.385T>A or c.386G>C) change in OTULIN and a presentation consistent with OTULIN-related autoinflammatory syndrome. Authors observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. Patients presented with very early onset chronic inflammation, sterlie pustulosis, wound dehiscence. Variant is posed to have a dominant-negative effect.

PMID: 38914362 Caballero-Oteyza et al., 2024
Novel homozygous missense mutation OTULIN c.595T>A; p.(Trp199Arg) detected in a Moroccan infant with an ORAS phenotype of severe, sterile systemic inflammation, panniculitis. Method: WES + Sanger. Literature review in the paper includes 9 AR ORAS, 17 OTULIN Haploinsufficiency (AR Immunodeficiency) and 3 Dominant negative ORAS cases (including one from this study).

OMIM has associations for OTULIN-related Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, OMIM:617099 and Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, OMIM:621030 (accessed 22nd May 2026).
Adult onset neurodegenerative disorder v9.1 PLEKHG5 Oliver Ziff gene: PLEKHG5 was added
gene: PLEKHG5 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: PLEKHG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHG5 were set to 23844677; 17564964
Phenotypes for gene: PLEKHG5 were set to Charcot Marie Tooth disease, recessive intermediate C, 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, 611067
Penetrance for gene: PLEKHG5 were set to Complete
Mode of pathogenicity for gene: PLEKHG5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Causes a late-onset distal hereditary motor neuropathy and SMA with progressive LMN signs that mimic PMA. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 HSPB8 Oliver Ziff gene: HSPB8 was added
gene: HSPB8 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: HSPB8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HSPB8 were set to Charcot Marie Tooth disease, axonal, type 2L, 608673; Neuropathy, distal hereditary motor, type IIA, 158590; Neuropathy, distal hereditary motor, type IIA, 158590
Penetrance for gene: HSPB8 were set to Incomplete
Mode of pathogenicity for gene: HSPB8 was set to Other
Review for gene: HSPB8 was set to GREEN
Added comment: Heat shock protein variant classically present with a late-onset, progressive lower motor neuron phenotype that clinically mimics progressive muscular atrophy. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SIGMAR1 Oliver Ziff reviewed gene: SIGMAR1: Rating: GREEN; 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: 26205306, 21842496, 26088964, 25678561, 26088963, 26078401; Phenotypes: Neuropathy, distal hereditary motor, type IIB, OMIM:608634, Charcot-Marie-Tooth disease, type 2F, OMIM:606595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v9.1 HSPB1 Oliver Ziff gene: HSPB1 was added
gene: HSPB1 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: HSPB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPB1 were set to 15122254; 28379183
Phenotypes for gene: HSPB1 were set to Neuropathy, distal hereditary motor, type IIB, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595
Penetrance for gene: HSPB1 were set to Incomplete
Mode of pathogenicity for gene: HSPB1 was set to Other
Review for gene: HSPB1 was set to GREEN
gene: HSPB1 was marked as current diagnostic
Added comment: HSPB1 variants (typically toxic gain-of-function missense mutations) frequently present with a late-onset, progressive lower motor neuron phenotype that clinically mimics progressive muscular atrophy (PMA) and ALS. Adding this target to the Adult onset neurodegenerative disorder component panel is necessary to capture these LMN mimics upfront on WGS requests for suspected MND (R460.1), preventing sequential and costly WGS reanalysis requests for the neuropathy panel (R78).
Sources: Expert Review, Literature
Proteinuric renal disease v6.1 STS John Sayer gene: STS was added
gene: STS was added to Proteinuric renal disease. Sources: Expert list
Mode of inheritance for gene: STS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STS were set to 22419362; 17468528
Phenotypes for gene: STS were set to Proteinuria; ichthyosis
Penetrance for gene: STS were set to Complete
Review for gene: STS was set to GREEN
Added comment: Good evidence this is a proteinuric gene. Cases of whole gene deletion of STS in Genomics England with phenotypes.
Sources: Expert list
Autoinflammatory disorders v3.9 OTULIN Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 22nd May 2026.
Autoinflammatory disorders v3.9 OTULIN Ida Ertmanska Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099 to Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, OMIM:617099; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, OMIM:621030
Autoinflammatory disorders v3.8 OTULIN Ida Ertmanska Publications for gene: OTULIN were set to 27559085; 27523608
Autoinflammatory disorders v3.7 OTULIN Ida Ertmanska Tag Q2_26_MOI tag was added to gene: OTULIN.
Autoinflammatory disorders v3.7 OTULIN Ida Ertmanska commented on gene: OTULIN: Comment on mode of inheritance: There are now 3 unrelated individuals reported with heterozygous missense (putative dominant-negative) variants in OTULIN, and an ORAS-like autoinflammatory syndrome. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on Autoinflammatory disorders.
Autoinflammatory disorders v3.7 OTULIN Ida Ertmanska reviewed gene: OTULIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 38630025, 38914362; Phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, OMIM:617099, Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, OMIM:621030; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v4.19 CARD11 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: CARD11.
Rare genetic inflammatory skin disorders v4.19 CARD11 Ida Ertmanska commented on gene: CARD11: Comment on mode of inheritance: There are at least 3 unrelated individuals reported in literature with biallelic CARD11 variants and inflammatory skin presentation (severe atopic dermatitis, lichenification of the palms and soles). In 1 case, dermatitis was the main phenotype, with no severe recurrent infections noted. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on Rare genetic inflammatory skin disorders.
Rare genetic inflammatory skin disorders v4.19 CARD11 Ida Ertmanska Publications for gene: CARD11 were set to 28628108
Rare genetic inflammatory skin disorders v4.18 CARD11 Ida Ertmanska reviewed gene: CARD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 26289640, 36729250, https://doi.org/10.1186/s43042-024-00489-3, https://doi.org/10.4049/jimmunol.212.supp.0307.5377; Phenotypes: Immunodeficiency 11B with atopic dermatitis, OMIM:617638, Immunodeficiency 11A, OMIM:615206; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v7.10 GRHL2 Ida Ertmanska Phenotypes for gene: GRHL2 were changed from ECTODERMAL DYSPLASIA/SHORT STATURE SYNDROME to Ectodermal dysplasia/short stature syndrome, OMIM:616029
Fetal anomalies v7.9 GRHL2 Ida Ertmanska Publications for gene: GRHL2 were set to
Fetal anomalies v7.8 GRHL2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: GRHL2.
Fetal anomalies v7.8 GRHL2 Ida Ertmanska reviewed gene: GRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152456, 27612988; Phenotypes: Ectodermal dysplasia/short stature syndrome, OMIM:616029; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.13 GRHL2 Ida Ertmanska Publications for gene: GRHL2 were set to PMID:12393799; 20938050; 21610158; 23813623; 25152456
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska edited their review of gene: GRHL2: Changed publications to: 12393799, 23813623, 25152456, 27612988, 27911912, 32048449
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska changed review comment from: PMID: 25152456 Petros et al., 2013
2 consanguineous Kuwaiti families with 6 total affected individuals with ectodermal dysplasia. Shared features: nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, short stature (≤25th percentile), and dysphagia. Patients in family ED-01 also presented with sensorineural deafness. ED-01 members were homozygous for GRHL2 c.1192T>C (p.Tyr398His), and ED-02 were homozygous for c.1445T>A (p.Ile482Lys).

PMID: 27612988 Walne et al., 2016
Report of 2 consanguineous families from Kuwait and Turkey.
Family 9: index patient homozygous for GRHL2 c.1445T>A p.Ile482Lys
Family 10: index patient homozygous for GRHL2 c.1213C>A p.Pro405Thr
Shared phenotype of the 2 probands: abnormal dentition, nail dystrophy, abnormal skin pigmentation, growth restriction (short stature). No mention of hearing loss.; to: BIALLELIC CASES:
PMID: 25152456 Petros et al., 2013
2 consanguineous Kuwaiti families with 6 total affected individuals with ectodermal dysplasia. Shared features: nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, short stature (≤25th percentile), and dysphagia. Patients in family ED-01 also presented with sensorineural deafness. ED-01 members were homozygous for GRHL2 c.1192T>C (p.Tyr398His), and ED-02 were homozygous for c.1445T>A (p.Ile482Lys).

PMID: 27612988 Walne et al., 2016
Report of 2 consanguineous families from Kuwait and Turkey.
Family 9: index patient homozygous for GRHL2 c.1445T>A p.Ile482Lys
Family 10: index patient homozygous for GRHL2 c.1213C>A p.Pro405Thr
Shared phenotype of the 2 probands: abnormal dentition, nail dystrophy, abnormal skin pigmentation, growth restriction (short stature). No mention of hearing loss.

MONOALLELIC CASES:
PMID: 12393799 Peters et al., 2002
Large American family with an autosomal dominant form of progressive non-syndromic sensorineural hearing loss. Variant c.1609-1610insC in GRHL2 (old name TFCP2L3) segregated with hearing loss.

PMID: 23813623 Vona et al., 2013
Large pedigree with post-lingual hearing loss with a highly variable age of onset and progression - segregated with a heterozygous non-classical splice site mutation in GRHL2: c.1258-1G>A, p.Gly420Glufs*111.

PMID: 27911912 Iwasa et al., 2016
3 Japanese families with AD hearing loss and heterozygous GRHL2 variants (2 missense, 1 frameshift)

PMID: 32048449 Wu et al., 2020
Han Chinese family with AD non-syndromic deafness, a het GRHL2 p.R426X variant segregated with hearing loss.
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska commented on gene: GRHL2: Comment on mode of inheritance: While there are several individuals reported with monoallelic GRHL2 variants and hearing loss, only 1/4 families reported with biallelic variants presented with hearing loss. Hence, the MOI for Monogenic hearing loss should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: GRHL2.
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska reviewed gene: GRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152456, 27612988; Phenotypes: Ectodermal dysplasia/short stature syndrome, OMIM:616029; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ehlers Danlos syndrome with a likely monogenic cause v4.9 LOX Ida Ertmanska Publications for gene: LOX were set to 26838787; 27432961
Ehlers Danlos syndrome with a likely monogenic cause v4.8 LOX Ida Ertmanska Tag Q2_26_MOI tag was added to gene: LOX.
Ehlers Danlos syndrome with a likely monogenic cause v4.8 LOX Ida Ertmanska commented on gene: LOX: Comment on mode of inheritance: There are 2 unrelated probands reported with biallelic missense LOX variants and a shared phenotype of cutis laxa, arterial dilatation, thickened heart, bone fragility, and respiratory failure. Mouse models are supportive, with knockout mouse showing abnormal collagen fibers in skin, impaired airway development, aneurysms and aortic wall dysplasia, with death occuring shortly after birth. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ehlers Danlos syndrome with a likely monogenic cause v4.8 LOX Ida Ertmanska reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 16192629, 27432961, 33866545; Phenotypes: Aortic aneurysm, familial thoracic 10, OMIM:617168; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v5.3 LOX Ida Ertmanska Phenotypes for gene: LOX were changed from Aortic aneurysm, familial thoracic 10, 617168; aortic aneurysm to Aortic aneurysm, familial thoracic 10, OMIM:617168
Thoracic aortic aneurysm or dissection (GMS) v5.2 LOX Ida Ertmanska Publications for gene: LOX were set to 26838787; 27432961
Thoracic aortic aneurysm or dissection (GMS) v5.1 LOX Ida Ertmanska Tag Q2_26_MOI tag was added to gene: LOX.
Thoracic aortic aneurysm or dissection (GMS) v5.1 LOX Ida Ertmanska commented on gene: LOX: Comment on mode of inheritance: There are 2 unrelated probands reported with biallelic missense LOX variants and a shared phenotype of cutis laxa, arterial dilatation, thickened heart, bone fragility, and respiratory failure. Mouse models are supportive, with knockout mouse showing abnormal collagen fibers in skin, impaired airway development, aneurysms and aortic wall dysplasia, with death occuring shortly after birth. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Thoracic aortic aneurysm or dissection (GMS) v5.1 LOX Ida Ertmanska reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 16192629, 27432961, 33866545; Phenotypes: Aortic aneurysm, familial thoracic 10, OMIM:617168; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric motor neuronopathies v3.16 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: A 'treatable' tag was added as high-dose riboflavin supplementation early on is effective in stopping disease progression and possibly lifesaving (https://www.ncbi.nlm.nih.gov/books/NBK299312/).
Monogenic hearing loss v6.12 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: A 'treatable' tag was added as high-dose riboflavin supplementation early on is effective in stopping disease progression and possibly lifesaving (https://www.ncbi.nlm.nih.gov/books/NBK299312/).
Hereditary neuropathy or pain disorder v8.3 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: A 'treatable' tag was added as high-dose riboflavin supplementation early on is effective in stopping disease progression and possibly lifesaving (https://www.ncbi.nlm.nih.gov/books/NBK299312/).
Likely inborn error of metabolism v9.4 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Likely inborn error of metabolism v9.4 SLC52A3 Ida Ertmanska commented on gene: SLC52A3
Mitochondrial disorders v10.4 SLC52A3 Ida Ertmanska commented on gene: SLC52A3
Mitochondrial disorders v10.4 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Paediatric motor neuronopathies v3.16 SLC52A3 Ida Ertmanska Phenotypes for gene: SLC52A3 were changed from Brown-Vialetto-Van Laere syndrome 1, OMIM:211530 to Brown-Vialetto-Van Laere syndrome 1, OMIM:211530; Brown-Vialetto-van Laere syndrome 1, MONDO:0024537; ?Fazio-Londe disease, OMIM:211500; riboflavin transporter deficiency, MONDO:0008891
Paediatric motor neuronopathies v3.15 SLC52A3 Ida Ertmanska Publications for gene: SLC52A3 were set to 20206331; 20920669
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: SLC52A3.
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Hereditary neuropathy or pain disorder v8.3 SLC52A3 Ida Ertmanska Phenotypes for gene: SLC52A3 were changed from Fazio-Londe disease; dHMN; Brown-Vialetto-Van Laere syndrome 1 to Brown-Vialetto-Van Laere syndrome 1, OMIM:211530; Brown-Vialetto-van Laere syndrome 1, MONDO:0024537; ?Fazio-Londe disease, OMIM:211500; riboflavin transporter deficiency, MONDO:0008891
Hereditary neuropathy or pain disorder v8.2 SLC52A3 Ida Ertmanska Publications for gene: SLC52A3 were set to 20206331
Hereditary neuropathy or pain disorder v8.1 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Tag Q2_26_MOI tag was added to gene: SLC52A3.
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: Comment on mode of inheritance: There are more than 3 unrelated patients with both monoallelic and biallelic variants in SLC52A3 and Brown-Vialetto-Van Laere syndrome. Both modes of inheritance result in the same phenotype of hearing loss and ponto-bulbar palsy / bilateral vestibular neuropathy. Hence, the mode of inheritance for Paediatric motor neuronopathies should be updated from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v8.1 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: Comment on mode of inheritance: There are more than 3 unrelated patients with both monoallelic and biallelic variants in SLC52A3 and Brown-Vialetto-Van Laere syndrome. Both modes of inheritance result in the same phenotype of hearing loss and ponto-bulbar palsy / bilateral vestibular neuropathy. Hence, the mode of inheritance for Hereditary neuropathy or pain disorder should be updated from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v8.1 SLC52A3 Ida Ertmanska reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22718020, 29053833, 34384672, 38469093, 40539137; Phenotypes: Brown-Vialetto-Van Laere syndrome 1, OMIM:211530, Brown-Vialetto-van Laere syndrome 1, MONDO:0024537, ?Fazio-Londe disease, OMIM:211500, riboflavin transporter deficiency, MONDO:0008891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22718020, 29053833, 34384672, 38469093, 40539137; Phenotypes: Brown-Vialetto-Van Laere syndrome 1, OMIM:211530, Brown-Vialetto-van Laere syndrome 1, MONDO:0024537, ?Fazio-Londe disease, OMIM:211500, riboflavin transporter deficiency, MONDO:0008891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v6.12 SLC52A3 Ida Ertmanska Publications for gene: SLC52A3 were set to 20206331; 20920669
Monogenic hearing loss v6.11 SLC52A3 Ida Ertmanska Phenotypes for gene: SLC52A3 were changed from Brown-Vialetto-Van Laere syndrome 1, OMIM:211530 to Brown-Vialetto-Van Laere syndrome 1, OMIM:211530; Brown-Vialetto-van Laere syndrome 1, MONDO:0024537; ?Fazio-Londe disease, OMIM:211500; riboflavin transporter deficiency, MONDO:0008891
Monogenic hearing loss v6.10 SLC52A3 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: SLC52A3.
Monogenic hearing loss v6.10 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: Comment on mode of inheritance: There are more than 3 unrelated patients with both monoallelic and biallelic variants in SLC52A3 and Brown-Vialetto-Van Laere syndrome. Both modes of inheritance result in the same phenotype of hearing loss and ponto-bulbar palsy / bilateral vestibular neuropathy. Hence, the mode of inheritance for Monogenic hearing loss should be updated from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Monogenic hearing loss v6.10 SLC52A3 Ida Ertmanska reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22718020, 29053833, 34384672, 38469093, 40539137; Phenotypes: Brown-Vialetto-Van Laere syndrome 1, OMIM:211530, Brown-Vialetto-van Laere syndrome 1, MONDO:0024537, ?Fazio-Londe disease, OMIM:211500, riboflavin transporter deficiency, MONDO:0008891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Palmoplantar keratodermas v4.11 KRT10 Ida Ertmanska Phenotypes for gene: KRT10 were changed from Pachyonychia congenita; Palmoplantar keratoderma; Ichythosis with confetti; Epidermolytic hyperkeratosis to Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707; Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150
Palmoplantar keratodermas v4.10 KRT10 Ida Ertmanska Publications for gene: KRT10 were set to
Palmoplantar keratodermas v4.9 KRT10 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: KRT10.
Palmoplantar keratodermas v4.9 KRT10 Ida Ertmanska commented on gene: KRT10: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and epidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with erosion improvement later in life and progressive hyperkeratosis (often on scalp and palmoplantar). Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Palmoplantar keratodermas v4.9 KRT10 Ida Ertmanska reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16505000, 20302579, 23957016, 29277919, 34273205, 38741524; Phenotypes: Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707, Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v4.14 KRT10 Ida Ertmanska Phenotypes for gene: KRT10 were changed from Epidermolytic hyperkeratosis (EHK), OMIM:113800; ichthyosis with confetti, OMIM:609165; Ichthyosis, cyclic, with epidermolytic hyperkeratosis, OMIM:607602 to Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707; Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150
Ichthyosis and erythrokeratoderma v4.13 KRT10 Ida Ertmanska Publications for gene: KRT10 were set to
Ichthyosis and erythrokeratoderma v4.12 KRT10 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: KRT10.
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and pidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life. Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and epidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life. Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ichthyosis and erythrokeratoderma v4.12 KRT10 Ida Ertmanska commented on gene: KRT10: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and epidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life (progression to hyperkeratosis). Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ichthyosis and erythrokeratoderma v4.12 KRT10 Ida Ertmanska reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16505000, 20302579, 23957016, 29277919, 34273205, 38741524; Phenotypes: Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707, Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska edited their review of gene: KRT10: Changed publications to: 16505000, 20302579, 23957016, 29277919, 34273205, 38741524
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska commented on gene: KRT10: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and pidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life. Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska Phenotypes for gene: KRT10 were changed from Epidermolytic hyperkeratosis, OMIM:113800 to Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707; Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150
Epidermolysis bullosa and congenital skin fragility v2.14 KRT10 Ida Ertmanska Publications for gene: KRT10 were set to
Epidermolysis bullosa and congenital skin fragility v2.13 KRT10 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: KRT10.
Epidermolysis bullosa and congenital skin fragility v2.13 KRT10 Ida Ertmanska reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16505000, 20302579, 29277919, 34273205, 38741524; Phenotypes: Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707, Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cholestasis v4.5 PEX6 Ida Ertmanska Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger) 614862 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Cholestasis v4.4 PEX6 Ida Ertmanska Publications for gene: PEX6 were set to 10408779; 8670792; 8940266
Cholestasis v4.3 PEX6 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: PEX6.
Cholestasis v4.3 PEX6 Ida Ertmanska commented on gene: PEX6: Comment on mode of inheritance: As there are 5 unrelated families reported in PMID: 29220678 with monoallelic PEX6 variants and apparently dominant Zellweger syndrome with hepatomegaly/liver dysfunction, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Cholestasis v4.3 PEX6 Ida Ertmanska reviewed gene: PEX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29220678; Phenotypes: Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862, Peroxisome biogenesis disorder 4B, OMIM:614863; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v7.8 RET Ida Ertmanska commented on gene: RET: Comment on mode of inheritance: I have found very limited evidence of RET-related recessive disease - 2 cases of severe Hirschsprung disease, and no cases with biallelic RET variants and renal agenesis. Hence, the MOI should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.
Fetal anomalies v7.8 RET Ida Ertmanska Publications for gene: RET were set to
Fetal anomalies v7.7 RET Ida Ertmanska Tag Q2_26_MOI tag was added to gene: RET.
Paediatric pseudo-obstruction syndrome v2.6 RET Ida Ertmanska Tag Q2_26_MOI was removed from gene: RET.
Paediatric pseudo-obstruction syndrome v2.6 RET Ida Ertmanska Tag Q2_26_MOI tag was added to gene: RET.
Fetal anomalies v7.7 RET Ida Ertmanska reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: 9090527, 34267336; Phenotypes: {Hirschsprung disease, susceptibility to, 1}, OMIM:142623; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v2.6 RET Ida Ertmanska reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: 9090527, 34267336; Phenotypes: {Hirschsprung disease, susceptibility to, 1}, OMIM:142623; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypogonadotropic hypogonadism (GMS) v5.2 PROKR2 Ida Ertmanska commented on gene: PROKR2: Comment on mode of inheritance: The majority (up to 90%) of cases reported in literature with Hypogonadotropic hypogonadism and PROKR2 variants are heterozygotes. There are at least 22 patients with HH and biallelic PROKR2 variants - mostly biallelic missense. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Hypogonadotropic hypogonadism (GMS) v5.2 PROKR2 Ida Ertmanska Publications for gene: PROKR2 were set to 36694982
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: PROKR2.
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska changed review comment from: PMID: 36843573 Martinez-Mayer and Perez-Millan, 2023
Literature review of 435 cases with PROKR2 variants, 108 with hypogonadotropic hypogonadism (HH) and 236 with Kallmann syndrome (KS). 90% of cases are heterozygous, 7% homozygous and 3% comp het.

Biallelic case examples:
PMID: 18682503 Abreu et al., 2008
PROKR2 p.Y140X change was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous.

PMID: 35236788 Sugisawa et al., 2022
We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. Diagnosed with sexual immaturity at 20 yrs old. He was comp het for PROKR2 variants p.Trp178Ser and p.Trp212*.

PROKR2 is associated with AD,AR Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200 (accessed 20th May 2026).; to: PMID: 36843573 Martinez-Mayer and Perez-Millan, 2023
Literature review of 435 cases with PROKR2 variants, 108 with hypogonadotropic hypogonadism (HH) and 236 with Kallmann syndrome (KS). 90% of cases are heterozygous, 7% homozygous and 3% comp het.

Biallelic case examples:
PMID: 18682503 Abreu et al., 2008
PROKR2 p.Y140X change was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous.

PMID: 35236788 Sugisawa et al., 2022
Report of a case of a 31-year-old Japanese man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. Diagnosed with sexual immaturity at 20 yrs old. He was comp het for PROKR2 variants p.Trp178Ser and p.Trp212*.
Literature review in same article found 21 other patients from 17 families with biallelic PROKR2 variants and CHH (86% diagnosed with KS). 17/22 patients had missense variants on both alleles; only 1 had biallelic truncating variants.

PROKR2 is associated with AD,AR Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200 (accessed 20th May 2026).
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska reviewed gene: PROKR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18682503, 35236788, 36843573; Phenotypes: Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare anaemia v4.2 SLC4A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.; to: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - some had mild hematological incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.; to: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska edited their review of gene: SLC4A1: Changed publications to: 37448902, 36776909, 29483102, 18174378, 16252102
Rare anaemia v4.2 SLC4A1 Ida Ertmanska changed review comment from: Biallelic anaemia cases:
PMID: 37448902 Shaikh, Suratkal, and Bhave, 2023
Report of an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia. The patient was treated for suspicion of autoimmune hemolytic anemia but was recalcitrant to treatment. Genetic analysis revealed the patient to be homozygous for SLC4A1 c.2573C>A (p.Ala858Asp). The patient’s parents and siblings had no clinical history of hematological or renal disease.

PMID: 29483102 Yang et al., 2018
Patient with anemia and distal renal tubular acidosis, homozygous for SLC4A1 c.2173A>C, p.Ser725Arg. 6-day-old male infant presented with tachypnea, intermittent hypoxia, scleral icterus, splenomegaly, and severe anemia, hemoglobin 6.6 g/dL, and marked spherocytosis. Mother and father (first cousins from Pakistan) were het for the variant, also had Band 3 deficiency and a level of hemolysis, though much lower than in the proband.

PMID: 18174378 Toye et al., 2008
Proband developed a transfusion-dependent, hemolytic anemia following birth. Immunoblotting showed band 3 was reduced to approximately 35% of wildtype. Homozygous SLC4A1 c.2000C>T, p.Ser667Phe variant detected. Parents are first cousins from Algerina, both het for the variant - showed compensated hemolysis and spherocytosis, which they were unaware of.; to: Biallelic anaemia cases:
PMID: 37448902 Shaikh, Suratkal, and Bhave, 2023
Report of an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia. The patient was treated for suspicion of autoimmune hemolytic anemia but was recalcitrant to treatment. Genetic analysis revealed the patient to be homozygous for SLC4A1 c.2573C>A (p.Ala858Asp). The patient’s parents and siblings had no clinical history of hematological or renal disease.

PMID: 36776909 Yang et al., 2023 - literature review
"almost half of the patients with AR dRTA had hematological abnormalities, while it was uncommon in patients with AD dRTA'
dRTA = distal renal tubular acidosis
"Autosomal recessive inheritance was more often found in Asian patients (P < 0.05)."

PMID: 29483102 Yang et al., 2018
Patient with anemia and distal renal tubular acidosis, homozygous for SLC4A1 c.2173A>C, p.Ser725Arg. 6-day-old male infant presented with tachypnea, intermittent hypoxia, scleral icterus, splenomegaly, and severe anemia, hemoglobin 6.6 g/dL, and marked spherocytosis. Mother and father (first cousins from Pakistan) were het for the variant, also had Band 3 deficiency and a level of hemolysis, though much lower than in the proband.

PMID: 22126643 Fawaz et al., 2012
Study of 7 children from 5 consanguineous Omani families presenting with hyperchloremic normal anion gap metabolic acidosis, failure to thrive, and mild to moderate compensated hemolytic anemia, homozygous for c.2573C>A; p.Ala858Asp (confirmed het in all parents). Reported striking acanthocytosis in the homozygous state and only a mild acanthocytosis in parents.

PMID: 18174378 Toye et al., 2008
Proband developed a transfusion-dependent, hemolytic anemia following birth. Immunoblotting showed band 3 was reduced to approximately 35% of wildtype. Homozygous SLC4A1 c.2000C>T, p.Ser667Phe variant detected. Parents are first cousins from Algerina, both het for the variant - showed compensated hemolysis and spherocytosis, which they were unaware of.

PMID: 16252102 Choo et al., 2005
Patient 2, Sarawak boy with profound hemolytic anemia - comp het for SLC4A1 p.Q759H and p.Ala400_Ala408del variants. Admitted to hospital at 3 weeks due to anemia and failure to thrive, required blood transfusions.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska commented on gene: SLC4A1: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska Publications for gene: SLC4A1 were set to 1722314
Rare anaemia v4.1 SLC4A1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: SLC4A1.
Rare anaemia v4.1 SLC4A1 Ida Ertmanska reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37448902, 29483102, 18174378; Phenotypes: Distal renal tubular acidosis 4 with hemolytic anemia, OMIM:611590, Cryohydrocytosis, OMIM:185020, Spherocytosis, type 4, OMIM:612653; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v9.3 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v9.3 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are nine patients from six unrelated families reported with cerebellar anomalies and with biallelic MAB21L1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v9.3 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v9.2 MAB21L1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MAB21L1.
Ataxia and cerebellar anomalies - narrow panel v9.2 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 27103078; 30487245
Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome, OMIM:618479; cerebellar, ocular, craniofacial, and genital syndrome, MONDO:0032774
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in an 8-year-old Algerian boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from five consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cerebellar anomalies such as cerebellar hypoplasia/ Dandy-Walker malformation/ Cerebellovermian hypoplasia with/ without pontine involvement was reported in eight patients from five families.

Biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 19 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388)
Sources: Literature
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram edited their review of gene: TUBA4A: Changed rating: AMBER
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Carl Fratter on Bleeding and platelet disorders panel (https://panelapp.genomicsengland.co.uk/panels/545/gene/TUBA4A/), there is only one published human case of macrothrombocytopenia and functional evidence from mouse model reported in association with variants in TUBA4A gene. This gene has been classified with 'Limited' rating by the Hemostasis Thrombosis expert panel in ClinGen. This gene can therefore be rated amber with the current evidence.
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Alexander Symon-Allen, there are 4 unrelated individuals reported in literature with monoallelic KCNJ4 variants and epilepsy. Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: As reviewed by Alexander Symon-Allen, there are 4 unrelated individuals reported in literature with monoallelic KCNJ4 variants and early-onset epilepsy. Hence, this gene should be promoted to Green at the next GMS update.
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska edited their review of gene: KCNJ4: Changed rating: GREEN
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: KCNJ4.
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Classified gene: KCNJ4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Alexander Symon-Allen, there are 4 unrelated individuals reported in literature with monoallelic KCNJ4 variants and epilepsy. Hence, this gene should be promoted to Green at the next GMS update.
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Gene: kcnj4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.6 SCN9A Ida Ertmanska Tag refuted tag was added to gene: SCN9A.
Malformations of cortical development v8.3 CEP76 Ida Ertmanska edited their review of gene: CEP76: Changed rating: RED
Malformations of cortical development v8.3 CEP76 Ida Ertmanska changed review comment from: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed non-cortical brain anomalies including molar tooth sign (brainstem and cerebellum anomaly), cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene can only be rated Red for Malformations of cortical development.; to: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed non-cortical brain anomalies including molar tooth sign (brainstem and cerebellum anomaly), cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene is not relevant to this panel - a curate_removed tag has been added.
Malformations of cortical development v8.3 CEP76 Ida Ertmanska Classified gene: CEP76 as No list
Malformations of cortical development v8.3 CEP76 Ida Ertmanska Gene: cep76 has been removed from the panel.
Malformations of cortical development v8.2 CEP76 Ida Ertmanska Tag curated_removed tag was added to gene: CEP76.
Malformations of cortical development v8.2 CEP76 Ida Ertmanska Classified gene: CEP76 as Red List (low evidence)
Malformations of cortical development v8.2 CEP76 Ida Ertmanska Gene: cep76 has been classified as Red List (Low Evidence).
Malformations of cortical development v8.1 CEP76 Ida Ertmanska changed review comment from: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed cortical anomalies including molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene should be promoted to Green for Malformations of cortical development.; to: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed non-cortical brain anomalies including molar tooth sign (brainstem and cerebellum anomaly), cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene can only be rated Red for Malformations of cortical development.
Malformations of cortical development v8.1 CEP76 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: CEP76.
Fetal anomalies v7.7 LMNB2 Arina Puzriakova Tag watchlist_moi tag was added to gene: LMNB2.
Early onset or syndromic epilepsy v9.6 EIF4A2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 18th May 2026.
Early onset or syndromic epilepsy v9.6 EIF4A2 Ida Ertmanska Phenotypes for gene: EIF4A2 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, OMIM:620455; neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, MONDO:0957541
Intellectual disability v10.17 EIF4A2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 18th May 2026.
Intellectual disability v10.17 EIF4A2 Ida Ertmanska Phenotypes for gene: EIF4A2 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, OMIM:620455; neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, MONDO:0957541
Childhood onset hereditary spastic paraplegia v9.1 DSTYK Ida Ertmanska Tag founder-effect tag was added to gene: DSTYK.
Hypertrophic cardiomyopathy v6.2 MYPN Ida Ertmanska Tag disputed tag was added to gene: MYPN.
Hypertrophic cardiomyopathy v6.2 MYPN Ida Ertmanska Classified gene: MYPN as Red List (low evidence)
Hypertrophic cardiomyopathy v6.2 MYPN Ida Ertmanska Gene: mypn has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy v6.1 MYPN Ida Ertmanska changed review comment from: The association between MYPN and Hypertrophic cardiomyopathy was classified as Disputed in ClinGen (Hereditary Cardiovascular Disease GCEP, 2023).; to: The association between MYPN and Hypertrophic cardiomyopathy was classified as Disputed in ClinGen (Hereditary Cardiovascular Disease GCEP, 2023), due to the lack of genetic evidence, minimal experimental evidence, and no new evidence since the initial curation.
Hypertrophic cardiomyopathy v6.1 MYPN Ida Ertmanska commented on gene: MYPN
Childhood onset dystonia, chorea or related movement disorder v8.3 NTN1 Ida Ertmanska Classified gene: NTN1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v8.3 NTN1 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals reported in literature with heterozygous variants in NTN1 and congenital mirror movements. A knockout mouse model supports this gene disease association. Hence, this gene should be promoted to Green at the next update.
Childhood onset dystonia, chorea or related movement disorder v8.3 NTN1 Ida Ertmanska Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v8.2 NTN1 Ida Ertmanska gene: NTN1 was added
gene: NTN1 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Q2_26_promote_green tags were added to gene: NTN1.
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to 28945198; 33472083
Phenotypes for gene: NTN1 were set to Mirror movements 4, OMIM:618264; mirror movements 4, MONDO:0032641
Review for gene: NTN1 was set to GREEN
Added comment: PMID: 28945198 Meneret et al., 2017
NTN1 c.1801T>C/p.Cys601Arg variant of NTN1 segregated in a dominant manner with congenital mirror movements (CMM) in three affected members of a French family - though there were 2 asymptomatic carriers as well.
Heterozygous variant c.1552_1554del/p.Ile518del in NTN1 segregated with CMM in all 3 affected members of a family from the United Kingdom.
NTN1 variant c.1802G>C/p.Cys601Ser found in a sporadic case with CMM.

PMID: 33472083 Pourchet et al., 2021
Mouse model - a conditional ntn1 knockout in the brainstem impairs midline crossing of corticospinal axons and leads to mirror movements.
Sources: Literature
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska changed review comment from: Additional cases:
PMID: 41506652 Mandia et al., 2026
Male proband B:II:1 with variant in MRPS23 (NM_016070.4):c.119C>T, p.(Pro40Leu) - homozygous. Individual exhibited leukoencephalopathy with distinctive white matter abnormalities, intellectual impairment, sensorineural deafness, cerebellar ataxia, pyramidal syndrome, and amyotrophic weakness in distal limbs, attributed to distal motor neuropathy. Folinic acid treatment resulted in great improvement. Fibroblast analysis showed a decrease in expression of complex I and IV subunits.

PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. 1 individual had severe hearing impairment. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.; to: Additional cases:
PMID: 41506652 Mandia et al., 2026
Male proband B:II:1 with variant in MRPS23 (NM_016070.4):c.119C>T, p.(Pro40Leu) - homozygous. Individual exhibited leukoencephalopathy with distinctive white matter abnormalities, intellectual impairment, sensorineural deafness, cerebellar ataxia, pyramidal syndrome, and amyotrophic weakness in distal limbs, attributed to distal motor neuropathy. Folinic acid treatment resulted in great improvement. Fibroblast analysis showed a decrease in expression of complex I and IV subunits.

PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. 1 individual had severe hearing impairment. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MRPS23.
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska commented on gene: MRPS23: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska Phenotypes for gene: MRPS23 were changed from hepatic disease and combined respiratory chain complex deficiencies to ?Combined oxidative phosphorylation deficiency 46, OMIM:618952; combined oxidative phosphorylation deficiency 46, MONDO:0033534
Mitochondrial disorders v10.3 MRPS23 Ida Ertmanska Publications for gene: MRPS23 were set to 26741492
Mitochondrial disorders v10.2 MRPS23 Ida Ertmanska Classified gene: MRPS23 as Amber List (moderate evidence)
Mitochondrial disorders v10.2 MRPS23 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic MRPS23 missense variants and a Combined oxidative phosphorylation deficiency (defects in CI and CIV shown in fibroblast cultures). Hence, this gene should be promoted to Green at the next GMS update.
Mitochondrial disorders v10.2 MRPS23 Ida Ertmanska Gene: mrps23 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v10.1 MRPS23 Ida Ertmanska reviewed gene: MRPS23: Rating: GREEN; Mode of pathogenicity: None; Publications: 38086984, 41506652; Phenotypes: ?Combined oxidative phosphorylation deficiency 46, OMIM:618952, combined oxidative phosphorylation deficiency 46, MONDO:0033534; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v9.4 MRPS23 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Likely inborn error of metabolism v9.4 MRPS23 Ida Ertmanska Phenotypes for gene: MRPS23 were changed from hepatic disease and combined respiratory chain complex deficiencies to ?Combined oxidative phosphorylation deficiency 46, OMIM:618952; combined oxidative phosphorylation deficiency 46, MONDO:0033534
Likely inborn error of metabolism v9.3 MRPS23 Ida Ertmanska Publications for gene: MRPS23 were set to PMID: 26741492
Likely inborn error of metabolism v9.2 MRPS23 Ida Ertmanska Classified gene: MRPS23 as Amber List (moderate evidence)
Likely inborn error of metabolism v9.2 MRPS23 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic MRPS23 missense variants and a Combined oxidative phosphorylation deficiency (defects in CI and CIV shown in fibroblast cultures). Hence, this gene should be promoted to Green at the next GMS update.
Likely inborn error of metabolism v9.2 MRPS23 Ida Ertmanska Gene: mrps23 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v9.1 MRPS23 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MRPS23.
Possible mitochondrial disorder - nuclear genes v5.4 MRPS23 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MRPS23.
Likely inborn error of metabolism v9.1 MRPS23 Ida Ertmanska reviewed gene: MRPS23: Rating: GREEN; Mode of pathogenicity: None; Publications: 38086984, 41506652; Phenotypes: ?Combined oxidative phosphorylation deficiency 46, OMIM:618952, combined oxidative phosphorylation deficiency 46, MONDO:0033534; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v5.4 MRPS23 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Possible mitochondrial disorder - nuclear genes v5.4 MRPS23 Ida Ertmanska Phenotypes for gene: MRPS23 were changed from Hepatic disease to Combined oxidative phosphorylation deficiency 46, OMIM:618952; combined oxidative phosphorylation deficiency 46, MONDO:0033534
Possible mitochondrial disorder - nuclear genes v5.3 MRPS23 Ida Ertmanska Publications for gene: MRPS23 were set to 26741492
Possible mitochondrial disorder - nuclear genes v5.2 MRPS23 Ida Ertmanska Classified gene: MRPS23 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v5.2 MRPS23 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic MRPS23 missense variants and a Combined oxidative phosphorylation deficiency (defects in CI and CIV shown in fibroblast cultures). Hence, this gene should be promoted to Green at the next GMS update.
Possible mitochondrial disorder - nuclear genes v5.2 MRPS23 Ida Ertmanska Gene: mrps23 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v5.1 MRPS23 Ida Ertmanska edited their review of gene: MRPS23: Changed publications to: 38086984, 41506652
Possible mitochondrial disorder - nuclear genes v5.1 MRPS23 Ida Ertmanska changed review comment from: Additional case:
PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.; to: Additional cases:
PMID: 41506652 Mandia et al., 2026
Male proband B:II:1 with variant in MRPS23 (NM_016070.4):c.119C>T, p.(Pro40Leu) - homozygous. Individual exhibited leukoencephalopathy with distinctive white matter abnormalities, intellectual impairment, sensorineural deafness, cerebellar ataxia, pyramidal syndrome, and amyotrophic weakness in distal limbs, attributed to distal motor neuropathy. Folinic acid treatment resulted in great improvement. Fibroblast analysis showed a decrease in expression of complex I and IV subunits.

PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. 1 individual had severe hearing impairment. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.
Possible mitochondrial disorder - nuclear genes v5.1 MRPS23 Ida Ertmanska reviewed gene: MRPS23: Rating: GREEN; Mode of pathogenicity: None; Publications: 38086984; Phenotypes: ?Combined oxidative phosphorylation deficiency 46, OMIM:618952, combined oxidative phosphorylation deficiency 46, MONDO:0033534; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v7.7 RNF2 Ida Ertmanska Classified gene: RNF2 as Amber List (moderate evidence)
Fetal anomalies v7.7 RNF2 Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with heterozygous variants (mostly de novo missense) and Luo-Schoch-Yamamoto syndrome. Prenatal complications were present in all 6 patients. Hence, this gene will be recommended for promotion to Green once PMID:40831499 is published.
Fetal anomalies v7.7 RNF2 Ida Ertmanska Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.16 RNF2 Ida Ertmanska Classified gene: RNF2 as Amber List (moderate evidence)
Intellectual disability v10.16 RNF2 Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with heterozygous variants (mostly de novo missense) and Luo-Schoch-Yamamoto syndrome. Syndromic GDD / ID was present in 5/6 patients. Hence, this gene will be recommended for promotion to Green once PMID:40831499 is published.
Intellectual disability v10.16 RNF2 Ida Ertmanska Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v7.6 RNF2 Ida Ertmanska gene: RNF2 was added
gene: RNF2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF2 were set to 33864376; 40831499
Phenotypes for gene: RNF2 were set to Luo-Schoch-Yamamoto syndrome, OMIM:619460; Luo-Schoch-Yamamoto syndrome, MONDO:0859171
Review for gene: RNF2 was set to GREEN
Added comment: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 4 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 3/4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (3/4), seizures (1/3), spasticity (2/4), developmental delay and intellectual disability (3/4).

PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
Intellectual disability v10.15 RNF2 Ida Ertmanska gene: RNF2 was added
gene: RNF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF2 were set to 33864376; 40831499
Phenotypes for gene: RNF2 were set to Luo-Schoch-Yamamoto syndrome, OMIM:619460; Luo-Schoch-Yamamoto syndrome, MONDO:0859171
Review for gene: RNF2 was set to GREEN
Added comment: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 4 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 3/4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (3/4), seizures (1/3), spasticity (2/4), developmental delay and intellectual disability (3/4).

PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska changed review comment from: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 6 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (5/6), seizures (3/6), spasticity (2/6), developmental delay and intellectual disability (5/6), microcephaly (2/6).; to: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 4 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 3/4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (3/4), seizures (1/3), spasticity (2/4), developmental delay and intellectual disability (3/4).
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska Classified gene: RNF2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with heterozygous variants (mostly de novo missense) and Luo-Schoch-Yamamoto syndrome. Seizures were present in 3/6 patients. Hence, this gene will be recommended for promotion to Green once PMID:40831499 is published.
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.4 RNF2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Early onset or syndromic epilepsy v9.4 RNF2 Ida Ertmanska Phenotypes for gene: RNF2 were changed from epilepsy; intellectual disability; intrauterine growth retardation to Luo-Schoch-Yamamoto syndrome, OMIM:619460; Luo-Schoch-Yamamoto syndrome, MONDO:0859171
Early onset or syndromic epilepsy v9.3 RNF2 Ida Ertmanska Publications for gene: RNF2 were set to 33864376
Early onset or syndromic epilepsy v9.2 RNF2 Ida Ertmanska Mode of inheritance for gene: RNF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.1 RNF2 Ida Ertmanska reviewed gene: RNF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40831499; Phenotypes: Luo-Schoch-Yamamoto syndrome, OMIM:619460, Luo-Schoch-Yamamoto syndrome, MONDO:0859171; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v9.3 VPS51 Ida Ertmanska Classified gene: VPS51 as Amber List (moderate evidence)
Severe microcephaly v9.3 VPS51 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and severe syndromic ID / GDD. While severity was not stated, microcephaly was a consistent feature in all individuals. Hence, this gene can be promoted to Green at the next update.
Severe microcephaly v9.3 VPS51 Ida Ertmanska Gene: vps51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.14 VPS51 Ida Ertmanska changed review comment from: Additional cases:
PMID: 40565173 Aygun et al., 2025
2 sibs exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. Both homozygous for a c.1511C>T; p.Thr504Met VPS51 variant.

PMID: 40176246 Bhanudeep & Koneti, 2025
Proband: 15 month old boy with severe global developmental delay, failure to thrive, microcephaly, generalized hypotonia, nystagmus, Brisk DTRs. Neuroimaging showed diffuse hypomyelinated white matter, severely hypoplastic corpus callosum, and cerebral and cerebellar atrophy.; to: Additional cases:
PMID: 40565173 Aygun et al., 2025
2 sibs exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. Both homozygous for a c.1511C>T; p.Thr504Met VPS51 variant.

PMID: 40176246 Bhanudeep & Koneti, 2025
Proband: 15 month old boy with severe global developmental delay, failure to thrive, microcephaly, generalized hypotonia, nystagmus, Brisk DTRs. Neuroimaging showed diffuse hypomyelinated white matter, severely hypoplastic corpus callosum, and cerebral and cerebellar atrophy. WES revealed a homozygous VPS51 duplication p.Lys126_Met132dup.
Severe microcephaly v9.2 VPS51 Ida Ertmanska gene: VPS51 was added
gene: VPS51 was added to Severe microcephaly. Sources: Literature
Q2_26_promote_green tags were added to gene: VPS51.
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318; 40176246; 40565173
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, OMIM:618606; pontocerebellar hypoplasia, type 13, MONDO:0032831; neurodevelopmental disorder, MONDO:0700092
Review for gene: VPS51 was set to GREEN
Added comment: PMID: 40565173 Aygun et al., 2025
2 sibs exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. Both homozygous for a c.1511C>T; p.Thr504Met VPS51 variant.

PMID: 40176246 Bhanudeep & Koneti, 2025
Proband: 15 month old boy with severe global developmental delay, failure to thrive, microcephaly, generalized hypotonia, nystagmus, Brisk DTRs. Neuroimaging showed diffuse hypomyelinated white matter, severely hypoplastic corpus callosum, and cerebral and cerebellar atrophy. WES revealed a homozygous VPS51 duplication p.Lys126_Met132dup.

PMID: 30624672 (2019) - 6-year-old girl with severe global developmental delay, pontocerebellar abnormalities, microcephaly, hypotonia, epilepsy and several systemic and peripheral dysfunctions. Exome sequencing revealed compound heterozygous variants in VPS51 ([c.2232delC; p.Asp745Thrfs*93];[c.1468C>T; p.Arg490Cys]). Functional studies of both variants indicate impaired function of the mutant protein.

PMID: 31207318 (2019) - two sisters with a homozygous three bp in-frame deletion (c.1419_1421del; p.Phe474del) in VPS51 associated with developmental delay, absent speech, severe ID and microcephaly. Development in both sisters was initially unremarkable; however, following an episode of fever (at 1 and 12 months of age, respectively), pyschomotor development was severely delayed. At 30 months and 9 years of age, respectively, neither sister had any language. No functional studies of the variant or patient cells were undertaken.
Sources: Literature
Intellectual disability v10.14 VPS51 Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and sever syndromic ID / GDD. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and severe syndromic ID / GDD. Hence, this gene can be promoted to Green at the next update.
Intellectual disability v10.14 VPS51 Ida Ertmanska Phenotypes for gene: VPS51 were changed from Pontocerebellar hypoplasia, type 13, MIM# 618606 to Pontocerebellar hypoplasia, type 13, OMIM:618606; pontocerebellar hypoplasia, type 13, MONDO:0032831; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v10.13 VPS51 Ida Ertmanska Publications for gene: VPS51 were set to 30624672; 31207318
Intellectual disability v10.12 VPS51 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: VPS51.
Intellectual disability v10.12 VPS51 Ida Ertmanska Classified gene: VPS51 as Amber List (moderate evidence)
Intellectual disability v10.12 VPS51 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and sever syndromic ID / GDD. Hence, this gene can be promoted to Green at the next update.
Intellectual disability v10.12 VPS51 Ida Ertmanska Gene: vps51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.11 VPS51 Ida Ertmanska reviewed gene: VPS51: Rating: GREEN; Mode of pathogenicity: None; Publications: 40565173, 40176246; Phenotypes: Pontocerebellar hypoplasia, type 13, OMIM:618606, pontocerebellar hypoplasia, type 13, MONDO:0032831, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 RNF31 Ida Ertmanska Phenotypes for gene: RNF31 were changed from Bacterial infections, autoinflammation, amylopectinosis, lymphangiectasia; Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis; Polyglucosan body myopathy, early-onset, with or without immunodeficiency; autoinflammation and combined immunodeficiency; Combined immunodeficiencies with associated or syndromic features to Immunodeficiency 115 with autoinflammation, OMIM:620632; immunodeficiency 115 with autoinflammation, MONDO:0957981
Primary immunodeficiency or monogenic inflammatory bowel disease v9.8 RNF31 Ida Ertmanska Publications for gene: RNF31 were set to 30936877; 32086639; 26008899; 32048120
Autoinflammatory disorders v3.7 RNF31 Ida Ertmanska Classified gene: RNF31 as Amber List (moderate evidence)
Autoinflammatory disorders v3.7 RNF31 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals with biallelic RNF31 (HOIP) variants and primary immunodeficiency with autoinflammation. Hence, this gene can be promoted to Green at the next update.
Autoinflammatory disorders v3.7 RNF31 Ida Ertmanska Gene: rnf31 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.7 RNF31 Ida Ertmanska Classified gene: RNF31 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.7 RNF31 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals with biallelic RNF31 (HOIP) variants and primary immunodeficiency with autoinflammation. Hence, this gene can be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.7 RNF31 Ida Ertmanska Gene: rnf31 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 RNF31 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: RNF31.
Autoinflammatory disorders v3.6 RNF31 Ida Ertmanska gene: RNF31 was added
gene: RNF31 was added to Autoinflammatory disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: RNF31.
Mode of inheritance for gene: RNF31 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF31 were set to 26008899; 30936877; 39009172; 41026334
Phenotypes for gene: RNF31 were set to Immunodeficiency 115 with autoinflammation, OMIM:620632; immunodeficiency 115 with autoinflammation, MONDO:0957981
Review for gene: RNF31 was set to GREEN
Added comment: PMID: 41026334 L. Wang et al., 2025
Proband: 1-year-6-month-old Chinese boy with early-onset autoinflammation and immunodeficiency, leading to early death. He experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period. WES + Sanger detected comp het RNF31 variants: c.1654 C > T, p.Gln552Ter and c.3038 A > C, p.His1013Pro. Diagnosed with purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation before 18 months of age. Immunophenotyping showed decrease in T cell frequency and total CD4 T cell counts.

PMID: 39009172 M. Wang et al., 2024
12yo Chinese male, homozygous for c.1883del, p.Gly628Alafs*52 in RNF31. He presented with infectious mononucleosis, necrotizing lymphadenitis, sepsis, primary peritonitis, lobar pneumonia, and recurrent viral and bacterial infections.
Functional: variant impairs MAPK signalling and sensitizes cells to TNF-induced cell death.

PMID: 30936877 Oda et al., 2019
8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Noted to have eczematous dermatitis and chronic inflammation on skin biopsy. She had comp het variants in RNF31: c.1197G>C and c.1737+3A>G. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells

PMID: 26008899 Boisson et al., 2015
Female patient born to consanguineous parents of Kuwaiti descent; presented with multiorgan autoinflammation, systemic lymphangiectasia, weakness at lower extremities, subclinical amylopectinosis, and a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections, associated with lymphopenia, antibody deficiency and an impaired distribution and function of T lymphocytes. She was homozygous for c.215T>C, p.Leu72Pro in RNF31.

The association between RNF31 and AR immunodeficiency 115 with autoinflammation was classified as Moderate in ClinGen (SCID-CID GCEP, 2025).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 RNF31 Ida Ertmanska changed review comment from: PMID: 41026334 L. Wang et al., 2025
Proband: 1-year-6-month-old Chinese boy with early-onset autoinflammation and immunodeficiency, leading to early death. He experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period. WES + Sanger detected comp het RNF31 variants: c.1654 C > T, p.Gln552Ter and c.3038 A > C, p.His1013Pro. Diagnosed with purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation before 18 months of age. Immunophenotyping showed decrease in T cell frequency and total CD4 T cell counts.

PMID: 39009172 M. Wang et al., 2024
12yo Chinese male, homozygous for c.1883del, p.Gly628Alafs*52 in RNF31. He presented with infectious mononucleosis, necrotizing lymphadenitis, sepsis, primary peritonitis, lobar pneumonia, and recurrent viral and bacterial infections.
Functional: variant impairs MAPK signalling and sensitizes cells to TNF-induced cell death.

PMID: 30936877 Oda et al., 2019
8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Noted to have eczematous dermatitis and chronic inflammation on skin biopsy. She had comp het variants in RNF31: c.1197G>C and c.1737+3A>G. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells

PMID: 26008899 Boisson et al., 2015
Female patient born to consanguineous parents of Kuwaiti descent; presented with multiorgan autoinflammation, systemic lymphangiectasia, weakness at lower extremities, subclinical amylopectinosis, and a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections, associated with lymphopenia, antibody deficiency and an impaired distribution and function of T lymphocytes.
She was homozygous for c.215T>C, p.Leu72Pro in RNF31; to: PMID: 41026334 L. Wang et al., 2025
Proband: 1-year-6-month-old Chinese boy with early-onset autoinflammation and immunodeficiency, leading to early death. He experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period. WES + Sanger detected comp het RNF31 variants: c.1654 C > T, p.Gln552Ter and c.3038 A > C, p.His1013Pro. Diagnosed with purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation before 18 months of age. Immunophenotyping showed decrease in T cell frequency and total CD4 T cell counts.

PMID: 39009172 M. Wang et al., 2024
12yo Chinese male, homozygous for c.1883del, p.Gly628Alafs*52 in RNF31. He presented with infectious mononucleosis, necrotizing lymphadenitis, sepsis, primary peritonitis, lobar pneumonia, and recurrent viral and bacterial infections.
Functional: variant impairs MAPK signalling and sensitizes cells to TNF-induced cell death.

PMID: 30936877 Oda et al., 2019
8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Noted to have eczematous dermatitis and chronic inflammation on skin biopsy. She had comp het variants in RNF31: c.1197G>C and c.1737+3A>G. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells

PMID: 26008899 Boisson et al., 2015
Female patient born to consanguineous parents of Kuwaiti descent; presented with multiorgan autoinflammation, systemic lymphangiectasia, weakness at lower extremities, subclinical amylopectinosis, and a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections, associated with lymphopenia, antibody deficiency and an impaired distribution and function of T lymphocytes. She was homozygous for c.215T>C, p.Leu72Pro in RNF31.

The association between RNF31 and AR immunodeficiency 115 with autoinflammation was classified as Moderate in ClinGen (SCID-CID GCEP, 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 RNF31 Ida Ertmanska reviewed gene: RNF31: Rating: GREEN; Mode of pathogenicity: None; Publications: 26008899, 30936877, 39009172, 41026334; Phenotypes: Immunodeficiency 115 with autoinflammation, OMIM:620632, immunodeficiency 115 with autoinflammation, MONDO:0957981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v5.4 TXNRD2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th May 2026.
Congenital adrenal hypoplasia v5.4 TXNRD2 Ida Ertmanska Phenotypes for gene: TXNRD2 were changed from Familial glucocorticoid deficiency to ?Glucocorticoid deficiency 5 , OMIM:617825; glucocorticoid deficiency 5, MONDO:0040502
Congenital adrenal hypoplasia v5.3 TXNRD2 Ida Ertmanska Publications for gene: TXNRD2 were set to PMC4207928; 24601690
Congenital adrenal hypoplasia v5.2 TXNRD2 Ida Ertmanska Classified gene: TXNRD2 as Amber List (moderate evidence)
Congenital adrenal hypoplasia v5.2 TXNRD2 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals reported with biallelic TXNRD2 variants and Glucocorticoid deficiency, evidenced by loss of cortisol production and severe elevation of ACTH. Hence, this gene should be promoted to Green at the next update.
Congenital adrenal hypoplasia v5.2 TXNRD2 Ida Ertmanska Gene: txnrd2 has been classified as Amber List (Moderate Evidence).
Congenital adrenal hypoplasia v5.1 TXNRD2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TXNRD2.
Congenital adrenal hypoplasia v5.1 TXNRD2 Ida Ertmanska reviewed gene: TXNRD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24601690, 30237576, 38011841, 39097530, 40726908; Phenotypes: ?Glucocorticoid deficiency 5 , OMIM:617825, glucocorticoid deficiency 5, MONDO:0040502; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v3.22 SLC4A3 Ida Ertmanska Publications for gene: SLC4A3 were set to 29167417; 29697308; 36806574; 18382206; 19862833; 30420954
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska edited their review of gene: SLC4A3: Changed publications to: 36806574, 41039816
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska changed review comment from: PMID: 36806574 Christiansen et al., 2023
Identified 4 patients with SQTS, heterozygous for novel nonsynonymous SLC4A3 variants: p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His, and 1 patient with the known p.Arg370His variant.
Functional: Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals. This was rescued by the WT human SLC4A3 protein expression, but not by the mutant proteins.

The relationship between SLC4A3 and Short QT syndrome was classified as Moderate in ClinGen (Short QT Syndrome GCEP, 2020).; to: PMID: 41039816 Crea et al., 2025
A novel heterozygous SLC4A3 mutation (c.1157G>T; p.Gly386Val) was identified in the proband and her mother, both with short QT intervals. The family history included multiple cases of sudden unexplained death and epilepsy

PMID: 36806574 Christiansen et al., 2023
Identified 4 patients with SQTS, heterozygous for novel nonsynonymous SLC4A3 variants: p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His, and 1 patient with the known p.Arg370His variant.
Functional: Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals. This was rescued by the WT human SLC4A3 protein expression, but not by the mutant proteins.

The relationship between SLC4A3 and Short QT syndrome was classified as Moderate in ClinGen (Short QT Syndrome GCEP, 2020).
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th May 2026.
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska Phenotypes for gene: SLC4A3 were changed from short QT; ventricular fibrillation; cardiac arrest to Short QT syndrome 7, OMIM:620231; short QT syndrome 7, MONDO:0859368
Short QT syndrome v3.20 SLC4A3 Ida Ertmanska Publications for gene: SLC4A3 were set to 29167417; 29697308
Short QT syndrome v3.19 SLC4A3 Ida Ertmanska Mode of inheritance for gene: SLC4A3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Short QT syndrome v3.18 SLC4A3 Ida Ertmanska Classified gene: SLC4A3 as Amber List (moderate evidence)
Short QT syndrome v3.18 SLC4A3 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated patients with heterozygous SLC4A3 variants and short QT syndrome. Christiansen et al. (PMID: 36806574, 2023) pose that variants in SLC4A3 represent the most common cause of SQTS. Hence, this gene should be promoted to Green at the next update.
Short QT syndrome v3.18 SLC4A3 Ida Ertmanska Gene: slc4a3 has been classified as Amber List (Moderate Evidence).
Short QT syndrome v3.17 SLC4A3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: SLC4A3.
Short QT syndrome v3.17 SLC4A3 Ida Ertmanska reviewed gene: SLC4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36806574; Phenotypes: Short QT syndrome 7, OMIM:620231, short QT syndrome 7, MONDO:0859368; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v4.14 TUBA8 Achchuthan Shanmugasundram Classified gene: TUBA8 as Amber List (moderate evidence)
Bleeding and platelet disorders v4.14 TUBA8 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Carl Fratter, PMID:34662886 (2021) reported UK Biobank cohort study, of which one variant was reported in TUBA8 gene as associated with increased platelet distribution width (but no association reported with platelet count).

PMID:34704371 (2022) reported the identification of six distinct heterozygous variants in six unrelated individuals from a large cohort of French blood donors with mild thrombocytopenia. The individuals were generally asymptomatic and one had menorrhagia. There is also some functional data.

As these reported individuals are from large cohorts and they are mostly asymptomatic, this can only be rated amber with current evidence.
Bleeding and platelet disorders v4.14 TUBA8 Achchuthan Shanmugasundram Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.9 TBX2 Ida Ertmanska Classified gene: TBX2 as Amber List (moderate evidence)
Skeletal dysplasia v9.9 TBX2 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated individuals reported with heterozygous TBX2 variants and skeletal malformations - a proband with severe chondrodysplasia punctata, a family with dominant osteochondrodysplasia, a patient with congenital fusions of the thoracic spine and hemivertebrae with scoliosis, and another individual rib fusions and scoliosis. Hence, this gene can now be promoted to Green on Skeletal dysplasia.
Skeletal dysplasia v9.9 TBX2 Ida Ertmanska Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.13 TUBA8 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: OMIM phenotype last accessed on 13 May 2026; to: Comment on phenotypes: OMIM phenotype last accessed on 13 May 2026.
Bleeding and platelet disorders v4.13 TUBA8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 13 May 2026
Bleeding and platelet disorders v4.13 TUBA8 Achchuthan Shanmugasundram Phenotypes for gene: TUBA8 were changed from to Macrothrombocytopenia, isolated, 2, autosomal dominant, OMIM:619840; macrothrombocytopenia, isolated, 2, autosomal dominant, MONDO:0030827
Bleeding and platelet disorders v4.12 TUBA8 Achchuthan Shanmugasundram Publications for gene: TUBA8 were set to PMID: 34662886)
Bleeding and platelet disorders v4.11 TUBA8 Achchuthan Shanmugasundram reviewed gene: TUBA8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Macrothrombocytopenia, isolated, 2, autosomal dominant, OMIM:619840, macrothrombocytopenia, isolated, 2, autosomal dominant, MONDO:0030827; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v9.8 TBX2 Ida Ertmanska gene: TBX2 was added
gene: TBX2 was added to Skeletal dysplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: TBX2.
Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX2 were set to 29726930; 35311234; 36733940
Phenotypes for gene: TBX2 were set to Vertebral anomalies and variable endocrine and T-cell dysfunction, OMIM:618223; vertebral anomalies and variable endocrine and T-cell dysfunction, MONDO:0032607; chondrodysplasia, MONDO:0022723
Review for gene: TBX2 was set to GREEN
Added comment: PMID: 36733940 Rafeeq et al., 2023
Patient (5yo female from Pakistan) with severe chondrodysplasia punctata with developmental delay, deceased at 5yrs. WES detected a de novo heterozygous c.529A>T; p.Lys177* variant in TBX2. MRI and radiographs showed platybasia at the skull base, delayed myelination for the patient’s age, and severe skeletal deformities. No hearing loss.

PMID: 35311234 Makitie et al., 2022
Report of a three-generation Finnish family with an unusual, autosomal dominant form of osteochondrodysplasia and an empty sella. Affected individuals (age range 24-44 years) exhibit codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Joint pain, obesity, and dysmorphic features were also noted. WES detected heterozygous c.899C>T (p.Thr300Met) variant in TBX2. Proband's father, and grandfather were similarly affected, deceased in their 40s - only proband and unaffected family members were sequenced. Clinical diagnosis of osteochondrodysplasia and osteoarthritis. No hearing loss or impaired cognition.

PMID: 29726930 Liu et al., 2018
Four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies (PDA, double outlet right ventricle), skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome. All 4 are heterozygotes for TBX2 variants: p.R20Q variant is shared by three affected family members - segregated in autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Skeletal features: congenital fusions of the thoracic spine and hemivertebrae with scoliosis (P4), rib fusions, scoliosis (P1), campodactyly (P1-3).
Sources: Literature
Bleeding and platelet disorders v4.11 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Amber List (moderate evidence)
Bleeding and platelet disorders v4.11 TUBA4A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Carl Fratter, there is only one published human case of macrothrombocytopenia and functional evidence from mouse model reported in association with variants in TUBA4A gene. This gene has been classified with 'Limited' rating by the Hemostasis Thrombosis expert panel in ClinGen. This gene can therefore be rated amber with the current evidence.
Bleeding and platelet disorders v4.11 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.10 TUBA4A Achchuthan Shanmugasundram Publications for gene: TUBA4A were set to PMID: 30760556; 36026602
Corneal dystrophy v4.9 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Corneal dystrophy v4.9 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 11 patients from six unrelated families reported with bilateral corneal opacities/ corneal dystrophy and with biallelic MAB21L1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Corneal dystrophy v4.9 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v4.8 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Corneal dystrophy. Sources: Literature
Q2_26_promote_green tags were added to gene: MAB21L1.
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 27103078; 30487245
Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome, OMIM:618479; cerebellar, ocular, craniofacial, and genital syndrome, MONDO:0032774
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from five consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

Biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 12 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388).
Sources: Literature
Albinism or congenital nystagmus v4.8 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Albinism or congenital nystagmus v4.8 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 10 patients from five unrelated families reported with horizontal nystagmus and with biallelic MAB21L1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Albinism or congenital nystagmus v4.8 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v4.7 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Albinism or congenital nystagmus. Sources: Literature
Q2_26_promote_green tags were added to gene: MAB21L1.
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 27103078; 30487245
Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome, OMIM:618479; cerebellar, ocular, craniofacial, and genital syndrome, MONDO:0032774
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from five consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

Biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 12 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388).
Sources: Literature
Intellectual disability v10.11 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 12 May 2026.
Intellectual disability v10.11 MAB21L1 Achchuthan Shanmugasundram Phenotypes for gene: MAB21L1 were changed from Global developmental delay; Intellectual disability; Cerebellar hypoplasia; Abnormality of the eye; Abnormality of the genital system; No OMIM number to Cerebellar, ocular, craniofacial, and genital syndrome OMIM:618479
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MAB21L1.
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Biallelic variants in MAB21L1 are associated with a syndromic phenotype including ophthalmological presentations such as horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration. These phenotypes are not relevant for this panel.

However, there is sufficient evidence available for the association of monoallelic MAB21L1 variants with phenotypes relevant to this panel such as microphthalmia and aniridia. Hence, this gene should be promoted to green rating with MOI set as 'MONOALLELIC' in the next GMS update.
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v5.4 MAB21L1 Achchuthan Shanmugasundram Phenotypes for gene: MAB21L1 were changed from to microphthalmia, MONDO:0021129; aniridia, MONDO:0019172
Structural eye disease v5.3 MAB21L1 Achchuthan Shanmugasundram Publications for gene: MAB21L1 were set to 33973683; 36413568; 36446583; 36892533; 39016008
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram edited their review of gene: MAB21L1: Changed phenotypes to: microphthalmia, MONDO:0021129, aniridia, MONDO:0019172
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram changed review comment from: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature; to: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.

Only biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 12 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388). However, only monoallelic variants are associated with phenotypes relevant to this panel.
Sources: Literature
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram edited their review of gene: MAB21L1: Changed publications to: 27103078, 30487245, 33973683, 36413568, 36446583, 36892533, 39016008
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram changed review comment from: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature; to: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram edited their review of gene: MAB21L1: Changed publications to: 30487245, 33973683, 36413568, 36446583, 36892533, 39016008
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram changed review comment from: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature; to: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: MAB21L1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAB21L1 were set to 33973683; 36413568; 36446583; 36892533; 39016008
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature
Paediatric disorders - additional genes v8.6 PRDM6 Ida Ertmanska Publications for gene: PRDM6 were set to
Paediatric disorders - additional genes v8.5 PRDM6 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 12 May 2026.
Paediatric disorders - additional genes v8.5 PRDM6 Ida Ertmanska Phenotypes for gene: PRDM6 were changed from Patent ductus arteriosus 3 to Patent ductus arteriosus 3, OMIM:617039; patent ductus arteriosus 3, MONDO:0024266
Paediatric disorders - additional genes v8.4 PRDM6 Ida Ertmanska Mode of inheritance for gene: PRDM6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v8.3 PRDM6 Ida Ertmanska Classified gene: PRDM6 as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.3 PRDM6 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families with heterozygous PRDM6 variants and isolated patent ductus arteriosus. Hence, this gene should be promoted to Green at the next update.
Paediatric disorders - additional genes v8.3 PRDM6 Ida Ertmanska Gene: prdm6 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.2 PRDM6 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PRDM6.
Paediatric disorders - additional genes v8.2 PRDM6 Ida Ertmanska reviewed gene: PRDM6: Rating: GREEN; Mode of pathogenicity: None; Publications: 27181681, 38071433; Phenotypes: Patent ductus arteriosus 3, OMIM:617039, patent ductus arteriosus 3, MONDO:0024266; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.5 PLCG1 Ida Ertmanska Classified gene: PLCG1 as Amber List (moderate evidence)
Autoinflammatory disorders v3.5 PLCG1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with heterozygous PLCG1 variants and an immune dysregulation disorder, including variable autoimmune feature. Hence, this gene should be promoted to Green at the next update.
Autoinflammatory disorders v3.5 PLCG1 Ida Ertmanska Gene: plcg1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.10 PLCG1 Ida Ertmanska Phenotypes for gene: PLCG1 were changed from ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790 to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790; hearing loss disorder, MONDO:0005365
Monogenic hearing loss v6.9 PLCG1 Ida Ertmanska Phenotypes for gene: PLCG1 were changed from hearing impairment; ophthalmologic abnormalities; cardiac septal defects to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790
Monogenic hearing loss v6.8 PLCG1 Ida Ertmanska Publications for gene: PLCG1 were set to 38260438
Monogenic hearing loss v6.7 PLCG1 Ida Ertmanska Tag watchlist was removed from gene: PLCG1.
Tag Q2_26_promote_green tag was added to gene: PLCG1.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 PLCG1 Ida Ertmanska Classified gene: PLCG1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 PLCG1 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals with heterozygous PLCG1 variants and an immune dysregulation disorder, including recurrent infections due to immunological deficiencies. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 PLCG1 Ida Ertmanska Gene: plcg1 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v3.4 PLCG1 Ida Ertmanska gene: PLCG1 was added
gene: PLCG1 was added to Autoinflammatory disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: PLCG1.
Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLCG1 were set to 37422272; 40862571
Phenotypes for gene: PLCG1 were set to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790
Review for gene: PLCG1 was set to GREEN
Added comment: PMID: 40862571 Ma et al., 2025 (based on pre-print mentioned in previous reviews)
Report of seven individuals from 4 unrelated families with heterozygous missense variants in PLCG1: 3 individuals with de novo het variants: c.3056A>G, p.(Asp1019Gly)], [c.1139A>G, p.(His380Arg)] and [c.3494A>G, p.(Asp1165Gly)]. Individuals 4–7 are from the same family, and all carry the PLCG1 variant [c.1789C>T p.(Leu597Phe)].
Phenotypic spectrum: hearing loss (5/7, mild to profound), cardiac septal defects (3/6), and other less specific syndromic findings. Abnormal brain MRI findings in 2/3 assessed. Various immunological issues included:
P3: T lymphocytopenia, recurrent pulmonary infections;
P4: joint inflammation, tarsal synovitis, recurrent respiratory and lung infections, as well as inflammatory lymphadenopathy;
P5: immune thrombocytopenic purpura, polyarthritis, autoimmune pulmonary fibrosis, pneumococcal sepsis with chronic thrombocytopenia and IgA and IgG2 deficiency;
P6: history of recurrent upper respiratory and lung infections due to a mild IgA and IgG2 deficiency;

PMID: 37422272 Tao et al., 2024
7yo female patient with a de novo p.S1021F variant in PLCG1 and early-onset immune dysregulation disease: recurrent skin ecchymosis, epistaxis and gingival bleeding, lymphadenopathy. No mention of hearing loss.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.5 PLCG1 Ida Ertmanska gene: PLCG1 was added
gene: PLCG1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Q2_26_promote_green tags were added to gene: PLCG1.
Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLCG1 were set to 37422272; 40862571
Phenotypes for gene: PLCG1 were set to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790
Review for gene: PLCG1 was set to GREEN
Added comment: PMID: 40862571 Ma et al., 2025 (based on pre-print mentioned in previous reviews)
Report of seven individuals from 4 unrelated families with heterozygous missense variants in PLCG1: 3 individuals with de novo het variants: c.3056A>G, p.(Asp1019Gly)], [c.1139A>G, p.(His380Arg)] and [c.3494A>G, p.(Asp1165Gly)]. Individuals 4–7 are from the same family, and all carry the PLCG1 variant [c.1789C>T p.(Leu597Phe)].
Phenotypic spectrum: hearing loss (5/7, mild to profound), cardiac septal defects (3/6), and other less specific syndromic findings. Abnormal brain MRI findings in 2/3 assessed. Various immunological issues included:
P3: T lymphocytopenia, recurrent pulmonary infections;
P4: joint inflammation, tarsal synovitis, recurrent respiratory and lung infections, as well as inflammatory lymphadenopathy;
P5: immune thrombocytopenic purpura, polyarthritis, autoimmune pulmonary fibrosis, pneumococcal sepsis with chronic thrombocytopenia and IgA and IgG2 deficiency;
P6: history of recurrent upper respiratory and lung infections due to a mild IgA and IgG2 deficiency;

PMID: 37422272 Tao et al., 2024
7yo female patient with a de novo p.S1021F variant in PLCG1 and early-onset immune dysregulation disease: recurrent skin ecchymosis, epistaxis and gingival bleeding, lymphadenopathy. No mention of hearing loss.
Sources: Literature
Monogenic hearing loss v6.7 PLCG1 Ida Ertmanska reviewed gene: PLCG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37422272, 40862571; Phenotypes: ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska changed review comment from: New HGNC approved gene symbol for MKL1 is MRTFA; to: New HGNC approved gene symbol for MKL1 is MRTFA; new-gene-name tag was added.
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska commented on gene: MKL1: New HGNC approved gene symbol for MKL1 is MRTFA
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska Classified gene: MKL1 as Red List (low evidence)
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska Added comment: Comment on list classification: As only one case with biallelic MKL1 variants presented with broad autoinflammation symptoms, this gene can only be rated Red with current evidence.
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska Gene: mkl1 has been classified as Red List (Low Evidence).
Autoinflammatory disorders v3.2 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Sources: Literature; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, erythematous rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. Inflammatory bowel disease was suspected. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Sources: Literature
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Autoinflammatory disorders v3.2 MKL1 Ida Ertmanska gene: MKL1 was added
gene: MKL1 was added to Autoinflammatory disorders. Sources: Literature
new-gene-name tags were added to gene: MKL1.
Mode of inheritance for gene: MKL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MKL1 were set to 26224645; 27479822; 32128589; 40808667
Phenotypes for gene: MKL1 were set to ?Immunodeficiency 66 , OMIM:618847; immunodeficiency 66, MONDO:0030013; neutropenia, MONDO:0001475
Review for gene: MKL1 was set to RED
Added comment: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Sources: Literature
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L).

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska edited their review of gene: MKL1: Changed publications to: 26224645, 27479822, 32128589, 40808667
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska Classified gene: MKL1 as Amber List (moderate evidence)
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated individuals reported in literature with biallelic MKL1 variants associated with immunodeficiency as well thrombocytopenia, neutropenia, and lymphopenia. Hence, this gene should be promoted to Green at the next update.
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska Gene: mkl1 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.8 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 26224645 Record et al., 2015
Patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. He was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L).

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Bleeding and platelet disorders v4.8 MKL1 Ida Ertmanska Publications for gene: MKL1 were set to 27479822
Bleeding and platelet disorders v4.7 MKL1 Ida Ertmanska Mode of inheritance for gene: MKL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v4.6 MKL1 Ida Ertmanska changed review comment from: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 26224645 Record et al., 2015
Patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. He was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Bleeding and platelet disorders v4.6 MKL1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MKL1.
Bleeding and platelet disorders v4.6 MKL1 Ida Ertmanska reviewed gene: MKL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26224645, 32128589, 40808667; Phenotypes: ?Immunodeficiency 66 , OMIM:618847, immunodeficiency 66, MONDO:0030013, neutropenia, MONDO:0001475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska changed review comment from: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA).

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutrophil defects. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutropenia and neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska Phenotypes for gene: MKL1 were changed from ?Immunodeficiency 66 , OMIM:618847; neutropenia, MONDO:0001475 to ?Immunodeficiency 66 , OMIM:618847; immunodeficiency 66, MONDO:0030013; neutropenia, MONDO:0001475
Primary immunodeficiency or monogenic inflammatory bowel disease v9.3 MKL1 Ida Ertmanska Phenotypes for gene: MKL1 were changed from Susceptibility to severe bacterial infection; Mild thrombocytopenia; Congenital defects of phagocyte number or function to ?Immunodeficiency 66 , OMIM:618847; neutropenia, MONDO:0001475
Primary immunodeficiency or monogenic inflammatory bowel disease v9.2 MKL1 Ida Ertmanska Classified gene: MKL1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.2 MKL1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutropenia and neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.2 MKL1 Ida Ertmanska Gene: mkl1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 MKL1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MKL1.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 MKL1 Ida Ertmanska changed review comment from: 3rd case:
PMID: 40808667 Li et al., 2025
Patient presented with early-onset infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA).

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA).

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 MKL1 Ida Ertmanska reviewed gene: MKL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40808667; Phenotypes: ?Immunodeficiency 66 , OMIM:618847; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.7 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Skeletal dysplasia v9.7 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome. Skeletal findings included mild spondylo-epi-metaphyseal dysplasia in 1 case, and shortening of metacarpals and metatarsals in 3 sisters. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including skeletal dysplasia. As the skeletal findings are relatively mild, this gene should remain Amber on Skeletal dysplasia.
Skeletal dysplasia v9.7 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.6 LOXL3 Ida Ertmanska Publications for gene: LOXL3 were set to 25663169
Skeletal dysplasia v9.5 LOXL3 Ida Ertmanska Phenotypes for gene: LOXL3 were changed from Stickler syndrome to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Monogenic hearing loss v6.7 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Monogenic hearing loss v6.7 LOXL3 Ida Ertmanska Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska edited their review of gene: LOXL3: Changed publications to: 25663169, 30362103, 34150778, 36610533, 36917121, 38957076, 41052910
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska changed review comment from: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature; to: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence:
PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
PMID: 34150778 Liu et al., 2021 - targeted deletion of Loxl3 in the inner ear caused progressive hearing loss, degeneration of hair cells and secondary degeneration of spiral ganglion neurons in mouse.
Sources: Literature
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including conductive hearing loss in 2/4 families. A mouse model with a targeted Loxl3 knockout in the inner ear caused progressive hearing loss. Hence, this gene can be promoted to Green at the next update.
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Tag Q2_26_demote_red tag was added to gene: DNMT3A.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Classified gene: DNMT3A as Green List (high evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Added comment: Comment on list classification: Following on the review from Terri McVeigh, request for demotion of this gene from green rating has been requested by the NHS Genomic Medicine Service and verbally agreed with PanelApp team.

This change was requested because there are no clinical guidelines to manage variants on this gene on this panel.

This change will be implemented at the next update - tagging for demotion.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Gene: dnmt3a has been classified as Green List (High Evidence).
Retinal disorders v9.3 LOXL3 Ida Ertmanska changed review comment from: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and non-specific retinal changes. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and peripheral retinal degeneration. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.3 LOXL3 Ida Ertmanska changed review comment from: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature; to: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss. On fundus examination, the father had myopic fundi and peripheral retinal degeneration - seen at age 40 years. The son, age 11 years, had vitreous degeneration/detachment in both eyes.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.1 DNMT3A Achchuthan Shanmugasundram reviewed gene: DNMT3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v9.3 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Retinal disorders v9.3 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and non-specific retinal changes. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.3 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Retinal disorders v9.2 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Clefting v7.3 LOXL3 Ida Ertmanska changed review comment from: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including cleft palate in 2 unrelated families. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including clefting. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including cleft palate in 4 individuals from 2 unrelated families. Another unrelated individual presented with a high-arched palate. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including clefting. Hence, this gene should be promoted to Green at the next update.
Clefting v7.3 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Clefting v7.3 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including cleft palate in 2 unrelated families. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including clefting. Hence, this gene should be promoted to Green at the next update.
Clefting v7.3 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Clefting v7.2 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Skeletal dysplasia v9.4 LOXL3 Ida Ertmanska reviewed gene: LOXL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25663169, 30362103, 36610533, 36917121, 38957076, 41052910; Phenotypes: Myopia 28, autosomal recessive, OMIM:619781, Stickler syndrome, MONDO:0019354; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.5 LOXL3 Ida Ertmanska gene: LOXL3 was added
gene: LOXL3 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Review for gene: LOXL3 was set to GREEN
Added comment: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Retinal disorders v9.2 LOXL3 Ida Ertmanska gene: LOXL3 was added
gene: LOXL3 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Review for gene: LOXL3 was set to GREEN
Added comment: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Clefting v7.2 LOXL3 Ida Ertmanska gene: LOXL3 was added
gene: LOXL3 was added to Clefting. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Review for gene: LOXL3 was set to GREEN
Added comment: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Stickler syndrome v4.8 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Stickler syndrome v4.8 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome: high myopia (consistent finding), retinal disease (3 families), cleft palate (2 unrelated families), hearing loss (2 unrelated families), skeletal dysplasia (2 families). Another 9 patients reported in PMID: 36917121 had isolated high myopia (predominantly LOF variants). A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features. Hence, this gene should be promoted to Green at the next update.
Stickler syndrome v4.8 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Stickler syndrome v4.7 LOXL3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Stickler syndrome v4.7 LOXL3 Ida Ertmanska Phenotypes for gene: LOXL3 were changed from Stickler syndrome, MONDO:0019354 to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Stickler syndrome v4.6 LOXL3 Ida Ertmanska Publications for gene: LOXL3 were set to 25663169; 30362103
Stickler syndrome v4.5 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Stickler syndrome v4.5 LOXL3 Ida Ertmanska reviewed gene: LOXL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25663169, 30362103, 36610533, 36917121, 38957076, 41052910; Phenotypes: Myopia 28, autosomal recessive, OMIM:619781, Stickler syndrome, MONDO:0019354; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.10 HS6ST2 Ida Ertmanska Publications for gene: HS6ST2 were set to 30471091; 36993824; 38015989; 40686562
Intellectual disability v10.9 HS6ST2 Ida Ertmanska Publications for gene: HS6ST2 were set to 30471091; 36993824; 40686562
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram changed review comment from: PMID:41822111 (2026) reported three affected individuals from a two-generation consanguineous Lebanese family of eight members with idiopathic infantile nystagmus. All three affected individuals carried the same homozygous CACNB3 variant (c.316G>C; p.Gly106Arg), fully segregating across 8 family members. There is also functional evidence available for the p.Gly106Arg variant.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 11 May 2026), Gene2Phenotype or ClinGen.; to: PMID:41822111 (2026) reported three affected individuals from a two-generation consanguineous Lebanese family of eight members with idiopathic infantile nystagmus. All three affected individuals carried the same homozygous CACNB3 variant (c.316G>C; p.Gly106Arg), fully segregating across 8 family members. There is also functional evidence available for the p.Gly106Arg variant.

There are no other cases reported so far in the peer-reviewed literature.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 11 May 2026), Gene2Phenotype or ClinGen.
Intellectual disability v10.8 HS6ST2 Ida Ertmanska edited their review of gene: HS6ST2: Changed publications to: 30471091, 36993824, 38015989, 40686562
Intellectual disability v10.8 HS6ST2 Ida Ertmanska changed review comment from: PMID: 30471091 Paganini et al., 2019
Two Italian male twins with intellectual disability and severe myopia and an X-linked hemizygous HS6ST2 variant c.916G>C, p.Gly306Arg (maternally inherited). Psychomotor delay diagnosed at 5 years. In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity.

PMID: 36993824 Sarmadian et al., 2023
Report of a 21mo boy from Iran, referred due to the absence of neck holding and hand tremors (manifestation of seizures). He had delayed developmental milestones such as neck holding, intellectual and walking impairment. Brain MRI showed cerebral atrophy and diffused white matter, and irregularities were seen in his EEG. He also had a ventricular septal defect. WES identified a hemizygous c.979C>T; p.Pro327Ser variant in HS6ST2 - classified as VUS, only 1 heterozygote reported in gnomAD v4.1.1.

PMID: 40686562 Zhang et al., 2025
Report of a 9 month old male Chinese proband with global developmental delay. WES detected a hemizygous c.764C>A (p.Pro255Glu) variant in HS6ST2. No abnormal vision. Brain CT scan revealed a wider left lateral ventricle compared to the contralateral ventricle.; to: PMID: 30471091 Paganini et al., 2019
Two Italian male twins with intellectual disability and severe myopia and an X-linked hemizygous HS6ST2 variant c.916G>C, p.Gly306Arg (maternally inherited). Psychomotor delay diagnosed at 5 years. In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity.

PMID: 36993824 Sarmadian et al., 2023
Report of a 21mo boy from Iran, referred due to the absence of neck holding and hand tremors (manifestation of seizures). He had delayed developmental milestones such as neck holding, intellectual and walking impairment. Brain MRI showed cerebral atrophy and diffused white matter, and irregularities were seen in his EEG. He also had a ventricular septal defect. WES identified a hemizygous c.979C>T; p.Pro327Ser variant in HS6ST2 - classified as VUS, only 1 heterozygote reported in gnomAD v4.1.1.

PMID: 40686562 Zhang et al., 2025
Report of a 9 month old male Chinese proband with global developmental delay. WES detected a hemizygous c.764C>A (p.Pro255Glu) variant in HS6ST2. No abnormal vision. Brain CT scan revealed a wider left lateral ventricle compared to the contralateral ventricle.

Functional evidence: PMID: 38015989 Moon et al., 2024 - Knockout of Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory, providing a link to human HS6ST2-related brain disorders.
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram Classified gene: CACNB3 as Amber List (moderate evidence)
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one affected family and functional evidence available in support of the association of biallelic CACNB3 variants with infantile nystagmus. Hence, this gene should be added with amber rating on this panel.
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram Gene: cacnb3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.8 HS6ST2 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated male individuals with hemizygous HS6ST2 variants and a neurodevelopmental syndrome (ID and/or GDD) - diagnosed with so called Paganini-Miozzo syndrome. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated male individuals with hemizygous HS6ST2 variants and a neurodevelopmental syndrome (ID and/or GDD) - diagnosed with so called Paganini-Miozzo syndrome. Hence, this gene should be promoted to Green at the next update. MOI is set to X-LINKED: hemizygous mutation in males, biallelic mutations in females, as heterozygous mother of male sibs in PMID: 30471091 was not affected.
Albinism or congenital nystagmus v4.5 CACNB3 Achchuthan Shanmugasundram reviewed gene: CACNB3: Rating: AMBER; Mode of pathogenicity: None; Publications: 41822111; Phenotypes: Infantile nystagmus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.8 HS6ST2 Ida Ertmanska Publications for gene: HS6ST2 were set to
Intellectual disability v10.7 HS6ST2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Intellectual disability v10.7 HS6ST2 Ida Ertmanska Phenotypes for gene: HS6ST2 were changed from to ?Paganini-Miozzo syndrome , OMIM:301025; Paganini-Miozzo syndrome, MONDO:0026724
Intellectual disability v10.6 HS6ST2 Ida Ertmanska Mode of inheritance for gene: HS6ST2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: HS6ST2.
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Classified gene: HS6ST2 as Amber List (moderate evidence)
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated male individuals with hemizygous HS6ST2 variants and a neurodevelopmental syndrome (ID and/or GDD) - diagnosed with so called Paganini-Miozzo syndrome. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Gene: hs6st2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.4 HS6ST2 Ida Ertmanska reviewed gene: HS6ST2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30471091, 36993824, 40686562; Phenotypes: ?Paganini-Miozzo syndrome , OMIM:301025; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v7.5 GNPNAT1 Ida Ertmanska Phenotypes for gene: GNPNAT1 were changed from Talipes equinovarus; Rhizomelic dysplasia, Ain-Naz type to Talipes equinovarus; ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598; rhizomelic dysplasia, Ain-Naz type, MONDO:0859203
Fetal anomalies v7.4 GNPNAT1 Ida Ertmanska Publications for gene: GNPNAT1 were set to 39945447
Fetal anomalies v7.3 GNPNAT1 Ida Ertmanska commented on gene: GNPNAT1: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 missense variants and skeletal dysplasia, which is detectable on fetal ultrasound. Hence, this gene should be promoted to Green at the next update.
Fetal anomalies v7.3 GNPNAT1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: GNPNAT1.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 variants and skeletal dysplasia. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 missense variants and skeletal dysplasia. Hence, this gene should be promoted to Green at the next update.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska changed review comment from: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.
In the same family, a fetus was aborted at 4 months of pregnancy due to detected skeletal deformities diagnosed intrauterine - genotype not confirmed.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.; to: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.
In the same family, a fetus was aborted at 4 months of pregnancy due to detected skeletal deformities diagnosed intrauterine - genotype not confirmed.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Val- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska Classified gene: GNPNAT1 as Amber List (moderate evidence)
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 variants and skeletal dysplasia. Hence, this gene should be promoted to Green at the next update.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska Gene: gnpnat1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.3 GNPNAT1 Ida Ertmanska Publications for gene: GNPNAT1 were set to 32591345
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: GNPNAT1.
Fetal anomalies v7.3 GNPNAT1 Ida Ertmanska reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35427807, 36097642; Phenotypes: ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598, rhizomelic dysplasia, Ain-Naz type, MONDO:0859203; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska changed review comment from: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.; to: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.
In the same family, a fetus was aborted at 4 months of pregnancy due to detected skeletal deformities diagnosed intrauterine - genotype not confirmed.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska edited their review of gene: GNPNAT1: Added comment: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.; Changed rating: GREEN; Changed publications to: 35427807, 36097642, 39945447; Changed phenotypes to: ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598, rhizomelic dysplasia, Ain-Naz type, MONDO:0859203; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska Phenotypes for gene: GNPNAT1 were changed from Rhizomelic skeletal dysplasia to ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598; rhizomelic dysplasia, Ain-Naz type, MONDO:0859203
Cholestasis v4.3 FOCAD Ida Ertmanska changed review comment from: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies, hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature; to: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies (85.7%), hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature
Cholestasis v4.3 FOCAD Ida Ertmanska Classified gene: FOCAD as Amber List (moderate evidence)
Cholestasis v4.3 FOCAD Ida Ertmanska Added comment: Comment on list classification: There are now numerous individuals reported with biallelic FOCAD variants and severe congenital liver disease. Liver cirrhosis in the neonatal period was a consistent finding, with several individuals needing a liver transplant before age 3 years. Hence, this gene should be promoted to Green at the next GMS update.
Cholestasis v4.3 FOCAD Ida Ertmanska Gene: focad has been classified as Amber List (Moderate Evidence).
Cholestasis v4.2 FOCAD Ida Ertmanska gene: FOCAD was added
gene: FOCAD was added to Cholestasis. Sources: Literature
Q2_26_promote_green tags were added to gene: FOCAD.
Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOCAD were set to 35864190; 40662096; 41189834; 41608453
Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, OMIM:619991; liver disease, severe congenital, MONDO:0859273
Review for gene: FOCAD was set to GREEN
Added comment: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies, hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature
Paediatric disorders - additional genes v8.2 FGF5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Paediatric disorders - additional genes v8.2 FGF5 Ida Ertmanska Phenotypes for gene: FGF5 were changed from Hypertrichosis; long eyelashes to Trichomegaly, OMIM:190330; trichomegaly, MONDO:0008593
Limb disorders v8.6 FAM92A Ida Ertmanska Publications for gene: FAM92A were set to 30395363
Limb disorders v8.5 FAM92A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Limb disorders v8.5 FAM92A Ida Ertmanska Phenotypes for gene: FAM92A were changed from postaxial polydactyly type A9 to ?Polydactyly, postaxial, type A9, OMIM:618219; polydactyly, postaxial, type A9, MONDO:0032603
Limb disorders v8.4 FAM92A Ida Ertmanska changed review comment from: ADDITIONAL CASE:
PMID: 38853702 Umair et al., 2024
Report of an individual homozygous for FAM92A: c.472G>C; p.Ala158Pro variant, with non-syndromic postaxial polydactyly. Seq method: WES. Consanguineous parents, both heterozygous unaffected.; to: ADDITIONAL CASE:
PMID: 38853702 Umair et al., 2024
Report of an individual homozygous for FAM92A: c.472G>C; p.Ala158Pro variant, with non-syndromic postaxial polydactyly. Seq method: WES. Variant is not reported in gnomAD v4.1.1. Consanguineous parents, both heterozygous unaffected.
Limb disorders v8.4 FAM92A Ida Ertmanska Classified gene: FAM92A as Amber List (moderate evidence)
Limb disorders v8.4 FAM92A Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated families with biallelic FAM92A (CIBAR1) variants and non-syndromic postaxial polydactyly. A mouse knockout model showed abnormal digit morphology, which supports this gene-phenotype association. Based on available evidence, this gene can be promoted to Green at the next update.
Limb disorders v8.4 FAM92A Ida Ertmanska Gene: fam92a has been classified as Amber List (Moderate Evidence).
Limb disorders v8.3 FAM92A Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: FAM92A.
Limb disorders v8.3 FAM92A Ida Ertmanska edited their review of gene: FAM92A: Added comment: ADDITIONAL CASE:
PMID: 38853702 Umair et al., 2024
Report of an individual homozygous for FAM92A: c.472G>C; p.Ala158Pro variant, with non-syndromic postaxial polydactyly. Seq method: WES. Consanguineous parents, both heterozygous unaffected.; Changed publications to: 38853702; Changed phenotypes to: ?Polydactyly, postaxial, type A9, OMIM:618219, polydactyly, postaxial, type A9, MONDO:0032603
Limb disorders v8.3 FAM92A Ida Ertmanska reviewed gene: FAM92A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v8.3 FAM92A Ida Ertmanska Tag new-gene-name tag was added to gene: FAM92A.
Intellectual disability v10.4 DPH2 Ida Ertmanska changed review comment from: ADDITIONAL CASE:
PMID: 40130534 Gowda et al., 2025
1yr 9mo old female patient with DPH2: c.1429C>T, p.Arg477* with clinical features of developmental delay, failure to thrive, sparse hair (pseudo tiger tail appearance), seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. Seq method: WES.; to: ADDITIONAL CASE:
PMID: 40130534 Gowda et al., 2025
1yr 9mo old female patient with DPH2: c.1429C>T, p.Arg477* with clinical features of developmental delay, failure to thrive, sparse hair (pseudo tiger tail appearance), seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. Seq method: WES.
Intellectual disability v10.4 DPH2 Ida Ertmanska Classified gene: DPH2 as Amber List (moderate evidence)
Intellectual disability v10.4 DPH2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic DPH2 variants and syndromic developmental delay / intellectual disability. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v10.4 DPH2 Ida Ertmanska Gene: dph2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.3 DPH2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: DPH2.
Intellectual disability v10.3 DPH2 Ida Ertmanska edited their review of gene: DPH2: Added comment: ADDITIONAL CASE:
PMID: 40130534 Gowda et al., 2025
1yr 9mo old female patient with DPH2: c.1429C>T, p.Arg477* with clinical features of developmental delay, failure to thrive, sparse hair (pseudo tiger tail appearance), seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. Seq method: WES.; Changed rating: GREEN; Changed publications to: 40130534; Changed phenotypes to: Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, OMIM:620062, developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MONDO:0100217; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.3 DPH2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Intellectual disability v10.3 DPH2 Ida Ertmanska Phenotypes for gene: DPH2 were changed from Diphthamide-deficiency syndrome to Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, OMIM:620062; developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MONDO:0100217
Monogenic hearing loss v6.4 CLIC5 Ida Ertmanska changed review comment from: ADDITIONAL CASES SINCE 2019:

PMID: 40957967 Pshennikova et al., 2026
Founder variant in Eastern Siberia: CLIC5 c.644 G>A p.(Trp215*) causes progressive AR deafness. Found in homozygous state in 22 patients from 16 unrelated families in Siberia (Russia). Hearing loss was sensorineural, symmetrical and variable by severity (from moderate to profound). Founder calculated to have arisen 78 generations ago.

PMID: 40928595 Jagannath et al., 2025
Cohort of 105 Indian individuals with hearing loss. Family 19 - proband with congenital bilateral severe-to-profound sensorineural hearing loss, homozygous for variant (CLIC5):c.401A > G, (p.Asn134Ser) - only 1 het individual in gnomAD v4.1.1. Heterozygous family members unaffected. Method: Exome seq + Sanger. *Assessed to be VUS by ACMG criteria in the article.

PMID: 33114113 Wonkam-Tingang et al., 2020
Report of a Cameroonian family with non-syndromic hearing impairment and biallelic CLIC5 variants NM_016929.5:c.224T>C; p.(L75P) and NM_016929.5: c.63+1G>A. The variants segregated with disease, with 3 affected family members carrying both variants, and other individuals being unaffected if WT or carrying one of the mutations. The 3 affected sibs were 25-36 years old, no age of onset given.; to: ADDITIONAL CASES SINCE 2019:

PMID: 40957967 Pshennikova et al., 2026
Founder variant in Eastern Siberia: CLIC5 c.644 G>A p.(Trp215*) causes progressive AR deafness. Found in homozygous state in 22 patients from 16 unrelated families in Siberia (Russia). Hearing loss was sensorineural, symmetrical and variable by severity (from moderate to profound). Founder calculated to have arisen 78 generations ago. Method: WES + Sanger.

PMID: 40928595 Jagannath et al., 2025
Cohort of 105 Indian individuals with hearing loss. Family 19 - proband with congenital bilateral severe-to-profound sensorineural hearing loss, homozygous for variant (CLIC5):c.401A > G, (p.Asn134Ser) - only 1 het individual in gnomAD v4.1.1. Heterozygous family members unaffected. Method: Exome seq + Sanger. *Assessed to be VUS by ACMG criteria in the article.

PMID: 33114113 Wonkam-Tingang et al., 2020
Report of a Cameroonian family with non-syndromic hearing impairment and biallelic CLIC5 variants NM_016929.5:c.224T>C; p.(L75P) and NM_016929.5: c.63+1G>A. The variants segregated with disease, with 3 affected family members carrying both variants, and other individuals being unaffected if WT or carrying one of the mutations. The 3 affected sibs were 25-36 years old, no age of onset given.
Monogenic hearing loss v6.4 CLIC5 Ida Ertmanska Phenotypes for gene: CLIC5 were changed from #616042:?Deafness, autosomal recessive 103; PMID: 24781754 (Nijjmegen group) progressive hearing impairment, vestibular and possibly mild renal dysfunction to Deafness, autosomal recessive 103, OMIM:616042
Monogenic hearing loss v6.3 CLIC5 Ida Ertmanska Publications for gene: CLIC5 were set to PMID:10793131; 17021174; 18028448; 24781754
Monogenic hearing loss v6.2 CLIC5 Ida Ertmanska Classified gene: CLIC5 as Amber List (moderate evidence)
Monogenic hearing loss v6.2 CLIC5 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated families reported in literature with biallelic CLIC5 variants and non-syndromic hearing loss. Hence, this gene should be promoted to Green at the next update.
Monogenic hearing loss v6.2 CLIC5 Ida Ertmanska Gene: clic5 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.1 CLIC5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CLIC5.
Monogenic hearing loss v6.1 CLIC5 Ida Ertmanska reviewed gene: CLIC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33114113, 40928595, 40957967; Phenotypes: Deafness, autosomal recessive 103, OMIM:616042; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CLCF1.
Fetal anomalies v7.3 CLCF1 Ida Ertmanska Classified gene: CLCF1 as Amber List (moderate evidence)
Fetal anomalies v7.3 CLCF1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic CLCF1 variants and cold-induced sweating syndrome 2, with campodactyly and elbow contractures being a consistent feature in all 3 cases. Hence, this gene can be promoted to Green at the next update.
Fetal anomalies v7.3 CLCF1 Ida Ertmanska Gene: clcf1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Classified gene: CLCF1 as Amber List (moderate evidence)
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic CLCF1 variants and cold-induced sweating syndrome 2, with campodactyly and elbow contractures being a consistent feature in all 3 cases. Hence, this gene can be promoted to Green at the next update.
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Gene: clcf1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v7.2 CLCF1 Ida Ertmanska gene: CLCF1 was added
gene: CLCF1 was added to Fetal anomalies. Sources: Literature
Q2_26_promote_green tags were added to gene: CLCF1.
Mode of inheritance for gene: CLCF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLCF1 were set to 16782820; 20400119; 32512309
Phenotypes for gene: CLCF1 were set to Cold-induced sweating syndrome 2, OMIM:610313; cold-induced sweating syndrome 2, MONDO:0012467; Elbow contracture, HP:0034391; Bilateral camptodactyly, HP:0005617
Review for gene: CLCF1 was set to GREEN
Added comment: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.

This gene is associated with AR Cold-induced sweating syndrome 2, OMIM:610313 in OMIM (accessed 11th May 2026). CLCF1 is not yet associated with a condition in G2P or ClinGen.
Sources: Literature
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.

This gene is associated with AR Cold-induced sweating syndrome 2, OMIM:610313 in OMIM (accessed 11th May 2026). CLCF1 is not yet associated with a condition in G2P or ClinGen.
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling.; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.
Bleeding and platelet disorders v4.6 TUBA8 Carl Fratter reviewed gene: TUBA8: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34662886, 34704371; Phenotypes: Macrothrombocytopenia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and platelet disorders v4.6 TUBA8 Carl Fratter gene: TUBA8 was added
gene: TUBA8 was added to Bleeding and platelet disorders. Sources: NHS GMS
Mode of inheritance for gene: TUBA8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TUBA8 were set to PMID: 34662886)
Penetrance for gene: TUBA8 were set to unknown
Bleeding and platelet disorders v4.6 TUBA4A Carl Fratter gene: TUBA4A was added
gene: TUBA4A was added to Bleeding and platelet disorders. Sources: NHS GMS
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TUBA4A were set to PMID: 30760556; 36026602
Phenotypes for gene: TUBA4A were set to Macrothrombocytopenia
Penetrance for gene: TUBA4A were set to unknown
Review for gene: TUBA4A was set to AMBER
Added comment: Reviewed by regional haemostasis genomics MDT and propose amber rating.
ClinGen Gene-Disease Validity for association with AD macrothrombocytopenia has been classified as “limited”.
PMID: 30760556 – heterozygous double missense variant detected in an individual with mild macrothrombocytopenia and tubulin disorganisation in platelets; evidence for TUBA4A association with macrothrombocytopenia supported by mouse model (different variant) and other functional work demonstrating that alpha4A-tubulin is the predominant alpha-tubulin in platelets and is essential for platelet biogenesis.
PMID: 36026602 – further work in mice demonstrating importance of alpha4A-tubulin in platelets.
Vincenot et al. 2024 report 2 further families in a meeting abstract but not yet published in a peer review journal.
Sources: NHS GMS
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).
; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling.
Arthrogryposis v10.4 CLCF1 Ida Ertmanska Publications for gene: CLCF1 were set to
Arthrogryposis v10.3 CLCF1 Ida Ertmanska Phenotypes for gene: CLCF1 were changed from to Cold-induced sweating syndrome 2, OMIM:610313; cold-induced sweating syndrome 2, MONDO:0012467; Elbow contracture, HP:0034391; Bilateral camptodactyly, HP:0005617
Arthrogryposis v10.2 CLCF1 Ida Ertmanska Classified gene: CLCF1 as Amber List (moderate evidence)
Arthrogryposis v10.2 CLCF1 Ida Ertmanska Gene: clcf1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v10.1 CLCF1 Ida Ertmanska changed review comment from: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal;
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 - 24yo American woman (non-consanguineous parents, German & Irish ancestry) - excessive sweating in cold temp from age 2 years, contractures, campodactyly, unable to suck or swallow until 5 months of age, erythematous rash until age 5 years; psychomotor development was normal. Compound het for CLCF1 variants c.31_53del and c.303delC.

PMID: 16782820 Rousseau et al., 2006; to: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).
Arthrogryposis v10.1 CLCF1 Ida Ertmanska reviewed gene: CLCF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16782820, 20400119; Phenotypes: Cold-induced sweating syndrome 2, OMIM:610313, cold-induced sweating syndrome 2, MONDO:0012467; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Tag Q2_26_expert_review tag was added to gene: CHEK2.
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Classified gene: CHEK2 as Amber List (moderate evidence)
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Sahana Chatakondu, there are numerous individuals reported with CHEK2 variants (most often p.Ile157Thr) and myeloid malignancies. Hence, this gene will be suggested for promotion to Green on Inherited predisposition to acute myeloid leukaemia (AML), with a request of expert review to determine if the gene fits into panel scope.
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Gene: chek2 has been classified as Amber List (Moderate Evidence).
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 CHEK2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CHEK2.
Tag Q2_26_NHS_review tag was added to gene: CHEK2.
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 CHEK2 Ida Ertmanska changed review comment from: PMID: 40335619
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.; to: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 CHEK2 Ida Ertmanska reviewed gene: CHEK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40335619; Phenotypes: Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pulmonary arterial hypertension v4.11 FLNA Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: FLNA.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: XRCC2.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with AR Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with AR Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Classified gene: XRCC2 as Amber List (moderate evidence)
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with biallelic XRCC2 variants and Fanconi anaemia. All reported patients were homozygous for a recurrent p.(Arg215Ter) variant. Functional evidence is supportive of this gene-disease association. Hence, this gene should be promoted at the next GMS update.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v5.1 XRCC2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: XRCC2.
Pigmentary skin disorders v5.1 XRCC2 Ida Ertmanska reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 42071175, 30237576; Phenotypes: ?Fanconi anemia, complementation group U, OMIM:617247; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska Classified gene: XRCC2 as Amber List (moderate evidence)
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with biallelic XRCC2 variants and Fanconi anaemia. All reported patients were homozygous for a recurrent p.(Arg215Ter) variant. Functional evidence is supportive of this gene-disease association. Hence, this gene should be promoted at the next GMS update.
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Confirmed Fanconi anaemia or Bloom syndrome v2.13 XRCC2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: XRCC2.
Confirmed Fanconi anaemia or Bloom syndrome v2.13 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.13 XRCC2 Ida Ertmanska reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 42071175; Phenotypes: ?Fanconi anemia, complementation group U, OMIM:617247; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pulmonary arterial hypertension v4.11 FLNA Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals with monoallelic variants in FLNA and pulmonary hypertension. Hemizygous male and heterozygous females are affected (with variable penetrance and age of onset). Based on available evidence, this gene should be promoted to Green at the next update.; to: Comment on list classification: As reviewed by Karen Stals, there are more than 3 unrelated individuals with monoallelic variants in FLNA and pulmonary hypertension. Hemizygous male and heterozygous females are affected (with variable penetrance and age of onset). Based on available evidence, this gene should be promoted to Green at the next update.
Pulmonary arterial hypertension v4.11 FLNA Ida Ertmanska Publications for gene: FLNA were set to 40641615; 39510553; 30547349; 28457522
Pulmonary arterial hypertension v4.10 FLNA Ida Ertmanska edited their review of gene: FLNA: Changed publications to: 40641615, 39510553, 30557962
Pulmonary arterial hypertension v4.10 FLNA Ida Ertmanska changed review comment from: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.

FLNA is associated with multiple X-linked (dominant and recessive) disease entities in OMIM. Pulmonary incompetence is a feature of several FLNA-related disorders, e.g., Cardiac valvular dysplasia, X-linked, OMIM:314400.; to: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.

PMID: 30557962 Calcaterra et al., 2018
Progressive pulmonary disease in a male infant harbouring a FLNA c.7391_7403del; (p.Val2464AlafsTer5) variant. He developed significant lung disease resulting in emphysematous lesions and perivascular and interstitial fibrosis. He also exhibited general muscular hypotonia, bilateral inguinal hernia, and deformities of the lower limbs (pes tortus congenitalis and hip dysplasia). Brain MRI showed periventricular nodular heterotopia.

FLNA is associated with multiple X-linked (dominant and recessive) disease entities in OMIM. Pulmonary incompetence is a feature of several FLNA-related disorders, e.g., Cardiac valvular dysplasia, X-linked, OMIM:314400.
Pulmonary arterial hypertension v4.10 FLNA Ida Ertmanska Mode of pathogenicity for gene: FLNA was changed from None to None
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: FLNA.
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska edited their review of gene: FLNA: Changed phenotypes to: pulmonary hypertension, MONDO:0005149, Cardiac valvular dysplasia, X-linked, OMIM:314400
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska changed review comment from: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.; to: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.

FLNA is associated with multiple X-linked (dominant and recessive) disease entities in OMIM. Pulmonary incompetence is a feature of several FLNA-related disorders, e.g., Cardiac valvular dysplasia, X-linked, OMIM:314400.
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Classified gene: FLNA as Amber List (moderate evidence)
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with monoallelic variants in FLNA and pulmonary hypertension. Hemizygous male and heterozygous females are affected (with variable penetrance and age of onset). Based on available evidence, this gene should be promoted to Green at the next update.
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Gene: flna has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v4.8 FLNA Ida Ertmanska Phenotypes for gene: FLNA were changed from Pulmonary hypertension; respiratory failure to pulmonary hypertension, MONDO:0005149; Cardiac valvular dysplasia, X-linked, OMIM:314400
Pulmonary arterial hypertension v4.7 FLNA Ida Ertmanska Publications for gene: FLNA were set to PMID: 30547349; PMID: 28457522
Pulmonary arterial hypertension v4.6 FLNA Ida Ertmanska Mode of inheritance for gene: FLNA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pulmonary arterial hypertension v4.5 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)
Pulmonary arterial hypertension v4.5 FLNA Ida Ertmanska reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 40641615, 39510553; Phenotypes: pulmonary hypertension, MONDO:0005149; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.1 DNMT3A Terri McVeigh reviewed gene: DNMT3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v10.2 RNU4ATAC Arina Puzriakova Publications for gene: RNU4ATAC were set to
Intellectual disability v10.1 RNU4ATAC Ida Ertmanska commented on gene: RNU4ATAC: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic RNU4ATAC variants and syndromic developmental and psychomotor delay. Hence, this gene should be promoted to Green on Intellectual disability.
Mitochondrial disorders v10.1 PTPMT1 William Macken commented on gene: PTPMT1
Limb disorders v8.3 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 reported a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska commented on gene: IFT57: Comment on list classification: There are two unrelated families reported in literature with biallelic IFT57 variants: one individual reported with a diagnosis of Bardet Biedl syndrome, and one family with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. Both publications demonstrate that the IFT57 variants result in ciliary defects. However, only one individual has features consistent with Bardet Biedl syndrome. Hence, this gene can only be rated Amber on this panel, given the current evidence.
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska edited their review of gene: IFT57: Changed rating: AMBER
Limb disorders v8.3 IFT57 Ida Ertmanska Classified gene: IFT57 as Amber List (moderate evidence)
Limb disorders v8.3 IFT57 Ida Ertmanska Gene: ift57 has been classified as Amber List (Moderate Evidence).
Limb disorders v8.2 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 reported a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature
Limb disorders v8.2 IFT57 Ida Ertmanska gene: IFT57 was added
gene: IFT57 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: IFT57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT57 were set to 27060890; 40273360
Phenotypes for gene: IFT57 were set to ?Orofaciodigital syndrome XVIII, OMIM:617927; ciliopathy, MONDO:0005308
Review for gene: IFT57 was set to GREEN
Added comment: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Sources: Literature
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: IFT57.
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska Deleted their comment
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy no excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Renal ciliopathies v5.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Renal dysfunction was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including bilateral cystic dilations of the pronephros. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Renal dysfunction was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including bilateral cystic dilations of the pronephros. Hence, this gene should be promoted to Green at the next update.
Renal ciliopathies v5.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).
Ophthalmological ciliopathies v6.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including abnormal retinal development. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 3 unrelated individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 3 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Ophthalmological ciliopathies v6.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).
Retinal disorders v9.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 3 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).
Bardet Biedl syndrome v2.17 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM entry states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Limb disorders v8.1 BBIP1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BBIP1.
Limb disorders v8.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: 2 patients reported in literature with BBS and biallelic BBIP1 variants had polydactyly / brachydactyly. Hence, this gene can only be rated Amber on Limb disorders given available evidence.; to: Comment on list classification: 3 unrelated patients reported in literature with BBS and biallelic BBIP1 variants had polydactyly / brachydactyly. Hence, this gene can be updated to Green on Limb disorders at the next update.
Limb disorders v8.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. No phenotypic details provided.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska Tag watchlist_moi tag was added to gene: PEX14.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 2 individuals reported with de novo heterozygous PEX14 variants and a mild peroxisome biogenesis disorder. The MOI should remain set to BIALLELIC, until more evidence emerges in support of dominant disease - added watchlist_moi tag.; to: Comment on mode of inheritance: There are 2 individuals reported with de novo heterozygous PEX14 variants and a mild peroxisome biogenesis disorder with bilateral cataracts. The MOI should remain set to BIALLELIC, until more evidence emerges in support of dominant disease - added watchlist_moi tag.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska commented on gene: PEX14: Comment on mode of inheritance: There are 2 individuals reported with de novo heterozygous PEX14 variants and a mild peroxisome biogenesis disorder. The MOI should remain set to BIALLELIC, until more evidence emerges in support of dominant disease - added watchlist_moi tag.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska reviewed gene: PEX14: Rating: GREEN; Mode of pathogenicity: None; Publications: 37493040; Phenotypes: Peroxisome biogenesis disorder 13A (Zellweger), OMIM:614887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.1 PABPN1_GCN Ida Ertmanska Tag STR tag was added to STR: PABPN1_GCN.
Tag NGS Not Validated tag was added to STR: PABPN1_GCN.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.1 PABPN1_GCN Ida Ertmanska commented on STR: PABPN1_GCN: There is enough evidence for this STR to be green on this panel; however, this STR has not been reviewed and approved by the NHS STR working group and therefore has been rated amber. The mode of inheritance should be validated by experts, particularly to confirm whether 11 repeats are considered to be reportable in a dominant or recessive state only.
Skeletal dysplasia v9.1 GNPNAT1 Sadaf Naz reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32591345, 35427807, 36097642; Phenotypes: Skeletal dysplasia, Rhizomelic dysplasia, Ain-Naz type; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.1 GNPNAT1 Sadaf Naz Deleted their review
Skeletal dysplasia v9.1 TMEM251 Sadaf Naz reviewed gene: TMEM251: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33252156, 40171858, 41858182; Phenotypes: Skeletal dysplasia, Dysostosis multiplex, Ain-Naz type, Mucolipidosis II-Like; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.1 GNPNAT1 Sadaf Naz reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32591345, 35427807, 36097642; Phenotypes: Skeletal dysplasia, ?Rhizomelic dysplasia, Ain-Naz type; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 SEPT6 Boaz Palterer gene: SEPT6 was added
gene: SEPT6 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: SEPT6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SEPT6 were set to 42088107, 34677878
Phenotypes for gene: SEPT6 were set to Congenital neutropenia; B cell deficiency; T cell lymphopenia; Abnormal newborn screening for SCID; Hypersegmented neutrophils; Myelodysplasia; Decreased circulating B cells; Leukopenia
Penetrance for gene: SEPT6 were set to unknown
Review for gene: SEPT6 was set to GREEN
Added comment: Gunderman et al. described stop loss variant in the X-linked SEPTIN6 gene, they identified 2 hemizygous male siblings. The researchers presented evidence characterized by severe congenital neutropenia, a profound lack of circulating B cells, and variable T cell lymphopenia, noting that maternal carriers show strong negative selection against the mutated allele in their hematopoietic cells. Clinical data and bone marrow analysis revealed progressive dysmyelopoiesis with myeloid tetraploidy and a predisposition to aneuploidy, while xenograft mouse models and spatial transcriptomics further demonstrated that the SEPTIN6 mutation leads to a significant reduction in early lymphoid progenitors rather than an absolute developmental block.

Renella et al. described a single patient with a de novo germline stop-loss mutation in the X-linked gene SEPT6 with a similar phenotype
Sources: Literature
Sudden unexplained death or survivors of a cardiac event v23.2 Ida Ertmanska Panel version 23.1 has been signed off on 2026-05-06
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Mitochondrial disorder with complex IV deficiency v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Mitochondrial disorder with complex IV deficiency v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Mitochondrial disorder with complex I deficiency v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Mitochondrial disorder with complex I deficiency v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Cytopenia - NOT Fanconi anaemia v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Cytopenia - NOT Fanconi anaemia v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Rare anaemia v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Rare anaemia v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Thrombophilia with a likely monogenic cause v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2026-05-06
Thrombophilia with a likely monogenic cause v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Iron metabolism disorders - NOT common HFE mutations v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Iron metabolism disorders - NOT common HFE mutations v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Structural eye disease v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Structural eye disease v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Inherited polyposis and early onset colorectal cancer - germline testing v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Inherited polyposis and early onset colorectal cancer - germline testing v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
DDG2P v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
DDG2P v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Paediatric disorders - additional genes v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Paediatric disorders - additional genes v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Fetal anomalies v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Fetal anomalies v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Ataxia and cerebellar anomalies - narrow panel v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Ataxia and cerebellar anomalies - narrow panel v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
White matter disorders and cerebral calcification - narrow panel v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
White matter disorders and cerebral calcification - narrow panel v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Adult onset neurodegenerative disorder v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Adult onset neurodegenerative disorder v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Hereditary ataxia with onset in adulthood v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Hereditary ataxia with onset in adulthood v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Early onset or syndromic epilepsy v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Early onset or syndromic epilepsy v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Primary immunodeficiency or monogenic inflammatory bowel disease v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Limb disorders v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Limb disorders v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Skeletal dysplasia v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Skeletal dysplasia v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Retinal disorders v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Retinal disorders v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Neonatal diabetes v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Neonatal diabetes v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Renal tubulopathies v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Renal tubulopathies v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Intellectual disability v10.1 Achchuthan Shanmugasundram Panel version 10.0 has been signed off on 2026-05-06
Intellectual disability v10.0 Achchuthan Shanmugasundram promoted panel to version 10.0
Cystic kidney disease v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Cystic kidney disease v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Arthrogryposis v10.1 Achchuthan Shanmugasundram Panel version 10.0 has been signed off on 2026-05-06
Arthrogryposis v10.0 Achchuthan Shanmugasundram promoted panel to version 10.0
Distal myopathies v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Distal myopathies v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Congenital myaesthenic syndrome v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Congenital myaesthenic syndrome v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Bilateral congenital or childhood onset cataracts v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Bilateral congenital or childhood onset cataracts v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Congenital muscular dystrophy v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Congenital muscular dystrophy v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Osteogenesis imperfecta v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Osteogenesis imperfecta v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Optic neuropathy v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Optic neuropathy v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Severe microcephaly v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Severe microcephaly v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Hereditary Erythrocytosis v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2026-05-06
Hereditary Erythrocytosis v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Nephrocalcinosis or nephrolithiasis v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Nephrocalcinosis or nephrolithiasis v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Cerebral vascular malformations v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Cerebral vascular malformations v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Congenital adrenal hypoplasia v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Congenital adrenal hypoplasia v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Inherited ovarian cancer (without breast cancer) v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Inherited ovarian cancer (without breast cancer) v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Severe early-onset obesity v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Severe early-onset obesity v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Monogenic hearing loss v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Monogenic hearing loss v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Mitochondrial disorders v10.1 Achchuthan Shanmugasundram Panel version 10.0 has been signed off on 2026-05-06
Mitochondrial disorders v10.0 Achchuthan Shanmugasundram promoted panel to version 10.0
Proteinuric renal disease v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Proteinuric renal disease v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Segmental overgrowth disorders - Deep sequencing v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Segmental overgrowth disorders - Deep sequencing v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Clefting v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Clefting v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Holoprosencephaly v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Holoprosencephaly v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Rhabdomyolysis and metabolic muscle disorders v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Rhabdomyolysis and metabolic muscle disorders v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Primary lymphoedema v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Primary lymphoedema v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Haematological malignancies cancer susceptibility v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Haematological malignancies cancer susceptibility v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Hypertrophic cardiomyopathy v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Hypertrophic cardiomyopathy v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Inherited prostate cancer v1.6 Achchuthan Shanmugasundram Panel version 1.5 has been signed off on 2026-05-06
Paediatric pseudo-obstruction syndrome v2.6 Achchuthan Shanmugasundram Panel version 2.5 has been signed off on 2026-05-06
Pulmonary fibrosis familial v1.10 Achchuthan Shanmugasundram Panel version 1.9 has been signed off on 2026-05-06
Cardiac arrhythmias - additional genes v3.12 Achchuthan Shanmugasundram Panel version 3.11 has been signed off on 2026-05-06
Neurological segmental overgrowth v3.5 Achchuthan Shanmugasundram Panel version 3.4 has been signed off on 2026-05-06
Endocrine neoplasia v3.5 Achchuthan Shanmugasundram Panel version 3.4 has been signed off on 2026-05-06
Adult onset hereditary spastic paraplegia v6.11 Achchuthan Shanmugasundram Panel version 6.10 has been signed off on 2026-05-06
Multiple monogenic benign skin tumours v2.6 Achchuthan Shanmugasundram Panel version 2.5 has been signed off on 2026-05-06
Tubulointerstitial kidney disease v3.33 Achchuthan Shanmugasundram Panel version 3.32 has been signed off on 2026-05-06
Bardet Biedl syndrome v2.17 Achchuthan Shanmugasundram Panel version 2.16 has been signed off on 2026-05-06
Pyruvate dehydrogenase (PDH) deficiency v1.40 Achchuthan Shanmugasundram Panel version 1.39 has been signed off on 2026-05-06
Lysosomal storage disorder v3.6 Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2026-05-06
Glycogen storage disease v2.7 Achchuthan Shanmugasundram Panel version 2.6 has been signed off on 2026-05-06
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2026-05-06
Inherited pancreatic cancer v3.3 Achchuthan Shanmugasundram Panel version 3.2 has been signed off on 2026-05-06
Inherited predisposition to GIST v1.16 Achchuthan Shanmugasundram Panel version 1.15 has been signed off on 2026-05-06
Inherited renal cancer v1.29 Achchuthan Shanmugasundram Panel version 1.28 has been signed off on 2026-05-06
Common craniosynostosis syndromes v1.17 Achchuthan Shanmugasundram Panel version 1.16 has been signed off on 2026-05-06
Progressive cardiac conduction disease v2.16 Achchuthan Shanmugasundram Panel version 2.15 has been signed off on 2026-05-06
Inherited MMR deficiency (Lynch syndrome) v1.14 Achchuthan Shanmugasundram Panel version 1.13 has been signed off on 2026-05-06
Hereditary systemic amyloidosis v1.29 Achchuthan Shanmugasundram Panel version 1.28 has been signed off on 2026-05-06
Pituitary hormone deficiency v4.7 Achchuthan Shanmugasundram Panel version 4.6 has been signed off on 2026-05-06
Hypophosphataemia or rickets v4.3 Achchuthan Shanmugasundram Panel version 4.2 has been signed off on 2026-05-06
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v3.8 Achchuthan Shanmugasundram Panel version 3.7 has been signed off on 2026-05-06
Monogenic diabetes v3.22 Achchuthan Shanmugasundram Panel version 3.21 has been signed off on 2026-05-06
Congenital hyperinsulinism v3.8 Achchuthan Shanmugasundram Panel version 3.7 has been signed off on 2026-05-06
Childhood solid tumours v5.12 Achchuthan Shanmugasundram Panel version 5.11 has been signed off on 2026-05-06
Hyperthyroidism v3.6 Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2026-05-06
Short QT syndrome v3.17 Achchuthan Shanmugasundram Panel version 3.16 has been signed off on 2026-05-06
Catecholaminergic polymorphic VT v5.4 Achchuthan Shanmugasundram Panel version 5.3 has been signed off on 2026-05-06
Atypical haemolytic uraemic syndrome v3.9 Achchuthan Shanmugasundram Panel version 3.8 has been signed off on 2026-05-06
Arrhythmogenic right ventricular cardiomyopathy v3.16 Achchuthan Shanmugasundram Panel version 3.15 has been signed off on 2026-05-06
Haematuria v2.18 Achchuthan Shanmugasundram Panel version 2.17 has been signed off on 2026-05-06
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 Achchuthan Shanmugasundram Panel version 3.8 has been signed off on 2026-05-06
Paediatric motor neuronopathies v3.14 Achchuthan Shanmugasundram Panel version 3.13 has been signed off on 2026-05-06
Long QT syndrome v3.13 Achchuthan Shanmugasundram Panel version 3.12 has been signed off on 2026-05-06
Congenital hypothyroidism v3.4 Achchuthan Shanmugasundram Panel version 3.3 has been signed off on 2026-05-06
Brugada syndrome and cardiac sodium channel disease v3.16 Achchuthan Shanmugasundram Panel version 3.15 has been signed off on 2026-05-06
Differences in sex development v4.21 Achchuthan Shanmugasundram Panel version 4.20 has been signed off on 2026-05-06
Hereditary ataxia with onset in adulthood v8.32 Arina Puzriakova List of related panels changed from Hereditary ataxia - adult onset; R54 to Hereditary ataxia - adult onset
Panel types changed to Component Of Super Panel; GMS signed-off
Childhood solid tumours v5.11 Achchuthan Shanmugasundram List of related panels changed from Paediatric congenital malformation-dysmorphism-tumour syndrome; Paediatric congenital malformation-dysmorphism-tumour syndromes; Paediatric congenital malformation-dysmorphism-tumour sydromes; Paediatric congenital malformation-dysmorphism-tumour syndrome; Tumour predisposition - childhood onset; R359 to Paediatric congenital malformation-dysmorphism-tumour syndrome; Paediatric congenital malformation-dysmorphism-tumour syndromes; Paediatric congenital malformation-dysmorphism-tumour sydromes; Paediatric congenital malformation-dysmorphism-tumour syndrome; Tumour predisposition - childhood onset
Panel types changed to Rare Disease 100K; GMS Cancer Germline Virtual; GMS signed-off
Severe insulin resistance and lipodystrophy syndromes v4.68 Eleanor Williams Panel name changed from Lipodystrophy - childhood onset to Severe insulin resistance and lipodystrophy syndromes
List of related panels changed from R158 to Lipodystrophy - childhood onset; R158
Adult onset neurodegenerative disorder v8.22 Achchuthan Shanmugasundram List of related panels changed from Neurodegenerative disorders - adult onset; R58 to Neurodegenerative disorders - adult onset; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy; R58
Panel types changed to GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Paediatric disorders v72.1632 Ida Ertmanska Changed child panels to: Intellectual disability; Early onset or syndromic epilepsy; Likely inborn error of metabolism; Skeletal dysplasia; Malformations of cortical development; Paediatric disorders - additional genes; Limb disorders; White matter disorders and cerebral calcification - narrow panel; DDG2P; Clefting; Neurological ciliopathies; Skeletal ciliopathies; Monogenic hearing loss; Ophthalmological ciliopathies; Holoprosencephaly; Renal ciliopathies; Neurological segmental overgrowth
Adult onset hereditary spastic paraplegia v6.10 Achchuthan Shanmugasundram List of related panels changed from Hereditary spastic paraplegia - adult onset; R60 to Hereditary spastic paraplegia - adult onset
Panel types changed to Component Of Super Panel; GMS signed-off
Holoprosencephaly v5.12 Eleanor Williams Panel name changed from Holoprosencephaly - NOT chromosomal to Holoprosencephaly
List of related panels changed from Rhombencephalosynapsis; Holoprosencephaly; R85 to Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85
Sudden unexplained death or survivors of a cardiac event v22.60 Ida Ertmanska List of related panels changed from Molecular autopsy; Sudden cardiac death; Sudden cardiac death PILOT; R138; R425 to Molecular autopsy; Sudden cardiac death; R138
Adult onset dystonia, chorea or related movement disorder v5.6 Achchuthan Shanmugasundram List of related panels changed from Adult onset movement disorder; R56 to Adult onset movement disorder
Panel types changed to Component Of Super Panel; GMS signed-off
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 CD48 Boaz Palterer gene: CD48 was added
gene: CD48 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: CD48 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CD48 were set to 31419545
Phenotypes for gene: CD48 were set to Hemophagocytic lymphohistiocytosis; Urticaria; Hives; Inflammation; Fever; Hepatosplenomegaly
Penetrance for gene: CD48 were set to unknown
Mode of pathogenicity for gene: CD48 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: CD48 was set to RED
Added comment: Volkmer et al. described a patient with heterozygous p.S220Y causing HLH-like phenotype.
Variant is likely dominant negative
Further patient described recently validating DN mechanism:
https://rupress.org/jhi/article/2/CIS2026/eCIS2026abstract.95/281844/S220-Variants-of-Human-CD48-Result-in-Aberrant
Sources: Literature
Adult-onset neurological disorders v8.28 Achchuthan Shanmugasundram Panel status changed from public to internal
Childhood interstitial lung disease v0.10 Achchuthan Shanmugasundram Panel status changed from public to internal
Sarcoma of possible germline origin v0.8 Achchuthan Shanmugasundram Panel status changed from public to internal
Embryonal tumour of possible germline origin v0.11 Achchuthan Shanmugasundram Panel status changed from public to internal
Retinal disorders v8.129 UBAP1L Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Retinal disorders v8.129 UBAP1L Ida Ertmanska Phenotypes for gene: UBAP1L were changed from Rod-cone dystrophy, HP:0000510; cone-rod dystrophy, MONDO:0015993; retinitis pigmentosa, MONDO:0019200 to Retinal dystrophy, Zeitz-Han type, OMIM:621558; Rod-cone dystrophy, HP:0000510; cone-rod dystrophy, MONDO:0015993; retinitis pigmentosa, MONDO:0019200
Ataxia and cerebellar anomalies - narrow panel v8.87 THG1L Ida Ertmanska Phenotypes for gene: THG1L were changed from Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800, MONDO:0032923 to Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800
Haematological malignancies cancer susceptibility v4.41 NAF1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Haematological malignancies cancer susceptibility v4.41 NAF1 Ida Ertmanska Phenotypes for gene: NAF1 were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, OMIM:620365; Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma
Fetal anomalies v6.198 FAM177A1 Ida Ertmanska Phenotypes for gene: FAM177A1 were changed from Neurodevelopmental disorder with white matter abnormalities and gait disturbance to Neurodevelopmental disorder with white matter abnormalities and gait disturbance, OMIM:621152
DDG2P v6.450 FAM177A1 Ida Ertmanska Phenotypes for gene: FAM177A1 were changed from FAM177A1-related neurodevelopmental disorder with macrocephaly; MONDO:0100038 to FAM177A1-related neurodevelopmental disorder with macrocephaly; MONDO:0100038; Neurodevelopmental disorder with white matter abnormalities and gait disturbance, OMIM:621152
Intellectual disability v9.405 FAM177A1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.405 FAM177A1 Ida Ertmanska Phenotypes for gene: FAM177A1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with white matter abnormalities and gait disturbance, OMIM:621152
Intellectual disability v9.404 CXorf56 Ida Ertmanska Tag gene-checked tag was added to gene: CXorf56.
Retinal disorders v8.128 C19orf44 Ida Ertmanska Tag gene-checked tag was added to gene: C19orf44.
Fetal anomalies v6.197 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Intellectual disability v9.404 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.404 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Intellectual disability v9.403 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Structural eye disease v4.44 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Structural eye disease v4.44 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Structural eye disease v4.43 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Anophthalmia or microphthalmia v1.57 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Anophthalmia or microphthalmia v1.57 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Anophthalmia or microphthalmia v1.56 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Skeletal dysplasia v8.47 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1sy May 2026.
Skeletal dysplasia v8.47 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Skeletal dysplasia v8.46 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Cerebellar hypoplasia v1.87 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Cerebellar hypoplasia v1.87 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Cerebellar hypoplasia v1.86 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Ocular coloboma v1.52 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Ocular coloboma v1.52 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Ocular coloboma v1.51 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Limb disorders v7.35 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Limb disorders v7.35 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Limb disorders v7.34 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Chondrodysplasia punctata v1.7 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added on 1st May 2026.
Chondrodysplasia punctata v1.7 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Chondrodysplasia punctata v1.6 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Limb disorders v7.34 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Limb disorders v7.34 TTC26 Ida Ertmanska Deleted their comment
Limb disorders v7.34 TTC26 Ida Ertmanska edited their review of gene: TTC26: Added comment: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.; Changed rating: RED
Renal ciliopathies v4.23 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Rare multisystem ciliopathy disorders v1.182 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Rare multisystem ciliopathy disorders v1.182 TTC26 Ida Ertmanska commented on gene: TTC26
Cholestasis v3.24 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Cholestasis v3.24 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
DDG2P v6.449 ATXN7L3 Ida Ertmanska Phenotypes for gene: ATXN7L3 were changed from ATXN7L3-related developmental delay, hypotonia and facial dysmorphism to ATXN7L3-related developmental delay, hypotonia and facial dysmorphism; Harel-Tora neurodevelopmental syndrome, OMIM:621377
Intellectual disability v9.403 ATXN7L3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.403 ATXN7L3 Ida Ertmanska Phenotypes for gene: ATXN7L3 were changed from syndromic neurodevelopmental disorder to Harel-Tora neurodevelopmental syndrome, OMIM:621377
Renal ciliopathies v4.23 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Neurological ciliopathies v6.21 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Fetal anomalies v6.197 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Limb disorders v7.34 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 TMEFF1 Ida Ertmanska Tag gene-checked tag was added to gene: TMEFF1.
Hereditary ataxia with onset in adulthood v8.31 RAB3A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Hereditary ataxia with onset in adulthood v8.31 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Hereditary ataxia with onset in adulthood v8.30 RAB3A Ida Ertmanska Tag gene-checked was removed from gene: RAB3A.
Intellectual disability v9.402 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Hereditary ataxia v1.345 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Ataxia and cerebellar anomalies - narrow panel v8.86 RAB3A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Ataxia and cerebellar anomalies - narrow panel v8.86 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Ataxia and cerebellar anomalies - narrow panel v8.85 RAB3A Ida Ertmanska Tag gene-checked was removed from gene: RAB3A.
Retinal disorders v8.128 RNU6-1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Retinal disorders v8.128 RNU6-1 Ida Ertmanska Phenotypes for gene: RNU6-1 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 103, OMIM:621561
Retinal disorders v8.127 RNU6-1 Ida Ertmanska Tag gene-checked was removed from gene: RNU6-1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.5 PSMC5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.5 PSMC5 Ida Ertmanska Phenotypes for gene: PSMC5 were changed from craniosynostosis, MONDO:0015469 to craniosynostosis, MONDO:0015469; Yu-Kury neurodevelopmental syndrome, OMIM:621565
Intellectual disability v9.401 PSMC5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.401 PSMC5 Ida Ertmanska Phenotypes for gene: PSMC5 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; Yu-Kury neurodevelopmental syndrome, OMIM:621565
Intellectual disability v9.400 PSMC5 Ida Ertmanska Tag gene-checked was removed from gene: PSMC5.
DDG2P v6.448 PSMC5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
DDG2P v6.448 PSMC5 Ida Ertmanska Phenotypes for gene: PSMC5 were changed from PSMC5-related developmental disorder (monoallelic) to PSMC5-related developmental disorder (monoallelic); Yu-Kury neurodevelopmental syndrome, OMIM:621565
DDG2P v6.447 PSMC5 Ida Ertmanska Tag gene-checked was removed from gene: PSMC5.
Monogenic short stature v1.38 GINS3 Ida Ertmanska Phenotypes for gene: GINS3 were changed from Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817 to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817; Meier-Gorlin syndrome 9, OMIM:621512
Monogenic short stature v1.37 GINS3 Ida Ertmanska Tag gene-checked was removed from gene: GINS3.
Fetal anomalies v6.197 GINS3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Fetal anomalies v6.197 GINS3 Ida Ertmanska Phenotypes for gene: GINS3 were changed from Meier-Gorlin syndrome to Meier-Gorlin syndrome; Meier-Gorlin syndrome 9, OMIM:621512
Fetal anomalies v6.196 GINS3 Ida Ertmanska Tag gene-checked was removed from gene: GINS3.
Severe microcephaly v8.53 GINS3 Ida Ertmanska Tag gene-checked was removed from gene: GINS3.
Severe microcephaly v8.53 GINS3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 1st May 2026.
Severe microcephaly v8.53 GINS3 Ida Ertmanska Phenotypes for gene: GINS3 were changed from Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817 to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817; Meier-Gorlin syndrome 9, OMIM:621512
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Tag Q2_26_demote_red tag was added to gene: AMPD1.
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Added comment: Comment on list classification: A rating change from Green to Red was requested by NHS Genomic Medicine Service and verbally agreed with PanelApp team. This change will be implemented at the next update - tagging for demotion.
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
Acute rhabdomyolysis v2.9 AMPD1 Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
Acute rhabdomyolysis v2.9 AMPD1 Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
Acute rhabdomyolysis v2.8 AMPD1 Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.36 HMBS Ida Ertmanska commented on gene: HMBS: Comment on mode of inheritance: An MOI change from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal was requested by NHS Genomic Medicine Service and verbally agreed with PanelApp team. This change will be implemented at the next update - tagging for MOI change.
Non-acute porphyrias v1.36 HMBS Ida Ertmanska Tag Q2_26_MOI tag was added to gene: HMBS.
Non-acute porphyrias v1.36 HMBS Ida Ertmanska Mode of inheritance for gene: HMBS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Non-acute porphyrias v1.35 HMBS Ida Ertmanska Deleted their comment
Adult-onset neurological disorders v8.26 Achchuthan Shanmugasundram Panel status changed from internal to public
Childhood interstitial lung disease v0.9 Achchuthan Shanmugasundram Panel status changed from internal to public
Sarcoma of possible germline origin v0.7 Achchuthan Shanmugasundram Panel status changed from internal to public
Embryonal tumour of possible germline origin v0.10 Achchuthan Shanmugasundram Panel status changed from internal to public
Monogenic short stature v1.37 SHOX Achchuthan Shanmugasundram Deleted their review
Monogenic short stature v1.37 SHOX Achchuthan Shanmugasundram Classified gene: SHOX as Green List (high evidence)
Monogenic short stature v1.37 SHOX Achchuthan Shanmugasundram Gene: shox has been classified as Green List (High Evidence).
Monogenic short stature v1.36 SHOX Achchuthan Shanmugasundram Tag technical-limitations was removed from gene: SHOX.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram changed review comment from: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. One of these patients were reported with WS2 and other with WS4, and both presented with heterochromia irides and hearing loss. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss and heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.; to: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. One of these patients were reported with WS2 and other with WS4, and both presented with heterochromia irides and hearing loss. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss or heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: SNAI2.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are three unrelated patients reported with monoallelic SNAI2 variants (excluding the family from Celia Moss, who has later been identified with KIT variant) and piebaldism (mild in the patient reported in PMID:24443330, who also had EDA1 variant). However, all three families reported with heterozygous variants in the recent literature (PMIDs: 30936914; 41073431) presented with Waardenburg syndrome (variants from two cases from PMID:30936914 had higher frequencies in population databases) and did not have any phenotype relevant to pigmentary skin disorders.

There are two unrelated patients reported with homozygous SNAI2 deletions and with Waardenburg syndrome. These patients presented with hearing loss and heterochromia iridis and not with any skin pigmentation phenotypes.

The MOI should therefore be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' as the patients with biallelic variants did not present with any skin pigmentation phenotypes.

The rating should remain amber as none of the recent monoallelic cases had piebaldism and the earlier cases with piebaldism were identified with SNAI2 deletion/variants via Southern blots/ single gene sequencing. The 'watchlist' tag has been added for reviewing this gene with new evidence in the future.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram Mode of inheritance for gene: SNAI2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.400 RNU4ATAC Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: RNU4ATAC.
Intellectual disability v9.400 RNU4ATAC Ida Ertmanska reviewed gene: RNU4ATAC: Rating: GREEN; Mode of pathogenicity: None; Publications: 29391254, 36802443, 41864208; Phenotypes: RNU4ATAC spectrum disorder, MONDO:0100558; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.195 SHROOM4 Ida Ertmanska Deleted their comment
Pigmentary skin disorders v4.20 SNAI2 Achchuthan Shanmugasundram Phenotypes for gene: SNAI2 were changed from Piebaldism to Waardenburg syndrome type 2, MONDO:0019517; piebaldism, MONDO:0008244
Pigmentary skin disorders v4.19 SNAI2 Achchuthan Shanmugasundram Publications for gene: SNAI2 were set to
Early onset or syndromic epilepsy v8.195 SHROOM4 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: SHROOM4.
Early onset or syndromic epilepsy v8.195 SHROOM4 Ida Ertmanska Tag Q2_26_expert_review was removed from gene: SHROOM4.
Pigmentary skin disorders v4.18 SNAI2 Achchuthan Shanmugasundram changed review comment from: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss and heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.; to: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. One of these patients were reported with WS2 and other with WS4, and both presented with heterochromia irides and hearing loss. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss and heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.
Pigmentary skin disorders v4.18 SNAI2 Achchuthan Shanmugasundram reviewed gene: SNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 12444107, 12955764, 24443330, 30936914, 41073431; Phenotypes: Waardenburg syndrome type 2, MONDO:0019517, piebaldism, MONDO:0008244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v3.21 MAFA Achchuthan Shanmugasundram Classified gene: MAFA as Amber List (moderate evidence)
Monogenic diabetes v3.21 MAFA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Kevin Colclough, there are three unrelated families reported in published literature with heterozygous variants in MAFA gene (two families with p.Ser64Phe variant and one family with p.Thr57Arg variant) and with insulinomatosis and diabetes. There is functional evidence available from experimental studies including heterozygous MAFA p.Ser64Phe mouse model in support of the disease association.

This gene can therefore be promoted to green rating in the next GMS update.
Monogenic diabetes v3.21 MAFA Achchuthan Shanmugasundram Gene: mafa has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.20 MAFA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with 'Insulinomatosis and diabetes mellitus' phenotype in OMIM (last accessed 29 April 2026).
Monogenic diabetes v3.20 MAFA Achchuthan Shanmugasundram Phenotypes for gene: MAFA were changed from Diabetes; Insulinomatosis; Hyperinsulinaemic Hypoglycaemia to Insulinomatosis and diabetes mellitus, OMIM:147630; islet cell adenomatosis, MONDO:0007834
Monogenic diabetes v3.19 MAFA Achchuthan Shanmugasundram Publications for gene: MAFA were set to PMID: 29339498; 34644565; 35406570; 17682063
Monogenic diabetes v3.18 MAFA Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MAFA.
Tag Q2_26_NHS_review tag was added to gene: MAFA.
Monogenic diabetes v3.18 MAFA Achchuthan Shanmugasundram reviewed gene: MAFA: Rating: GREEN; Mode of pathogenicity: None; Publications: 17682063, 29339498, 34644565, 35406570; Phenotypes: Insulinomatosis and diabetes mellitus, OMIM:147630, islet cell adenomatosis, MONDO:0007834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v3.13 MYLK3 Achchuthan Shanmugasundram changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GLHs agree that current evidence is insufficient to support haploinsufficiency of MYLK3 as a robust disease mechanism for dilated cardiomyopathy (DCM), and that loss-of-function variants in this gene should not yet be treated as clearly diagnostic. The gene shows no strong population-level constraint for heterozygous loss of function and lacks adequately powered, peer_reviewed casecontrol data and pathogenic LoF precedent needed to meet published PVS1 criteria, so variants in MYLK3 should not presently be reported as a definitive cause of disease or used to guide clinical management with high confidence.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GLHs agree that current evidence is insufficient to support haploinsufficiency of MYLK3 as a robust disease mechanism for dilated cardiomyopathy (DCM), and that loss-of-function variants in this gene should not yet be treated as clearly diagnostic. The gene shows no strong population-level constraint for heterozygous loss of function and lacks adequately powered, peer-reviewed case control data and pathogenic LoF precedent needed to meet published PVS1 criteria, so variants in MYLK3 should not presently be reported as a definitive cause of disease or used to guide clinical management with high confidence.
Fetal anomalies v6.196 ITCH Achchuthan Shanmugasundram changed review comment from: As reviewed by Ludmila Volozonoka, the single patient from PMID:36338154 is the only reported case presenting prenatally with intrauterine growth retardation. Hence, this gene can only be rated red on Fetal anomalies panel. This gene is rated with red rating on the fetal panel from PanelApp Australia.

This gene has already been rated green or proposed for green rating on panels relevant for this multi-system phenotype such as R15 Primary immunodeficiency or monogenic inflammatory bowel disease, R413 Autoinflammatory disorders and R27 Paediatric disorders (via DDG2P panel).; to: As reviewed by Ludmila Volozonoka, the single patient from PMID:36338154 is the only reported case presenting prenatally with intrauterine growth retardation. Hence, this gene can only be rated red on Fetal anomalies panel. This gene is rated with red rating on the fetal panel from PanelApp Australia.

This gene has been associated with 'Autoimmune disease, multisystem, with facial dysmorphism' phenotype (MIM #613385) in OMIM (last accessed 29 April 2026).

This gene has already been rated green or proposed for green rating on panels relevant for this multi-system phenotype such as R15 Primary immunodeficiency or monogenic inflammatory bowel disease, R413 Autoinflammatory disorders and R27 Paediatric disorders (via DDG2P panel).
Fetal anomalies v6.196 ITCH Achchuthan Shanmugasundram Phenotypes for gene: ITCH were changed from Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 to Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245
Fetal anomalies v6.195 ITCH Achchuthan Shanmugasundram Publications for gene: ITCH were set to 20170897; 31091003
Fetal anomalies v6.194 ITCH Achchuthan Shanmugasundram edited their review of gene: ITCH: Added comment: As reviewed by Ludmila Volozonoka, the single patient from PMID:36338154 is the only reported case presenting prenatally with intrauterine growth retardation. Hence, this gene can only be rated red on Fetal anomalies panel. This gene is rated with red rating on the fetal panel from PanelApp Australia.

This gene has already been rated green or proposed for green rating on panels relevant for this multi-system phenotype such as R15 Primary immunodeficiency or monogenic inflammatory bowel disease, R413 Autoinflammatory disorders and R27 Paediatric disorders (via DDG2P panel).; Changed rating: RED; Changed publications to: 36338154; Changed phenotypes to: Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385, syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram changed review comment from: PMID:28005958 (2016) reported a cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES, of which one patient reported with non-syndromic inherited retinal dystrophy was identified with compound heterozygous variants in SCLT1 gene.

PMID:37734845 (2023) reported a cohort of 1,000 probands with inherited retinal degeneration or inherited optic neuropathy, of which one patient with cone-rod dystrophy was identified to carry a heterozygous canonical splice site variant (predicted to alter the splice acceptor site of intron 15) in trans with a 1.4 kb deletion of the last coding exon (exon 21).

PMID:41963357 (2026) reported seven patients from six unrelated families with clinical phenotypes of retinal degeneration (early-onset severe retinal dystrophy or rod-cone dystrophy) associated with rare biallelic variants in SCLT1 gene. Five of these families were clearly or presumed to be diagnosed with autosomal recessive non-syndromic IRD and one with mild syndromic IRD. Ten different variants were identified in these patients, of which eight are novel variants. Five of ten variants affected splicing and one of the detected variants was a ~76kb in-frame tandem duplication encompassing exon 3-10 of the gene.; to: SCLT1 gene has previously been associated with autosomal recessive syndromic ciliopathies and rated green on relevant panels.

PMID:28005958 (2016) reported a cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES, of which one patient reported with non-syndromic inherited retinal dystrophy was identified with compound heterozygous variants in SCLT1 gene.

PMID:37734845 (2023) reported a cohort of 1,000 probands with inherited retinal degeneration or inherited optic neuropathy, of which one patient with cone-rod dystrophy was identified to carry a heterozygous canonical splice site variant (predicted to alter the splice acceptor site of intron 15) in trans with a 1.4 kb deletion of the last coding exon (exon 21).

PMID:41963357 (2026) reported seven patients from six unrelated families with clinical phenotypes of retinal degeneration (early-onset severe retinal dystrophy or rod-cone dystrophy) associated with rare biallelic variants in SCLT1 gene. Five of these families were clearly or presumed to be diagnosed with autosomal recessive non-syndromic IRD and one with mild syndromic IRD. Ten different variants were identified in these patients, of which eight are novel variants. Five of ten variants affected splicing and one of the detected variants was a ~76kb in-frame tandem duplication encompassing exon 3-10 of the gene.
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Tracy Lester, there is sufficient evidence available (>5 unrelated families) for the association of biallelic SCLT1 variants with non-syndromic inherited retinal dystrophy. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Tracy Lester, there is sufficient evidence available (>5 unrelated families) for the association of biallelic SCLT1 variants with non-syndromic inherited retinal dystrophy. Hence, this gene can be promoted to green rating in the next GMS update.
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram Classified gene: SCLT1 as Amber List (moderate evidence)
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester, there is sufficient evidence available (>5 unrelated families) for the association of biallelic SCLT1 variants with non-syndromic inherited retinal dystrophy. Hence, this gene can be promoted to green rating in the next GMS update.
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram Gene: sclt1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.126 SCLT1 Achchuthan Shanmugasundram Phenotypes for gene: SCLT1 were changed from retinal dystrophy to Retinal dystrophy, HP:0000556
Retinal disorders v8.125 SCLT1 Achchuthan Shanmugasundram Publications for gene: SCLT1 were set to 41963357; 37734845
Retinal disorders v8.124 SCLT1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: SCLT1.
Tag Q2_26_NHS_review tag was added to gene: SCLT1.
Retinal disorders v8.124 SCLT1 Achchuthan Shanmugasundram reviewed gene: SCLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28005958, 37734845, 41963357; Phenotypes: Retinal dystrophy, HP:0000556; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v4.5 CACNB3 Mervyn Thomas gene: CACNB3 was added
gene: CACNB3 was added to Albinism or congenital nystagmus. Sources: Literature
Mode of inheritance for gene: CACNB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNB3 were set to 41822111
Phenotypes for gene: CACNB3 were set to infantile nystagmus
Penetrance for gene: CACNB3 were set to Complete
Review for gene: CACNB3 was set to GREEN
Added comment: Recent evidence suggests this gene can be involved in infantile nystagmus please see publication - https://pubmed.ncbi.nlm.nih.gov/41822111/
Sources: Literature
Pulmonary arterial hypertension v4.5 FLNA Karen Stals gene: FLNA was added
gene: FLNA was added to Pulmonary arterial hypertension. Sources: Literature
Mode of inheritance for gene: FLNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FLNA were set to PMID: 30547349; PMID: 28457522
Phenotypes for gene: FLNA were set to Pulmonary hypertension; respiratory failure
Review for gene: FLNA was set to GREEN
gene: FLNA was marked as current diagnostic
Added comment: Multiple papers report loss of function FLNA variants as a cause of neonatal/childhood pulmonary hypertension (see PMID: 30547349), GeneReviews FLNA deficiency page lists pulmonary findings including pulmonary hypertension in list of clinical features.
Sources: Literature
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Severe developmental delay/ intellectual disability was reported in all ten patients. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Severe developmental delay/ intellectual disability was reported in all ten patients. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Ataxia was reported in seven patients from four of these five families. Cerebellar atrophy was also reported in some patients. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Ataxia was reported in seven patients from four of these five families. Cerebellar atrophy was also reported in some patients. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.53 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.53 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Spasticity was reported in five patients from three families. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.53 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Ataxia was reported in seven patients from four of these five families. Cerebellar atrophy was also reported in some patients. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.52 PGBD5 Achchuthan Shanmugasundram gene: PGBD5 was added
gene: PGBD5 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q2_26_promote_green tags were added to gene: PGBD5.
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to 41533792
Phenotypes for gene: PGBD5 were set to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Review for gene: PGBD5 was set to GREEN
Added comment: PMID:41533792 (2026) reported the identification of genetic variants in PGBD5 gene using GeneMatcher in ten individuals from five unrelated consanguineous families. Exome sequencing was used to identify distinct homozygous PGBD5 variants segregating with the affected family members and this was confirmed by Sanger sequencing. These affected children shared conserved clinical phenotypes across neurodevelopmental and motor domains.

Neurodevelopmental features included intellectual disability and developmental delay (ID/DD; ten of ten), epilepsy (nine of nine), limited or no speech (nine of nine), autism spectrum disorder, or social delay (ASD; four of six). Prominent motor features included axial hypotonia (nine of nine), increased peripheral tone (seven of nine) or decreased peripheral tone (two of nine), increased tendon reflexes (five of nine), or decreased tendon reflexes (four of nine). Other observed neurological phenotypes include spasticity that mainly affected the lower limbs (five of nine), intermittent dystonia (three of ten), and ataxia (seven of ten).

There is also evidence available from Pgbd5-null mice, which were runted and had significantly smaller brains compared to wildtype. Mutant mice showed increased locomotor activity, reduced anxiety-like behavior, impaired motor coordination, increased susceptibility to seizures, and decreased cortical volume on brain MRI. Analysis of neurons derived from Pgbd5-null mouse brains showed reduced DNA breakage and repair in postmitotic neuronal precursors during cortical development compared to controls.

This gene has already been associated with relevant phenotype in OMIM (MIM #41533792, last accessed 28 April 2026), but not yet in Gene2Phenotype.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.84 PGBD5 Achchuthan Shanmugasundram gene: PGBD5 was added
gene: PGBD5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_26_promote_green tags were added to gene: PGBD5.
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to 41533792
Phenotypes for gene: PGBD5 were set to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Review for gene: PGBD5 was set to GREEN
Added comment: PMID:41533792 (2026) reported the identification of genetic variants in PGBD5 gene using GeneMatcher in ten individuals from five unrelated consanguineous families. Exome sequencing was used to identify distinct homozygous PGBD5 variants segregating with the affected family members and this was confirmed by Sanger sequencing. These affected children shared conserved clinical phenotypes across neurodevelopmental and motor domains.

Neurodevelopmental features included intellectual disability and developmental delay (ID/DD; ten of ten), epilepsy (nine of nine), limited or no speech (nine of nine), autism spectrum disorder, or social delay (ASD; four of six). Prominent motor features included axial hypotonia (nine of nine), increased peripheral tone (seven of nine) or decreased peripheral tone (two of nine), increased tendon reflexes (five of nine), or decreased tendon reflexes (four of nine). Other observed neurological phenotypes include spasticity that mainly affected the lower limbs (five of nine), intermittent dystonia (three of ten), and ataxia (seven of ten).

There is also evidence available from Pgbd5-null mice, which were runted and had significantly smaller brains compared to wildtype. Mutant mice showed increased locomotor activity, reduced anxiety-like behavior, impaired motor coordination, increased susceptibility to seizures, and decreased cortical volume on brain MRI. Analysis of neurons derived from Pgbd5-null mouse brains showed reduced DNA breakage and repair in postmitotic neuronal precursors during cortical development compared to controls.

This gene has already been associated with relevant phenotype in OMIM (MIM #41533792, last accessed 28 April 2026), but not yet in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.194 PGBD5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: PGBD5.
Tag Q2_26_NHS_review tag was added to gene: PGBD5.
Early onset or syndromic epilepsy v8.194 PGBD5 Achchuthan Shanmugasundram Phenotypes for gene: PGBD5 were changed from Seizures; global developmental delay; spasticity; hypotonia to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Early onset or syndromic epilepsy v8.193 PGBD5 Achchuthan Shanmugasundram Publications for gene: PGBD5 were set to PMID: 41533792
Early onset or syndromic epilepsy v8.192 PGBD5 Achchuthan Shanmugasundram reviewed gene: PGBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41533792; Phenotypes: Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Severe developmental delay/ intellectual disability was reported in all ten patients. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.399 PGBD5 Achchuthan Shanmugasundram Phenotypes for gene: PGBD5 were changed from Seizures; global developmental delay; spasticity; hypotonia to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Intellectual disability v9.398 PGBD5 Achchuthan Shanmugasundram edited their review of gene: PGBD5: Changed phenotypes to: Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Intellectual disability v9.398 PGBD5 Achchuthan Shanmugasundram Publications for gene: PGBD5 were set to PMID: 41533792
Intellectual disability v9.397 PGBD5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: PGBD5.
Tag Q2_26_NHS_review tag was added to gene: PGBD5.
Intellectual disability v9.397 PGBD5 Achchuthan Shanmugasundram commented on gene: PGBD5: PMID:41533792 (2026) reported the identification of genetic variants in PGBD5 gene using GeneMatcher in ten individuals from five unrelated consanguineous families. Exome sequencing was used to identify distinct homozygous PGBD5 variants segregating with the affected family members and this was confirmed by Sanger sequencing. These affected children shared conserved clinical phenotypes across neurodevelopmental and motor domains.

Neurodevelopmental features included intellectual disability and developmental delay (ID/DD; ten of ten), epilepsy (nine of nine), limited or no speech (nine of nine), autism spectrum disorder, or social delay (ASD; four of six). Prominent motor features included axial hypotonia (nine of nine), increased peripheral tone (seven of nine) or decreased peripheral tone (two of nine), increased tendon reflexes (five of nine), or decreased tendon reflexes (four of nine). Other observed neurological phenotypes include spasticity that mainly affected the lower limbs (five of nine), intermittent dystonia (three of ten), and ataxia (seven of ten).

There is also evidence available from Pgbd5-null mice, which were runted and had significantly smaller brains compared to wildtype. Mutant mice showed increased locomotor activity, reduced anxiety-like behavior, impaired motor coordination, increased susceptibility to seizures, and decreased cortical volume on brain MRI. Analysis of neurons derived from Pgbd5-null mouse brains showed reduced DNA breakage and repair in postmitotic neuronal precursors during cortical development compared to controls.

This gene has already been associated with relevant phenotype in OMIM (MIM #41533792, last accessed 28 April 2026), but not yet in Gene2Phenotype.
Intellectual disability v9.397 PGBD5 Achchuthan Shanmugasundram reviewed gene: PGBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41533792; Phenotypes: Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO_0980968; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.45 SMN1 Eleanor Williams Tag Q2_26_expert_review tag was added to gene: SMN1.
Paediatric motor neuronopathies v3.13 SMN1 Eleanor Williams Tag Q2_26_expert_review tag was added to gene: SMN1.
Arthrogryposis v9.34 SMN1 Eleanor Williams Tag Q2_26_expert_review tag was added to gene: SMN1.
Fetal anomalies v6.194 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene. It needs to be confirmed whether variants in this gene can be reported in this test by the labs.
Fetal anomalies v6.194 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Tag Q2_26_demote_red tag was added to gene: SMN1.
Tag Q2_26_expert_review tag was added to gene: SMN1.
Hereditary neuropathy or pain disorder v7.45 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene.
Hereditary neuropathy or pain disorder v7.45 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Tag Q2_26_demote_red tag was added to gene: SMN1.
Paediatric motor neuronopathies v3.13 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene.
Paediatric motor neuronopathies v3.13 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Tag Q2_26_demote_red tag was added to gene: SMN1.
Arthrogryposis v9.34 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene.
Arthrogryposis v9.34 SMN1 Eleanor Williams Tag Q2_26_demote_red tag was added to gene: SMN1.
Arthrogryposis v9.34 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Parkinson Disease and Complex Parkinsonism v1.128 GBA Anjali Lloyd-Jani reviewed gene: GBA: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29385658; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.73 HGF Ida Ertmanska Tag watchlist was removed from gene: HGF.
Fetal anomalies v6.194 SKOR2 Eleanor Williams Phenotypes for gene: SKOR2 were changed from Cerebellar hypoplasia, neurodevelopmental delay to Cerebellar hypoplasia, neurodevelopmental delay; Valence-Farazi cerebellar ataxia syndrome, OMIM: 621386; Valence-Farazi cerebellar ataxia syndrome, MONDO:0980707
Limb disorders v7.34 TTC26 Eleanor Williams Tag Q2_26_promote_green was removed from gene: TTC26.
Tag curated_removed tag was added to gene: TTC26.
Limb disorders v7.34 TTC26 Eleanor Williams Classified gene: TTC26 as No list
Limb disorders v7.34 TTC26 Eleanor Williams Added comment: Comment on list classification: In line with other multisystem ciliopathy genes, this gene has been removed from the limb disorders panel and will be tested through the Rare multisystem ciliopathy Super panel https://panelapp.genomicsengland.co.uk/panels/728/
Limb disorders v7.34 TTC26 Eleanor Williams Gene: ttc26 has been removed from the panel.
Fetal anomalies v6.193 SNAPIN Eleanor Williams Phenotypes for gene: SNAPIN were changed from neurodevelopmental disorder; Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393 to neurodevelopmental disorder; Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Severe microcephaly v8.52 SNAPIN Eleanor Williams Phenotypes for gene: SNAPIN were changed from Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393 to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Ataxia and cerebellar anomalies - narrow panel v8.83 SNAPIN Eleanor Williams Phenotypes for gene: SNAPIN were changed from Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393 to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Retinal disorders v8.124 SCLT1 Tracy Lester gene: SCLT1 was added
gene: SCLT1 was added to Retinal disorders. Sources: NHS GMS
Mode of inheritance for gene: SCLT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCLT1 were set to 41963357; 37734845
Phenotypes for gene: SCLT1 were set to retinal dystrophy
Penetrance for gene: SCLT1 were set to unknown
Review for gene: SCLT1 was set to GREEN
Added comment: The authors describe five families with non-syndromic IRD and compound heterozygous for SLCT1 variants - 8 variants were novel. 4 missense, 2 single AA dels, 3 intronic. Four of these variants shown to impact splicing. A large in-frame tandem dup also reported. Another comp het case with IRD reported by Weisschuh et al
Meets criteria to be green on R32 panel.
Sources: NHS GMS
Adult onset neurodegenerative disorder v8.21 FIG4 Anjali Lloyd-Jani reviewed gene: FIG4: 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: PMID: 19118816; Phenotypes: Autosomal recessive Yunis-Varon syndrome and CMT4J; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v4.5 MLPH Achchuthan Shanmugasundram Classified gene: MLPH as Amber List (moderate evidence)
Albinism or congenital nystagmus v4.5 MLPH Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Albinism or congenital nystagmus v4.5 MLPH Achchuthan Shanmugasundram Gene: mlph has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v4.4 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from Griscelli syndrome, type 3 609227 AR to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, MONDO:0012220
Albinism or congenital nystagmus v4.3 MLPH Achchuthan Shanmugasundram Publications for gene: MLPH were set to
Albinism or congenital nystagmus v4.2 MLPH Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MLPH.
Albinism or congenital nystagmus v4.2 MLPH Achchuthan Shanmugasundram reviewed gene: MLPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12897212, 21883982, 22711375, 26337734, 30389201, 31721180, 35602484; Phenotypes: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, MONDO:0012220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Veronica Kinsler, there is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel.; to: Comment on list classification: As reviewed by Veronica Kinsler, there is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram Classified gene: MLPH as Amber List (moderate evidence)
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Veronica Kinsler, there is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel.
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram Gene: mlph has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v4.17 MLPH Achchuthan Shanmugasundram edited their review of gene: MLPH: Changed phenotypes to: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.17 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3, MONDO:0012220 to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.16 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3 to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.15 MLPH Achchuthan Shanmugasundram edited their review of gene: MLPH: Changed phenotypes to: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.15 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3
Pigmentary skin disorders v4.14 MLPH Achchuthan Shanmugasundram Publications for gene: MLPH were set to
Pigmentary skin disorders v4.13 MLPH Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MLPH.
Tag Q2_26_NHS_review tag was added to gene: MLPH.
Pigmentary skin disorders v4.13 MLPH Achchuthan Shanmugasundram reviewed gene: MLPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12897212, 21883982, 22711375, 26337734, 30389201, 31721180, 35602484; Phenotypes: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, Griscelli syndrome type 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v7.25 ATAD1 Achchuthan Shanmugasundram Classified gene: ATAD1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v7.25 ATAD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic variants with hyperekplexia. As other hyperekplexia-causing genes (e.g. GLRA1 & GLRB) are rated green on this panel, this gene should also be rated green in the next update.
Childhood onset dystonia, chorea or related movement disorder v7.25 ATAD1 Achchuthan Shanmugasundram Gene: atad1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.24 ATAD1 Achchuthan Shanmugasundram gene: ATAD1 was added
gene: ATAD1 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Q2_26_promote_green tags were added to gene: ATAD1.
Mode of inheritance for gene: ATAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD1 were set to 28180185; 29390050; 29659736; 33134516; 36933275
Phenotypes for gene: ATAD1 were set to Hyperekplexia 4, OMIM:618011; hyperekplexia 4, MONDO:0044330
Review for gene: ATAD1 was set to GREEN
Added comment: PMID:28180185 (2017) reported the identification of a homozygous nonsense variant in ATAD1 gene (p.Glu276Ter) in a large consanguineous Kuwaiti family. They presented with a neurological disorder characterised by hypertonia, seizures, and death. Detailed clinical information was available for two of the patients and they had no or little spontaneous movement. There is also functional evidence available from ATAD1 knockout mouse model, from which the authors suggested loss-of-function mechanism for the variant.

PMID:29390050 (2018) reported the identification of a homozygous frameshift variant in ATAD1 gene (p.His357Argfs*15) in three siblings from a consanguineous Tunisian family who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. The proband had exaggerated startle and clonic movements. Functional evidence was available which suggested that gain-of-function for the variant.

PMID:29659736 (2018) reported a female infant born of consanguineous parents with a similar disorder. She was identified with a homozygous ATAD1 variant (c.162G-C) that was predicted to result in a missense variant or a splicing defect causing loss of function. She was a stiff baby at birth and had no spontaneous movements.

PMID:33134516 (2020) reported two new unrelated patients presenting with a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. They were identified with homozygous variants in ATAD1 gene (Patient 1: p.His357Argfs*15; Patient 2: p.Gly128Val).

PMID:36933275 (2023) reported the identification of two novel heterozygous variants in ATAD1 gene (maternal: c.690+1G>c - splice site variant; paternal: c.148G>T - nonsense) in a female neonate presenting with hypertonia, tremulousness and clonus.

This gene has been associated with hyperekplexia 4 in OMIM (MIM #618011, last accessed 23 April 2026), but not in Gene2Phenotype or ClinGen.
Sources: Literature
Likely inborn error of metabolism v8.113 SLC6A5 Achchuthan Shanmugasundram Classified gene: SLC6A5 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.113 SLC6A5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants with hyperekplexia 3. This gene encodes a metabolite transporter and is rated definitive by General Inborn Errors of Metabolism GCEP for biallelic variants. This gene should therefore be promoted to green rating on R98 in the next GMS update.
Likely inborn error of metabolism v8.113 SLC6A5 Achchuthan Shanmugasundram Gene: slc6a5 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.112 SLC6A5 Achchuthan Shanmugasundram gene: SLC6A5 was added
gene: SLC6A5 was added to Likely inborn error of metabolism. Sources: Literature
Q2_26_promote_green tags were added to gene: SLC6A5.
Mode of inheritance for gene: SLC6A5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SLC6A5 were set to 16751771; 22753417
Phenotypes for gene: SLC6A5 were set to Hyperekplexia 3, OMIM:614618; hyperekplexia 3, MONDO:0013827
Review for gene: SLC6A5 was set to GREEN
Added comment: PMID:16751771 (2006) reported seven patients from six unrelated families presenting with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. Of these, six patients from five families were identified with homozygous or compound heterozygous variants in SLC6A5 gene. The seventh patient was identified with a heterozygous variant in the same gene. There is also functional evidence available for the variants, showing that they result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.
The SLC6A5 gene encodes the Sodium- and chloride-dependent glycine transporter 2 (GlyT2), a membrane protein responsible for re-uptake of glycine in the spinal cord and brainstem.

PMID:22753417 (2012) reported the identification of a new dominant SLC6A5 variant (p.Tyr705Cys) via single gene sequencing in eight individuals from three families in two cohorts of hyperekplexia patients. As well as classical hyperekplexia symptoms, certain individuals exhibited abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. This may be due to a complex phenotype caused by the variant or to the presence of additional unknown variants. There is also functional evidence available for this variant.

Both monoallelic and biallelic variants are associated with hyperekplexia 3 (MIM #614618) in OMIM (last accessed 23 April 2026). In addition, biallelic variants are associated with hyperekplexia 3 (MONDO:0013827) with 'Definitive' rating by General Inborn Errors of Metabolism GCEP in ClinGen.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v7.23 SLC6A5 Achchuthan Shanmugasundram Classified gene: SLC6A5 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v7.23 SLC6A5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants with hyperekplexia. As reviewed by Hannah Robinson, other hyperekplexia-causing genes (e.g. GLRA1 & GLRB) are rated green on this panel. Hence, this gene should be promoted to green rating in the next update.
Childhood onset dystonia, chorea or related movement disorder v7.23 SLC6A5 Achchuthan Shanmugasundram Gene: slc6a5 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.22 SLC6A5 Achchuthan Shanmugasundram Phenotypes for gene: SLC6A5 were changed from Hyperekplexia 3, 614618 to Hyperekplexia 3, OMIM:614618; hyperekplexia 3, MONDO:0013827
Childhood onset dystonia, chorea or related movement disorder v7.21 SLC6A5 Achchuthan Shanmugasundram Publications for gene: SLC6A5 were set to 16751771
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram Tag Q2_26_NHS_review tag was added to gene: SLC6A5.
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: SLC6A5.
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram edited their review of gene: SLC6A5: Changed publications to: 16751771, 22753417
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram reviewed gene: SLC6A5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperekplexia 3, OMIM:614618, hyperekplexia 3, MONDO:0013827; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v5.73 USP48 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 23rd Apr 2026.
Monogenic hearing loss v5.73 USP48 Ida Ertmanska Phenotypes for gene: USP48 were changed from non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497; Deafness, autosomal dominant 85, OMIM:620227
Hereditary ataxia with onset in adulthood v8.30 MFN2 Ida Ertmanska reviewed gene: MFN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 41402974, 38170145, 35418194; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260, Hereditary motor and sensory neuropathy VIA, OMIM:601152; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy and identified with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy and identified with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are five unrelated families reported with cardiac conduction disease. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are five unrelated families reported with cardiac conduction disease and with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy and identified with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram Classified gene: POPDC2 as Amber List (moderate evidence)
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with cardiac conduction disease. Hence, this gene can be promoted to green rating in the next GMS update.
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram Gene: popdc2 has been classified as Amber List (Moderate Evidence).
Progressive cardiac conduction disease v2.14 POPDC2 Achchuthan Shanmugasundram gene: POPDC2 was added
gene: POPDC2 was added to Progressive cardiac conduction disease. Sources: Literature
Q2_26_promote_green tags were added to gene: POPDC2.
Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POPDC2 were set to 40409267; 41456958
Phenotypes for gene: POPDC2 were set to Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367; cardiac conduction disease with or without cardiomyopathy 2, MONDO:0700389
Review for gene: POPDC2 was set to GREEN
Added comment: PMID:40409267 (2025) reported the identification of biallelic variants in POPDC2 gene in six patients from four families presenting with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. Modelling and electrophysiological studies suggested effects of identified POPDC2 variants on cAMP binding and TREK-1 current.

PMID:41456958 (2026) reported the identification of a novel homozygous POPDC2 variant in a patient presenting with early-onset cardiac conduction disease and hypertrophic cardiomyopathy.

This gene has been associated with relevant phenotype in OMIM (MIM #621367, record last accessed on 22 April 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram Classified gene: POPDC2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram Gene: popdc2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.101 POPDC2 Achchuthan Shanmugasundram Phenotypes for gene: POPDC2 were changed from cardiac conduction defects and hypertrophic cardiomyopathy to Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367; cardiac conduction disease with or without cardiomyopathy 2, MONDO:0700389
Paediatric or syndromic cardiomyopathy v7.100 POPDC2 Achchuthan Shanmugasundram Publications for gene: POPDC2 were set to PMID: 40409267
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Achchuthan Shanmugasundram edited their review of gene: POPDC2: Changed phenotypes to: Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367, cardiac conduction disease with or without cardiomyopathy 2, MONDO:0700389
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: POPDC2.
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Achchuthan Shanmugasundram reviewed gene: POPDC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40409267, 41456958; Phenotypes: Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic short stature v1.36 VPS50 Ida Ertmanska Tag curated_removed tag was added to gene: VPS50.
Monogenic short stature v1.36 VPS50 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: VPS50.
Monogenic short stature v1.36 VPS50 Ida Ertmanska Classified gene: VPS50 as No list
Monogenic short stature v1.36 VPS50 Ida Ertmanska Gene: vps50 has been removed from the panel.
Monogenic short stature v1.35 VPS50 Ida Ertmanska Classified gene: VPS50 as Red List (low evidence)
Monogenic short stature v1.35 VPS50 Ida Ertmanska Added comment: Comment on list classification: As per current Test Directory criteria for this panel, presence of microcephaly in an individual excludes R453 Monogenic short stature testing. While there are 3 individuals reported with short stature and biallelic VPS50 variants, including two individuals with more than -2 Z, all 3 had microcephaly as well. Hence, this gene should be Grey and tagged curated_removed on this panel.
Monogenic short stature v1.35 VPS50 Ida Ertmanska Gene: vps50 has been classified as Red List (Low Evidence).
Monogenic short stature v1.34 VPS50 Ida Ertmanska edited their review of gene: VPS50: Changed rating: RED
Cholestasis v3.24 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Monogenic short stature v1.34 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Her height was 77cm at 18 months (-1.69 Z). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Monogenic short stature v1.34 VPS50 Ida Ertmanska Deleted their comment
Cholestasis v3.24 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Her height was 77cm at 18 months (-1.69 Z). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.24 VPS50 Ida Ertmanska Deleted their comment
Monogenic short stature v1.34 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Monogenic short stature v1.33 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Monogenic short stature v1.32 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Intellectual disability v9.397 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.397 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Intellectual disability v9.396 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Intellectual disability v9.395 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Monogenic short stature v1.32 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Intellectual disability v9.395 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Monogenic short stature v1.32 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.395 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.192 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Early onset or syndromic epilepsy v8.191 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Early onset or syndromic epilepsy v8.191 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Early onset or syndromic epilepsy v8.190 VPS50 Ida Ertmanska Classified gene: VPS50 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.190 VPS50 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Early onset or syndromic epilepsy v8.190 VPS50 Ida Ertmanska Gene: vps50 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.189 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Early onset or syndromic epilepsy v8.189 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v8.51 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Severe microcephaly v8.51 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Severe microcephaly v8.50 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Severe microcephaly v8.49 VPS50 Ida Ertmanska Classified gene: VPS50 as Amber List (moderate evidence)
Severe microcephaly v8.49 VPS50 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Severe microcephaly v8.49 VPS50 Ida Ertmanska Gene: vps50 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.48 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Severe microcephaly v8.48 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v7.58 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Malformations of cortical development v7.58 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Malformations of cortical development v7.58 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Malformations of cortical development v7.57 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Malformations of cortical development v7.56 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Malformations of cortical development v7.56 VPS50 Ida Ertmanska edited their review of gene: VPS50: Changed rating: GREEN; Changed publications to: 38876772; Changed phenotypes to: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v3.24 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Malformations of cortical development v7.56 VPS50 Ida Ertmanska commented on gene: VPS50
Cholestasis v3.24 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Cholestasis v3.24 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Cholestasis v3.23 VPS50 Ida Ertmanska Classified gene: VPS50 as Amber List (moderate evidence)
Cholestasis v3.23 VPS50 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Cholestasis v3.23 VPS50 Ida Ertmanska Gene: vps50 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.22 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Intellectual disability v9.395 WDR91 Ida Ertmanska Phenotypes for gene: WDR91 were changed from Abnormal brain morphology, HP:0012443 to Abnormal brain morphology, HP:0012443; Neurodevelopmental delay, HP:0012758
Intellectual disability v9.394 WDR91 Ida Ertmanska Classified gene: WDR91 as Amber List (moderate evidence)
Intellectual disability v9.394 WDR91 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic WDR91 variants and syndromic neurodevelopmental delay. Animal models support the role of WDR91 in neuronal development and function. Mice lacking Wdr91 exhibited behavioural defects. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.394 WDR91 Ida Ertmanska Gene: wdr91 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.56 WDR91 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic WDR91 variants and brain malformations (1 case non-specific; 2 cases with findings such as CC agenesis, lissencephaly, cerebral hemisphere hypoplasia). Animal models support the role of WDR91 in neuronal development and function. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic WDR91 variants and cortical malformations (1 case non-specific; 2 cases with findings such as CC agenesis, lissencephaly, cerebral hemisphere hypoplasia). Animal models support the role of WDR91 in neuronal development and function. Hence, this gene should be promoted to Green at the next update.
Malformations of cortical development v7.56 WDR91 Ida Ertmanska Classified gene: WDR91 as Amber List (moderate evidence)
Malformations of cortical development v7.56 WDR91 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic WDR91 variants and brain malformations (1 case non-specific; 2 cases with findings such as CC agenesis, lissencephaly, cerebral hemisphere hypoplasia). Animal models support the role of WDR91 in neuronal development and function. Hence, this gene should be promoted to Green at the next update.
Malformations of cortical development v7.56 WDR91 Ida Ertmanska Gene: wdr91 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.393 WDR91 Ida Ertmanska gene: WDR91 was added
gene: WDR91 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: WDR91.
Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR91 were set to 32732226; 34028500; 34791078; 38041506; 40550703
Phenotypes for gene: WDR91 were set to Abnormal brain morphology, HP:0012443
Review for gene: WDR91 was set to GREEN
Added comment: PMID: 32732226 Lefebvre et al., 2021
Homozygous variant WDR91 c.240C>G, p.(Tyr80*) detected in a male fetus with hygroma, macrocephaly, abnormal ears, cerebellar hypoplasia, and hydrocephaly. Concordant segregation among 4 affected fetus, 2 healthy sibs, and both parents.

PMID: 34791078 Kurul et al., 2022
Large study, trio exome seq of consanguineous families with neurogenetic diseases. FMAL006_01 - female patient with 'brain malformation' was homozygous for WDR91 c.1395+1G>A. No more details provided.

PMID: 38041506 Rosina et al., 2024
Case 75 - male, 3yrs 5mo, homozygous for WDR91 NM_014149.4:c.511+1A>G. Phenotype: severe developmental delay, microcephaly, severe microlissencephaly, agenesis of corpus callosum, epilepsy, spastic tetraparesis, laryngomalacia, bicuspid aortic valve, congenital hip dislocation, growth retardation, dysmorphisms.

PMID: 40550703 Marinakis et al., 2026
Consanguineous Syrian family. Proband (4mo female) presented with severe microcephaly, dysmorphic features, organomegaly, early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Brain MRI revealed bilateral cerebral hemisphere hypoplasia with incomplete sulcation, agenesis of the corpus callosum, suspected bilateral periventricular heterotopias. WES identified a homozygous splice site variant, WDR91 NM_014149.4: c.1395+1G>A (same as in PMID: 34791078, but NOT the same patient).

Functional: PMID: 34028500 Xing et al., 2021 - Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At a cellular level, Wdr91 deficiency caused dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons.

WDR91 is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Malformations of cortical development v7.55 WDR91 Ida Ertmanska gene: WDR91 was added
gene: WDR91 was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: WDR91.
Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR91 were set to 32732226; 34028500; 34791078; 38041506; 40550703
Phenotypes for gene: WDR91 were set to Abnormal brain morphology, HP:0012443
Review for gene: WDR91 was set to GREEN
Added comment: PMID: 32732226 Lefebvre et al., 2021
Homozygous variant WDR91 c.240C>G, p.(Tyr80*) detected in a male fetus with hygroma, macrocephaly, abnormal ears, cerebellar hypoplasia, and hydrocephaly. Concordant segregation among 4 affected fetus, 2 healthy sibs, and both parents.

PMID: 34791078 Kurul et al., 2022
Large study, trio exome seq of consanguineous families with neurogenetic diseases. FMAL006_01 - female patient with 'brain malformation' was homozygous for WDR91 c.1395+1G>A. No more details provided.

PMID: 38041506 Rosina et al., 2024
Case 75 - male, 3yrs 5mo, homozygous for WDR91 NM_014149.4:c.511+1A>G. Phenotype: severe developmental delay, microcephaly, severe microlissencephaly, agenesis of corpus callosum, epilepsy, spastic tetraparesis, laryngomalacia, bicuspid aortic valve, congenital hip dislocation, growth retardation, dysmorphisms.

PMID: 40550703 Marinakis et al., 2026
Consanguineous Syrian family. Proband (4mo female) presented with severe microcephaly, dysmorphic features, organomegaly, early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Brain MRI revealed bilateral cerebral hemisphere hypoplasia with incomplete sulcation, agenesis of the corpus callosum, suspected bilateral periventricular heterotopias. WES identified a homozygous splice site variant, WDR91 NM_014149.4: c.1395+1G>A (same as in PMID: 34791078, but NOT the same patient).

Functional: PMID: 34028500 Xing et al., 2021 - Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At a cellular level, Wdr91 deficiency caused dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons.

WDR91 is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.189 ISCA-46297-Loss Arina Puzriakova edited their review of Region: ISCA-46297-Loss: Changed rating: RED
Intellectual disability v9.392 ISCA-46297-Loss Arina Puzriakova edited their review of Region: ISCA-46297-Loss: Changed rating: RED
Monogenic hearing loss v5.72 ISCA-46297-Loss Arina Puzriakova Phenotypes for Region: ISCA-46297-Loss were changed from to Autosomal recessive deafness-22
Monogenic hearing loss v5.71 ISCA-46297-Loss Arina Puzriakova Publications for Region: ISCA-46297-Loss were set to 31204719; 19888295; 20301607; 25719193; 30836598
Monogenic hearing loss v5.70 ISCA-46297-Loss Arina Puzriakova commented on Region: ISCA-46297-Loss: Homozygous distal 16p12.2 deletions, encompassing the OTOA gene, are associated with autosomal recessive deafness-22 (PMID: 19888295; 31204719; 39916398)
Early onset or syndromic epilepsy v8.189 ISCA-46297-Loss Arina Puzriakova Tag Q2_26_demote_red tag was added to Region: ISCA-46297-Loss.
Intellectual disability v9.392 ISCA-46297-Loss Arina Puzriakova Tag Q2_26_demote_red tag was added to Region: ISCA-46297-Loss.
Early onset or syndromic epilepsy v8.189 ISCA-46297-Loss Arina Puzriakova commented on Region: ISCA-46297-Loss: This region should be demoted from green to red at the next GMS panel update. ClinGen summary states that heterozygous deletions of this region are not dosage sensitive (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46297).

Homozygous distal 16p12.2 deletions, encompassing the OTOA gene, are associated with autosomal recessive deafness-22 (PMID: 19888295; 31204719; 39916398)

16p12.2 proximal deletions (distinct genomic coordinates) have been linked to neurodevelopmental phenotypes (PMID: 20154674; 25719193; 30836598; 30190612), however the evidence is classified as 'emerging' in ClinGen and is insufficient to add to diagnostic GMS panels at this time (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37409).
Intellectual disability v9.392 ISCA-46297-Loss Arina Puzriakova commented on Region: ISCA-46297-Loss: This region should be demoted from green to red at the next GMS panel update. ClinGen summary states that heterozygous deletions of this region are not dosage sensitive (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46297).

Homozygous distal 16p12.2 deletions, encompassing the OTOA gene, are associated with autosomal recessive deafness-22 (PMID: 19888295; 31204719; 39916398)

16p12.2 proximal deletions (distinct genomic coordinates) have been linked to neurodevelopmental phenotypes (PMID: 20154674; 25719193; 30836598; 30190612), however the evidence is classified as 'emerging' in ClinGen and is insufficient to add to diagnostic GMS panels at this time (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37409).
Fetal anomalies v6.192 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; Luo-Agrawal neurodevelopmental syndrome, OMIM:621552 neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.191 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; Luo-Agrawal neurodevelopmental syndrome, OMIM:621552 neurodevelopmental disorder, MONDO:0700092
Ataxia and cerebellar anomalies - narrow panel v8.82 WSB2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Ataxia and cerebellar anomalies - narrow panel v8.82 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental disorder, MONDO:0700092 to Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.392 WSB2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.392 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental disorder, MONDO:0700092 to Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.189 WSB2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Early onset or syndromic epilepsy v8.189 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental disorder, MONDO:0700092 to Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Severe microcephaly v8.48 ZNF668 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Severe microcephaly v8.48 ZNF668 Ida Ertmanska Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194 neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MONDO:0859350
Monogenic short stature v1.32 ZNF668 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Monogenic short stature v1.32 ZNF668 Ida Ertmanska Phenotypes for gene: ZNF668 were changed from Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194 to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194 neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MONDO:0859350
Intellectual disability v9.391 ZNF668 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.391 ZNF668 Ida Ertmanska Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194; neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MONDO:0859350
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Cholestasis v3.21 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.21 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.21 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.190 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Fetal anomalies v6.190 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Early onset or syndromic epilepsy v8.188 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Early onset or syndromic epilepsy v8.188 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Intellectual disability v9.390 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.390 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Likely inborn error of metabolism v8.111 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Likely inborn error of metabolism v8.111 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Severe microcephaly v8.47 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Severe microcephaly v8.47 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Congenital disorders of glycosylation v7.17 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Congenital disorders of glycosylation v7.17 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with pituitary involvement. Patients exhibited impaired pituitary function. Pituitary anomalies e.g., pituitary hypoplasia / stalk interruption, were seen on MRI in 5 different families. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies, hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies (including missing pituitary stalk on imaging), hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies, hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Rare multisystem ciliopathy disorders v1.182 TTC26 Ida Ertmanska Phenotypes for gene: TTC26 were changed from Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Rare multisystem ciliopathy disorders v1.181 TTC26 Ida Ertmanska Classified gene: TTC26 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.181 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Green List (High Evidence).
Limb disorders v7.33 TTC26 Ida Ertmanska changed review comment from: Comment on list classification: here are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with limb involvement. Patients consistently presented with polydactyly. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with limb involvement. Patients consistently presented with polydactyly. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Limb disorders v7.33 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Limb disorders v7.33 TTC26 Ida Ertmanska Added comment: Comment on list classification: here are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with limb involvement. Patients consistently presented with polydactyly. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Limb disorders v7.33 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.21 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Cholestasis v3.21 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with biliary involvement. Patients exhibited severe early-onset cholestasis, in some cases leading to liver transplants and early lethality. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Cholestasis v3.21 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with neurological involvement. Patients exhibited optic atrophy and pituitary hypoplasia seen on imaging. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with renal involvement. Patients exhibit impaired renal function and abnormal kidney morphology. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.22 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies, hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Cholestasis v3.20 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Cholestasis. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Pituitary hormone deficiency. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Renal ciliopathies v4.22 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Renal ciliopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Limb disorders v7.32 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Neurological ciliopathies v6.20 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Neurological ciliopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Intellectual disability v9.389 PGBD5 Karen Stals gene: PGBD5 was added
gene: PGBD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to PMID: 41533792
Phenotypes for gene: PGBD5 were set to Seizures; global developmental delay; spasticity; hypotonia
Penetrance for gene: PGBD5 were set to Complete
Review for gene: PGBD5 was set to GREEN
gene: PGBD5 was marked as current diagnostic
Added comment: Zapater et al. 2026 PMID:41533792 report 5 families with homozygous loss of function variants in PGBD5 co-segregating in two affected siblings in each family (variants identified via whole exome sequencing). Authors show that PGBD5 contributes to normal brain development in mice and humans.
Sources: Literature
Early onset or syndromic epilepsy v8.187 PGBD5 Karen Stals gene: PGBD5 was added
gene: PGBD5 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to PMID: 41533792
Phenotypes for gene: PGBD5 were set to Seizures; global developmental delay; spasticity; hypotonia
Penetrance for gene: PGBD5 were set to Complete
Review for gene: PGBD5 was set to GREEN
gene: PGBD5 was marked as current diagnostic
Added comment: Zapater et al. 2026 PMID:41533792 report 5 families with homozygous loss of function variants in PGBD5 co-segregating in two affected siblings in each family (variants identified via whole exome sequencing). Authors show that PGBD5 contributes to normal brain development in mice and humans.
Sources: Literature
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 9 unrelated individuals (3 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and evidence of a multisystem ciliopathy (molar tooth sign, features supporting a diagnosis of Meckel syndrome, Joubert syndrome). More than 3 unrelated individuals had polycystic kidneys, as well as other renal findings. Hence, this gene should be promoted to Green at the next update.
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.21 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Renal ciliopathies v4.21 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 9 unrelated individuals (3 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and evidence of a multisystem ciliopathy (molar tooth sign, features supporting a diagnosis of Meckel syndrome, Joubert syndrome). More than 3 unrelated individuals had renal finding such as renal dysplasia, polycystic kidneys, and enlarged, echogenic kidneys. Hence, this gene should be promoted to Green at the next update.
Renal ciliopathies v4.21 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.20 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Neurological ciliopathies v6.19 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Neurological ciliopathies v6.19 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 9 unrelated individuals (3 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and evidence of a multisystem ciliopathy (molar tooth sign, features supporting a diagnosis of Meckel syndrome, Joubert syndrome). Hence, this gene should be promoted to Green at the next update.
Neurological ciliopathies v6.19 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.18 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Limb disorders v7.31 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Limb disorders v7.31 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 8 unrelated individuals (2 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and polydactyly. Hence, this gene should be promoted to Green on Limb disorders at the next update.
Limb disorders v7.31 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.30 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Renal ciliopathies v4.20 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Renal ciliopathies. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Neurological ciliopathies v6.18 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Cystic kidney disease v8.14 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Cystic kidney disease. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Limb disorders v7.30 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Malformations of cortical development v7.54 SNAPIN Ida Ertmanska Classified gene: SNAPIN as Amber List (moderate evidence)
Malformations of cortical development v7.54 SNAPIN Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 3 unrelated families reported with biallelic SNAPIN variants and CC agenesis. Hence, this gene should be promoted to Green at the next update.
Malformations of cortical development v7.54 SNAPIN Ida Ertmanska Gene: snapin has been classified as Amber List (Moderate Evidence).
Arthrogryposis v9.34 SNAPIN Ida Ertmanska Classified gene: SNAPIN as Amber List (moderate evidence)
Arthrogryposis v9.34 SNAPIN Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 3 unrelated families reported with biallelic SNAPIN variants and flexion contractures. Hence, this gene should be promoted to Green at the next update.
Arthrogryposis v9.34 SNAPIN Ida Ertmanska Gene: snapin has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.189 SNAPIN Ida Ertmanska Tag Q1_26_promote_green was removed from gene: SNAPIN.
Malformations of cortical development v7.53 SNAPIN Ida Ertmanska gene: SNAPIN was added
gene: SNAPIN was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: SNAPIN.
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Review for gene: SNAPIN was set to GREEN
Added comment: Review by Achchuthan Shanmugasundram (Genomics England Curator) copied from Ataxia and cerebellar anomalies - narrow panel.

PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Arthrogryposis v9.33 SNAPIN Ida Ertmanska gene: SNAPIN was added
gene: SNAPIN was added to Arthrogryposis. Sources: Literature
Q2_26_promote_green tags were added to gene: SNAPIN.
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Review for gene: SNAPIN was set to GREEN
Added comment: Review by Achchuthan Shanmugasundram (Genomics England Curator) copied from Ataxia and cerebellar anomalies - narrow panel.

PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.389 SKOR2 Ida Ertmanska Classified gene: SKOR2 as Amber List (moderate evidence)
Intellectual disability v9.389 SKOR2 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic SKOR2 variants and syndromic intellectual disability / developmental delay. Hence, this gene should be promoted to Green at the next update. Though the intellectual disability was generally mild, addition to this panel also ensures inclusion on R27 Paediatric disorders.
Intellectual disability v9.389 SKOR2 Ida Ertmanska Gene: skor2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals with biallelic SKOR2 variants and childhood onset ataxia and /or evidence of cerebellar anomalies on MRI. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic SKOR2 variants and childhood onset ataxia and /or evidence of cerebellar anomalies on MRI. Hence, this gene should be promoted to Green at the next update.
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska Classified gene: SKOR2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with biallelic SKOR2 variants and childhood onset ataxia and /or evidence of cerebellar anomalies on MRI. Hence, this gene should be promoted to Green at the next update.
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska Gene: skor2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.388 SKOR2 Ida Ertmanska gene: SKOR2 was added
gene: SKOR2 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: SKOR2.
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 29997391; 40890458; 41821366
Phenotypes for gene: SKOR2 were set to Valence-Farazi cerebellar ataxia syndrome, OMIM: 621386; Valence-Farazi cerebellar ataxia syndrome, MONDO:0980707
Review for gene: SKOR2 was set to GREEN
Added comment: PMID: 29997391 Valence et al., 2019
Patient P15 - 10yo female, consanguineous Turkish parents; she presented with neonatal hypotonia and psychomotor delay; at age 10, she had scoliosis, nystagmus, mild ID, and a nonprogressive ataxia with ataxic gait. She was homozygous for SKOR2 variant NM_001278063.1: c.2750C>G; p.Ser917*. Cerebellar dysplasia seen on brain MRI.

PMID: 40890458 Farazi Fard et al., 2025
9 patients from 2 unrelated consanguineous Iranian families:
Family 1 - 8 affected individuals homozygous for SKOR2 c.374G>C, p.Arg125Pro variant; ataxia present in 6/8 individuals, cerebellar hypoplasia in 8/8. Other phenotypes: scoliosis (5/8), strabismus (4/8), and other more variable features.
Family 2 - affected 6yo female proband homozygous for SKOR2 c.1271_1274del, p.Lys424Argfs*71 variant; she had strabismus, hypotonia, cerebellar hypoplasia, and osteomalacia, but no ataxia reported.

PMID: 41821366 Abu-El-Haija et al., 2026 - Online ahead of print
Report of eight individuals from five unrelated families (from Iraq, Turkey, Pakistan, Morocco, and South East Asia) with biallelic variants in SKOR2 associated with a phenotypic spectrum of cerebellar hypoplasia, microcephaly, ataxia, developmental delays and intellectual disability. Disease with childhood-onset, consanguinity reported in 7/8 individuals. Ataxic gait noted in 4 individuals, generally delayed walking age (>2 years in 6 cases).
Intellectual disability was present in 5/5 individuals assessed (4 mild, IQ = 55-58, and 1 case with severe ID). Cerebellar anomalies noted on brain MRI in 6/6 patients, including cerebellar hypoplasia /atrophy in 4 cases. Scoliosis / kyphosis noted in 3 patients.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.80 SKOR2 Ida Ertmanska gene: SKOR2 was added
gene: SKOR2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_26_promote_green tags were added to gene: SKOR2.
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 29997391; 40890458; 41821366
Phenotypes for gene: SKOR2 were set to Valence-Farazi cerebellar ataxia syndrome, OMIM: 621386; Valence-Farazi cerebellar ataxia syndrome, MONDO:0980707
Review for gene: SKOR2 was set to GREEN
Added comment: PMID: 29997391 Valence et al., 2019
Patient P15 - 10yo female, consanguineous Turkish parents; she presented with neonatal hypotonia and psychomotor delay; at age 10, she had scoliosis, nystagmus, mild ID, and a nonprogressive ataxia with ataxic gait. She was homozygous for SKOR2 variant NM_001278063.1: c.2750C>G; p.Ser917*. Cerebellar dysplasia seen on brain MRI.

PMID: 40890458 Farazi Fard et al., 2025
9 patients from 2 unrelated consanguineous Iranian families:
Family 1 - 8 affected individuals homozygous for SKOR2 c.374G>C, p.Arg125Pro variant; ataxia present in 6/8 individuals, cerebellar hypoplasia in 8/8. Other phenotypes: scoliosis (5/8), strabismus (4/8), and other more variable features.
Family 2 - affected 6yo female proband homozygous for SKOR2 c.1271_1274del, p.Lys424Argfs*71 variant; she had strabismus, hypotonia, cerebellar hypoplasia, and osteomalacia, but no ataxia reported.

PMID: 41821366 Abu-El-Haija et al., 2026 - Online ahead of print
Report of eight individuals from five unrelated families (from Iraq, Turkey, Pakistan, Morocco, and South East Asia) with biallelic variants in SKOR2 associated with a phenotypic spectrum of cerebellar hypoplasia, microcephaly, ataxia, developmental delays and intellectual disability. Disease with childhood-onset, consanguinity reported in 7/8 individuals. Ataxic gait noted in 4 individuals, generally delayed walking age (>2 years in 6 cases).
Intellectual disability was present in 5/5 individuals assessed (4 mild, IQ = 55-58, and 1 case with severe ID). Cerebellar anomalies noted on brain MRI in 6/6 patients, including cerebellar hypoplasia /atrophy in 4 cases. Scoliosis / kyphosis noted in 3 patients.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU4-2.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia, arrhythmia, prolonged atrioventricular conduction. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia, arrhythmia, prolonged atrioventricular conduction. Heterozygous individuals in those families were asymptomatic. Mouse model is supportive of gene-disease association. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia / sinus arrest. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia, arrhythmia, prolonged atrioventricular conduction. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska Classified gene: CACNA1D as Amber List (moderate evidence)
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia / sinus arrest. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska Gene: cacna1d has been classified as Amber List (Moderate Evidence).
Cardiac arrhythmias - additional genes v3.10 CACNA1D Ida Ertmanska gene: CACNA1D was added
gene: CACNA1D was added to Cardiac arrhythmias - additional genes. Sources: Literature
Q2_26_promote_green tags were added to gene: CACNA1D.
Mode of inheritance for gene: CACNA1D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1D were set to 21131953; 30498240; 30054272; 32747562
Phenotypes for gene: CACNA1D were set to Sinoatrial node dysfunction and deafness, OMIM:614896; sinoatrial node dysfunction and deafness, MONDO:0013960
Review for gene: CACNA1D was set to GREEN
Added comment: PMID: 21131953 Baig et al., 2011
Report of 2 consanguineous Pakistani families with bradycardia and congenital deafness, harbouring c.1208_1209insGGG (p.Gly403_Val404insGly) variant in CACNA1D.

PMID: 30498240 Liaqat et al., 2018
5 Pakistani families with Sinoatrial node dysfunction and deafness and homozygous CACNA1D variants- 1 family with p.(A376V), and 4 pedigrees with a founder variant p.(G403_V404insG) - common distant ancestor confirmed, same as families in PMID: 21131953.

PMID: 30054272 Garza-Lopez et al., 2018
Male proband of Arabic descent with moderate hearing impairment and intellectual disability, homozygous for CACNA1D c.1701G>C, p.Gln567His variant.

PMID: 32747562 Rayyan et al., 2020
Palestinian population study of 491 families with hearing loss. In 4 families, the same homozygous CACNA1D p.(Ala376Val) founder variant was found to be responsible for moderate hearing loss associated with cardiac anomalies, including prolonged atrioventricular conduction on an electrocardiogram.

Functional evidence: PMID: 10929716 Platzer et al., 2000 - Cacna1d-deficient mice were deaf due to degeneration of outer and inner hair cells. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia).

The link between CACNA1D and autosomal recessive sinoatrial node dysfunction and deafness has been classified as Moderate in ClinGen (Hearing loss GCEP, 2024).
Sources: Literature
Intellectual disability v9.387 CACNA1D Ida Ertmanska changed review comment from: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (more than 3 unrelated cases e.g., PMIDs: 23913001, 2847230; 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Early onset or syndromic epilepsy should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.; to: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (more than 3 unrelated cases e.g., PMIDs: 23913001, 2847230; 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Intellectual disability should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals with hemizygous SHROOM4 variants and isolated epilepsy. Other cases have been reported with SHROOM4 variants and variable ID, congenital malformations, and CC agenesis - the mechanism of disease is not yet clear. Hence, SHROOM4 is tagged for promotion to Green with a request for expert review, due to confounding evidence of disease association. Addition of SHROOM4 to this panel would ensure inclusion on the R27 Paediatric disorders panel.; to: Comment on list classification: There are more than 3 unrelated individuals with hemizygous SHROOM4 variants (missense and non-canonical splice) and isolated epilepsy. Other cases have been reported with SHROOM4 variants and variable ID, congenital malformations, and CC agenesis - the mechanism of disease is not yet clear. Hence, SHROOM4 is tagged for promotion to Green with a request for expert review, due to confounding evidence of disease association. Addition of SHROOM4 to this panel would ensure inclusion on the R27 Paediatric disorders panel.
Intellectual disability v9.387 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to 40210679; 40442284
Early onset or syndromic epilepsy v8.187 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to 40210679; 40442284; 41912933
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska Classified gene: SHROOM4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with hemizygous SHROOM4 variants and isolated epilepsy. Other cases have been reported with SHROOM4 variants and variable ID, congenital malformations, and CC agenesis - the mechanism of disease is not yet clear. Hence, SHROOM4 is tagged for promotion to Green with a request for expert review, due to confounding evidence of disease association. Addition of SHROOM4 to this panel would ensure inclusion on the R27 Paediatric disorders panel.
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska Gene: shroom4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.186 SHROOM4 Ida Ertmanska gene: SHROOM4 was added
gene: SHROOM4 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_26_promote_green, Q2_26_expert_review tags were added to gene: SHROOM4.
Mode of inheritance for gene: SHROOM4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SHROOM4 were set to 16249884; 25167861; 26740508; 32565546; 32728808; 35663265; 35937050; 36379543; 40905141
Phenotypes for gene: SHROOM4 were set to epilepsy, MONDO:0005027
Review for gene: SHROOM4 was set to GREEN
Added comment: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36209347 Peduto et al., 2022
Report of a 2yo male with SHROOM4 c.4153C>T, p.Arg1385*, which is also present in an unaffected grandfather. The authors question pathogenicity of SHROOM4 LoF variants (missense GoF still seen as potentially disease causing).

PMID: 35937050 Lee et al., 2022
Cohort of patients with infantile spasms. Sample IS06 - male; trio WGS detected a SHROOM4 NM_020717: c.269+4A>G hemizygous variant - classified as VUS by authors.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Sources: Literature
Intellectual disability v9.386 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36209347 Peduto et al., 2022
Report of a 2yo male with SHROOM4 c.4153C>T, p.Arg1385*, which is also present in an unaffected grandfather. The authors question pathogenicity of SHROOM4 LoF variants (missense GoF still seen as potentially disease causing).

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Intellectual disability v9.386 SHROOM4 Ida Ertmanska Phenotypes for gene: SHROOM4 were changed from Stocco dos Santos X-linked mental retardation syndrome, 300434; Intellectual disability to neurodevelopmental disorder, MONDO:0700092; X-linked intellectual disability, Stocco dos Santos type, MONDO:0010325
Intellectual disability v9.385 SHROOM4 Ida Ertmanska Publications for gene: SHROOM4 were set to 12673656; 16249884; 26740508; 20613765
Intellectual disability v9.384 SHROOM4 Ida Ertmanska Tag disputed tag was added to gene: SHROOM4.
Intellectual disability v9.384 SHROOM4 Ida Ertmanska edited their review of gene: SHROOM4: Changed publications to: 16249884, 25167861, 26740508, 32565546, 32728808, 35663265, 36379543, 40905141
Intellectual disability v9.384 SHROOM4 Ida Ertmanska commented on gene: SHROOM4: Comment on list classification: The association between SHROOM4 and Intellectual disability has been disputed by ClinGen in 2021, mostly due to reported SHROOM4 variants being too common in gnomAD. Subsequent publications reported SHROOM4 variants as causal in six individuals with epilepsy without ID, two unrelated cases with syndromic congenital malformations without ID / DD, and two fetal cases with CC agenesis. There are 3 unrelated cases reported with ID / DD and insertion or deletion affecting SHROOM4, in addition to other genes. As the effect of disrupting other genes cannot be decoupled, these cases are not taken into account for gene-disease association. Due to limited and conflicting evidence linking SHROOM4 to Intellectual disability, this gene can only be rated Amber for now.
Intellectual disability v9.384 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Intellectual disability v9.384 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and also found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Intellectual disability v9.384 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and also found in unaffected family members.

Other publications:
PMID: 35663265 Bian et al., 2022

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A p.(Glu314Lys) - 1 affected male and 1 affected hemizygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and also found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Retinal disorders v8.124 AP5B1 Ida Ertmanska changed review comment from: 2 unrelated cases reported in PMID: 40081374 - see review by Sarah Leigh.

New cases:
PMID: 41830174 Hussian et al., 2026
2 unrelated European families reported with biallelic AP5B1 variants and AP5B1-related retinopathy.
Family 4: female proband, homozygous for AP5B1: c. 2354T>C, p.Leu785Pro. Diagnosed with retinal dystrophy at age 33yrs.
Family 5: female proband, age 44yrs (disease onset at 39yrs), with compound het AP5B1 variants: c. 2354T>C, p.Leu785Pro & c.188delA, p.Gln63Argfs*95.

This gene is not yet associated with a phenotype in OMIM (accessed 15th Apr 2026).; to: 2 unrelated cases reported in PMID: 40081374 - see review by Sarah Leigh.

New cases:
PMID: 41830174 Hussain et al., 2026
2 unrelated European families reported with biallelic AP5B1 variants and AP5B1-related retinopathy.
Family 4: female proband, homozygous for AP5B1: c. 2354T>C, p.Leu785Pro. Diagnosed with retinal dystrophy at age 33yrs.
Family 5: female proband, age 44yrs (disease onset at 39yrs), with compound het AP5B1 variants: c. 2354T>C, p.Leu785Pro & c.188delA, p.Gln63Argfs*95.

This gene is not yet associated with a phenotype in OMIM (accessed 15th Apr 2026).
Intellectual disability v9.384 SHROOM4 Ida Ertmanska reviewed gene: SHROOM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 16249884, 25167861, 26740508, 35663265, 36379543; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska commented on Region: ISCA-37432-Loss: Comment on list classification: 17q12 deletions affecting the gene HNF1B are a well established cause of Renal cysts and diabetes syndrome. Diabetes is often a presenting symptom in affected individuals. ClinGen Haploinsufficiency score is 3, suggesting dosage sensitivity. Hence, region ISCA-37432-Loss should be promoted to Green on Monogenic diabetes. The change is also tagged for expert review, in order to determine if there are any technical limitations that would prevent 17q12 deletions from being detected in this test.
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska reviewed Region: ISCA-37432-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: 28420700, 41809577; Phenotypes: Type 2 diabetes mellitus, OMIM:125853, Renal cysts and diabetes syndrome, OMIM:137920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v3.18 HNF1B Ida Ertmanska reviewed gene: HNF1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28420700, 41809577; Phenotypes: Type 2 diabetes mellitus, OMIM:125853, Renal cysts and diabetes syndrome, OMIM:137920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska Tag Q2_26_promote_green tag was added to Region: ISCA-37432-Loss.
Tag Q2_26_expert_review tag was added to Region: ISCA-37432-Loss.
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska Classified Region: ISCA-37432-Loss as Amber List (moderate evidence)
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska Region: isca-37432-loss has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.17 ISCA-37432-Loss Ida Ertmanska Tag curated_removed was removed from Region: ISCA-37432-Loss.
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Achchuthan Shanmugasundram Classified gene: RNU4-2 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are over 20 unrelated families reported with biallelic RNU4-2 variants and with a neurodevelopmental disorder, of which spasticity was reported in over 10 families. Spasticity was not reported as one of the presentations of ReNU syndrome (MIM #620851) that is associated with monoallelic RNU4-2 variants. Hence, the MOI should be set as 'BIALLELIC, autosomal or pseudoautosomal' and the gene should be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Achchuthan Shanmugasundram Gene: rnu4-2 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.50 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from to neurodevelopmental disorder, MONDO:0700092
Childhood onset hereditary spastic paraplegia v8.49 RNU4-2 Achchuthan Shanmugasundram gene: RNU4-2 was added
gene: RNU4-2 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q2_26_promote_green tags were added to gene: RNU4-2.
Mode of inheritance for gene: RNU4-2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU4-2 were set to 41951737; 41951959
Review for gene: RNU4-2 was set to GREEN
Added comment: PMID:41951737 (2026) reported a saturation genome editing experiment where they simultaneously measured the functional impact of variants across RNU4-2 in a haploid cell line. These data led them to identify a new recessive NDD caused by biallelic variants outside the T-loop and Stem III regions in which heterozygous variants cause ReNU syndrome.

PMID:41951959 (2026) reported a new recessive neurodevelopmental disorder associated with biallelic (both homozygous and compound heterozygous) variants in RNU4-2 gene. There were 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. Detailed phenotypic information was available for 31 patients from 24 unrelated families, which demonstrates that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Spasticity was reported in 14 individuals from 11 families, while movement and coordination abnormalities were observed in 13 of 31 individuals, nine with ataxia, three with dystonia, one with choreoathetosis and one unspecified abnormality of coordination.

Biallelic variants in RNU4-2 gene are not yet associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.185 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are over 20 unrelated families reported with biallelic RNU4-2 variants and with a neurodevelopmental disorder, of which seizures were reported in over 10 families. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.185 RNU4-2 Achchuthan Shanmugasundram Mode of inheritance for gene: RNU4-2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.184 RNU4-2 Achchuthan Shanmugasundram Publications for gene: RNU4-2 were set to 38821540; 38645094
Early onset or syndromic epilepsy v8.183 RNU4-2 Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: RNU4-2.
Tag Q2_26_NHS_review tag was added to gene: RNU4-2.
Early onset or syndromic epilepsy v8.183 RNU4-2 Achchuthan Shanmugasundram edited their review of gene: RNU4-2: Added comment: PMID:41951737 (2026) reported a saturation genome editing experiment where they simultaneously measured the functional impact of variants across RNU4-2 in a haploid cell line. These data led them to identify a new recessive NDD caused by biallelic variants outside the T-loop and Stem III regions in which heterozygous variants cause ReNU syndrome.

PMID:41951959 (2026) reported a new recessive neurodevelopmental disorder associated with biallelic (both homozygous and compound heterozygous) variants in RNU4-2 gene. There were 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. Detailed phenotypic information was available for 31 patients from 24 unrelated families, which demonstrates that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Seizures were reported in 19 individuals from 13 families.

Biallelic variants in RNU4-2 gene are not yet associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; Changed publications to: 41951737, 41951959; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.384 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are over 20 unrelated families reported with biallelic RNU4-2 variants and with a neurodevelopmental disorder comprising GDD/ ID. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.384 RNU4-2 Achchuthan Shanmugasundram Mode of inheritance for gene: RNU4-2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.383 RNU4-2 Achchuthan Shanmugasundram Tag Q2_26_NHS_review tag was added to gene: RNU4-2.
Intellectual disability v9.383 RNU4-2 Achchuthan Shanmugasundram Publications for gene: RNU4-2 were set to 38821540; 38645094; 38991538
Intellectual disability v9.382 RNU4-2 Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: RNU4-2.
Intellectual disability v9.382 RNU4-2 Achchuthan Shanmugasundram edited their review of gene: RNU4-2: Added comment: PMID:41951737 (2026) reported a saturation genome editing experiment where they simultaneously measured the functional impact of variants across RNU4-2 in a haploid cell line. These data led them to identify a new recessive NDD caused by biallelic variants outside the T-loop and Stem III regions in which heterozygous variants cause ReNU syndrome.

PMID:41951959 (2026) reported a new recessive neurodevelopmental disorder associated with biallelic (both homozygous and compound heterozygous) variants in RNU4-2 gene. There were 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. Detailed phenotypic information was available for 31 patients from 24 unrelated families, which demonstrates that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Global developmental delay (GDD) with moderate+ severity was reported in 28 individuals from 22 families and intellectual disability (ID) of moderate+ severity was reported in 24 individuals from 19 families.

Biallelic variants in RNU4-2 gene are not yet associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; Changed publications to: 41951737, 41951959; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v8.124 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #621560 in OMIM (OMIM record last accessed 20 April 2026).
Retinal disorders v8.124 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa 102, OMIM:621560
Hereditary neuropathy or pain disorder v7.45 APOPT1 Alexander Rossor gene: APOPT1 was added
gene: APOPT1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: APOPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOPT1 were set to 25175347; 38098475
Phenotypes for gene: APOPT1 were set to 25175347; 38098475Encephalopathic episodes; loss of developmental milestones; seizures; spasticity; cavitating leukodystrophy
Penetrance for gene: APOPT1 were set to Complete
Review for gene: APOPT1 was set to GREEN
Added comment: Sources: Expert list
Monogenic hearing loss v5.70 CACNA1D Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CACNA1D.
Monogenic hearing loss v5.70 CACNA1D Ida Ertmanska Phenotypes for gene: CACNA1D were changed from Sinoatrial node dysfunction and deafness, 614896 to Sinoatrial node dysfunction and deafness, OMIM:614896; sinoatrial node dysfunction and deafness, MONDO:0013960
Intellectual disability v9.382 CACNA1D Ida Ertmanska Phenotypes for gene: CACNA1D were changed from Primary aldosteronism, seizures, and neurologic abnormalities 615474 AD; Sinoatrial node dysfunction and deafness 614896 AR to Primary aldosteronism, seizures, and neurologic abnormalities, OMIM:615474; aldosterone-producing adenoma with seizures and neurological abnormalities, MONDO:0014200
Intellectual disability v9.381 CACNA1D Ida Ertmanska Publications for gene: CACNA1D were set to 28472301; 23913001
Intellectual disability v9.380 CACNA1D Ida Ertmanska Tag Q2_26_MOI tag was added to gene: CACNA1D.
Early onset or syndromic epilepsy v8.183 CACNA1D Ida Ertmanska edited their review of gene: CACNA1D: Changed publications to: 21131953, 30498240, 30054272, 32747562, 23913001, 2847230, 37122292
Intellectual disability v9.380 CACNA1D Ida Ertmanska reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131953, 30498240, 30054272, 32747562, 23913001, 2847230, 37122292; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities, OMIM:615474, aldosterone-producing adenoma with seizures and neurological abnormalities, MONDO:0014200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.183 CACNA1D Ida Ertmanska Phenotypes for gene: CACNA1D were changed from Primary aldosteronism, seizures, and neurologic abnormalities 615474 AD; Sinoatrial node dysfunction and deafness 614896 AR to Primary aldosteronism, seizures, and neurologic abnormalities, OMIM:615474; aldosterone-producing adenoma with seizures and neurological abnormalities, MONDO:0014200
Early onset or syndromic epilepsy v8.182 CACNA1D Ida Ertmanska Publications for gene: CACNA1D were set to 28472301; 23913001; 30698561; 30054272
Early onset or syndromic epilepsy v8.181 CACNA1D Ida Ertmanska Tag Q2_26_MOI tag was added to gene: CACNA1D.
Early onset or syndromic epilepsy v8.181 CACNA1D Ida Ertmanska changed review comment from: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (e.g., PMIDs: 23913001, 2847230; 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Early onset or syndromic epilepsy should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.; to: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (more than 3 unrelated cases e.g., PMIDs: 23913001, 2847230; 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Early onset or syndromic epilepsy should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.
Early onset or syndromic epilepsy v8.181 CACNA1D Ida Ertmanska changed review comment from: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (e.g., PMIDs: 23913001, 28472301, PMID: 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Early onset or syndromic epilepsy should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.; to: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (e.g., PMIDs: 23913001, 2847230; 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Early onset or syndromic epilepsy should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.
Early onset or syndromic epilepsy v8.181 CACNA1D Ida Ertmanska reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131953, 30498240, 30054272, 32747562; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities, OMIM:615474, aldosterone-producing adenoma with seizures and neurological abnormalities, MONDO:0014200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v5.69 CACNA1D Ida Ertmanska Publications for gene: CACNA1D were set to 21131953; 30498240; 30054272; 32747562
Monogenic hearing loss v5.68 CACNA1D Ida Ertmanska changed review comment from: PMID: 21131953 Baig et al., 2011
Report of 2 consanguineous Pakistani families with bradycardia and congenital deafness, harbouring c.1208_1209insGGG (p.Gly403_Val404insGly) variant in CACNA1D.

PMID: 30498240 Liaqat et al., 2018
5 Pakistani families with Sinoatrial node dysfunction and deafness and homozygous CACNA1D variants- 1 family with p.(A376V), and 4 pedigrees with a founder variant p.(G403_V404insG) - common distant ancestor confirmed, same as families in PMID: 21131953.

PMID: 30054272 Garza-Lopez et al., 2018
Male proband of Arabic descent with moderate hearing impairment and intellectual disability, homozygous for CACNA1D c.1701G>C, p.Gln567His variant.

PMID: 32747562 Rayyan et al., 2020
Palestinian population study of 491 families with hearing loss. In 4 families, the same homozygous CACNA1D p.(Ala376Val) founder variant was found to be responsible for moderate hearing loss associated with cardiac anomalies, including prolonged atrioventricular conduction on an electrocardiogram.

The link between CACNA1D and autosomal recessive sinoatrial node dysfunction and deafness has been classified as Moderate in ClinGen (Hearing loss GCEP, 2024).; to: PMID: 21131953 Baig et al., 2011
Report of 2 consanguineous Pakistani families with bradycardia and congenital deafness, harbouring c.1208_1209insGGG (p.Gly403_Val404insGly) variant in CACNA1D.

PMID: 30498240 Liaqat et al., 2018
5 Pakistani families with Sinoatrial node dysfunction and deafness and homozygous CACNA1D variants- 1 family with p.(A376V), and 4 pedigrees with a founder variant p.(G403_V404insG) - common distant ancestor confirmed, same as families in PMID: 21131953.

PMID: 30054272 Garza-Lopez et al., 2018
Male proband of Arabic descent with moderate hearing impairment and intellectual disability, homozygous for CACNA1D c.1701G>C, p.Gln567His variant.

PMID: 32747562 Rayyan et al., 2020
Palestinian population study of 491 families with hearing loss. In 4 families, the same homozygous CACNA1D p.(Ala376Val) founder variant was found to be responsible for moderate hearing loss associated with cardiac anomalies, including prolonged atrioventricular conduction on an electrocardiogram.

Functional evidence: PMID: 10929716 Platzer et al., 2000 - Cacna1d-deficient mice were deaf due to degeneration of outer and inner hair cells. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia).

The link between CACNA1D and autosomal recessive sinoatrial node dysfunction and deafness has been classified as Moderate in ClinGen (Hearing loss GCEP, 2024).
Monogenic hearing loss v5.68 CACNA1D Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and hearing loss. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and hearing loss. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Monogenic hearing loss v5.68 CACNA1D Ida Ertmanska Publications for gene: CACNA1D were set to 21131953; 30498240; 32747562
Monogenic hearing loss v5.67 CACNA1D Ida Ertmanska edited their review of gene: CACNA1D: Changed phenotypes to: Sinoatrial node dysfunction and deafness, OMIM:614896, sinoatrial node dysfunction and deafness, MONDO:0013960
Monogenic hearing loss v5.67 CACNA1D Ida Ertmanska edited their review of gene: CACNA1D: Changed publications to: 21131953, 30498240, 30054272, 32747562
Monogenic hearing loss v5.67 CACNA1D Ida Ertmanska Mode of inheritance for gene: CACNA1D was changed from to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.66 CACNA1D Ida Ertmanska Publications for gene: CACNA1D were set to
Monogenic hearing loss v5.65 CACNA1D Ida Ertmanska Classified gene: CACNA1D as Amber List (moderate evidence)
Monogenic hearing loss v5.65 CACNA1D Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and hearing loss. Hence, this gene should be promoted to Green at the next update.
Monogenic hearing loss v5.65 CACNA1D Ida Ertmanska Gene: cacna1d has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.64 CACNA1D Ida Ertmanska reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131953, 30498240, 32747562; Phenotypes: Sinoatrial node dysfunction and deafness, OMIM:614896; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dilated and arrhythmogenic cardiomyopathy v3.13 MYLK3 Matthew Edwards changed review comment from: Several mouse models (and a zebrafish), one of which is heterozygous KO which recapitulates DCM (31244672). Good expression/protein interaction evidence 17885681, 18202317)

Rare cases in literature - PMID: 29235529 has two families: Family A - two early onset sibs and their affected mother (later onset) had heterozygous MYLK3 LOF variant - sibs also had a FLNC LOF variant (from unaffected father), likely explaining early onset. Family B two later onset sibs with heterozygous MYLK3 LOF variant. functional studies of both showed reduced protein expression. PMID: 30690923: has proband with heterozygous LOF variant. 3 consanguineous families with hom LOf (2 families) and hom missense (1 family).

We've seen 10 LOF variants in DCM patients (with 3 detected in control set of non-DCM cases ~5000 samples - one possibly too young for phenotype, 2 with variant in only one of two isforms expressed in heart), but currently classify as VUS due to limited haploinsufficiency evidence. (Clin~Gen curation still pending); to: Several mouse models (and a zebrafish), one of which is heterozygous KO which recapitulates DCM (31244672). Good expression/protein interaction evidence 17885681, 18202317)

Rare cases in literature - PMID: 29235529 has two families: Family A - two early onset sibs and their affected mother (later onset) had heterozygous MYLK3 LOF variant - sibs also had a FLNC LOF variant (from unaffected father), likely explaining early onset. Family B two later onset sibs with heterozygous MYLK3 LOF variant. functional studies of both showed reduced protein expression. PMID: 30690923: has proband with heterozygous LOF variant. 3 consanguineous families with hom LOf (2 families) and hom missense (1 family).

We've seen 10 LOF variants in DCM patients in our lab cohort (with 3 detected in control set of non-DCM cases ~5000 samples - one possibly too young for phenotype, 2 with variant in only one of two isforms expressed in heart), but currently classify as VUS due to limited haploinsufficiency evidence. We have now curated the gene in ClinGen DCM expert group and applied moderate evidence.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.10 GNAS Eleanor Williams commented on gene: GNAS: The mode of inheritance of this gene should ideally be set to both MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) AND MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) since the gene has both paternally and maternally imprinted transcripts. However, this is not currently possible in PanelApp.

With the current mode of inheritance of MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown variants in imprinted transcripts will only be tiered under the 'incomplete penetrance' mode.

We are currently looking at the best options for updating the mode of inheritance to cover the maternal and paternal imprinting seen in this gene.
Congenital hypothyroidism v3.3 GNAS Eleanor Williams commented on gene: GNAS
Intellectual disability v9.380 GNAS Eleanor Williams commented on gene: GNAS
DDG2P v6.447 GNAS Eleanor Williams commented on gene: GNAS
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.4 GNAS Eleanor Williams commented on gene: GNAS: The mode of inheritance of this gene should ideally be set to both MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) AND MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) since the gene has both paternally and maternally imprinted transcripts. However, this is not currently possible in PanelApp.

With the current mode of inheritance of MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown variants in imprinted transcripts will only be tiered under the 'incomplete penetrance' mode.

We are currently looking at the best options for updating the mode of inheritance to cover the maternal and paternal imprinting seen in this gene.
Fetal anomalies v6.189 GNAS Eleanor Williams commented on gene: GNAS
Skeletal dysplasia v8.46 GNAS Eleanor Williams commented on gene: GNAS: The mode of inheritance of this gene should ideally be set to both MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) AND MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) since the gene has both paternally and maternally imprinted transcripts. However, this is not currently possible in PanelApp.

With the current mode of inheritance of MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown variants in imprinted transcripts will only be tiered under the 'incomplete penetrance' mode.

We are currently looking at the best options for updating the mode of inheritance to cover the maternal and paternal imprinting seen in this gene.
Mosaic skin disorders - deep sequencing v3.27 GNAS Eleanor Williams commented on gene: GNAS
Limb disorders v7.29 GNAS Eleanor Williams commented on gene: GNAS: The mode of inheritance of this gene should ideally be set to both MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) AND MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) since the gene has both paternally and maternally imprinted transcripts. However, this is not currently possible in PanelApp.

With the current mode of inheritance of MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown variants in imprinted transcripts will only be tiered under the 'incomplete penetrance' mode.

We are currently looking at the best options for updating the mode of inheritance to cover the maternal and paternal imprinting seen in this gene.
Adult onset neurodegenerative disorder v8.21 GLT8D1 Cassandra Smith reviewed gene: GLT8D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30811981, 38960585, 41917433; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Hannah Robinson reviewed gene: SLC6A5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hyperekplexia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v8.181 KCNJ4 Alexander Symon-Allen gene: KCNJ4 was added
gene: KCNJ4 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCNJ4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ4 were set to PMID: 41830586
Phenotypes for gene: KCNJ4 were set to Epileptic encephalopathy; Epilepsy; Developmental delay.
Penetrance for gene: KCNJ4 were set to unknown
Mode of pathogenicity for gene: KCNJ4 was set to Other
Review for gene: KCNJ4 was set to AMBER
Added comment: 1 study outlines four unrelated individuals with epilepsy with or without developmental delay that harbour four unique heterozygous KCNJ4 variants - 3 de novo, 1 inherited from an affected parent.
Other inwardly rectifying potassium (Kir) channels have been implicated in epilepsy.
Patch clamp studies provide preliminary evidence for both loss of function (Val206Met & Met293Lys) and gain of function (Gly136Ser & Glu384Lys) mechanisms.
Further independent studies required to confirm this association.
Sources: Literature
Paediatric disorders - additional genes v7.49 WDHD1 Achchuthan Shanmugasundram Classified gene: WDHD1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.49 WDHD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 14 unrelated families reported with biallelic WDHD1 variants and presenting with microcephalic primordial dwarfism (MPD) and a broad spectrum of additional abnormalities. Hence, this gene can be promoted to green rating in the next update.
Paediatric disorders - additional genes v7.49 WDHD1 Achchuthan Shanmugasundram Gene: wdhd1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.48 WDHD1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: WDHD1.
Paediatric disorders - additional genes v7.48 WDHD1 Achchuthan Shanmugasundram gene: WDHD1 was added
gene: WDHD1 was added to Paediatric disorders - additional genes. Sources: Literature
Mode of inheritance for gene: WDHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDHD1 were set to 41962535
Phenotypes for gene: WDHD1 were set to microcephalic osteodysplastic primordial dwarfism, MONDO:0000060
Review for gene: WDHD1 was set to GREEN
Added comment: PMID:41962535 (2026) reported the identification of biallelic hypomorphic variants in WDHD1 gene in 17 patients from 14 families with microcephalic primordial dwarfism (MPD) and a broad spectrum of additional abnormalities. All patients had severe IUGR and microcephaly.

The phenotypes in ten patients homozygous for the c.1769−1G>C variant was broad, ranging from foetal lethality to MPD with mild to moderate developmental delay and additional clinical features including severe malformations of multiple organs likely contributing to intrauterine death. The five patients that survived to birth but died as neonates had severe hepatic abnormalities, with acute liver failure (ALF) as the cause of death in four.

Among the seven living subjects, two were homozygous for the c.1769−1G>C variant, while the remaining subjects were compound heterozygous, with combinations of a loss-of-function allele and an intronic or missense variant or two non-coding variants. The most common clinical features among them were postnatal growth retardation, feeding difficulties, developmental delay, a small face with a bulbous nose and retrognathia, a high-pitched voice, and hip dislocation.

There is also functional evidence available from patient-derived fibroblasts which supports the disease association.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype (records last accessed 14 April 2026).
Sources: Literature
Retinal disorders v8.123 AP5B1 Ida Ertmanska Publications for gene: AP5B1 were set to 40081374
Retinal disorders v8.122 AP5B1 Ida Ertmanska Phenotypes for gene: AP5B1 were changed from Lysosomal macular dystrophy to macular dystrophy, retinal, MONDO:0031166
Retinal disorders v8.121 AP5B1 Ida Ertmanska Classified gene: AP5B1 as Amber List (moderate evidence)
Retinal disorders v8.121 AP5B1 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated cases with biallelic AP5B1 variants and retinal disease. Hence, this gene can be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Retinal disorders v8.121 AP5B1 Ida Ertmanska Gene: ap5b1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.120 AP5B1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: AP5B1.
Retinal disorders v8.120 AP5B1 Ida Ertmanska reviewed gene: AP5B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40081374, 41830174; Phenotypes: macular dystrophy, retinal, MONDO:0031166; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 FGR Boaz Palterer gene: FGR was added
gene: FGR was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: FGR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: FGR were set to Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease
Penetrance for gene: FGR were set to unknown
Mode of pathogenicity for gene: FGR 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: FGR was set to RED
Added comment: Price-Kuehne et al. described very large kindred with autosomal dominant Gain of function due to loss of regulatory tyrosine in FGR
https://link.springer.com/article/10.1007/s10875-026-01998-z
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 HCK Boaz Palterer edited their review of gene: HCK: Added comment: Two additional reports:
Priece-Kuehne et al. describing 3 additional kindreds with HCK GOF, similar phenotype and mechanism ( https://link.springer.com/article/10.1007/s10875-026-01998-z )
Berdeli et al. additional kindred with similar phenotype and mechanism (https://pmc.ncbi.nlm.nih.gov/articles/PMC12801773/)

Now reaching criteria for green rating; Changed rating: GREEN; Changed publications to: 34536415, 41382121; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v6.189 WDHD1 Achchuthan Shanmugasundram Classified gene: WDHD1 as Amber List (moderate evidence)
Fetal anomalies v6.189 WDHD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Foetal abnormalities were reported in 14 unrelated families with biallelic WDHD1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v6.189 WDHD1 Achchuthan Shanmugasundram Gene: wdhd1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.188 WDHD1 Achchuthan Shanmugasundram gene: WDHD1 was added
gene: WDHD1 was added to Fetal anomalies. Sources: Literature
Q2_26_promote_green tags were added to gene: WDHD1.
Mode of inheritance for gene: WDHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDHD1 were set to 41962535
Phenotypes for gene: WDHD1 were set to microcephalic osteodysplastic primordial dwarfism, MONDO:0000060; Intrauterine growth retardation, HP:0001511
Review for gene: WDHD1 was set to GREEN
Added comment: PMID:41962535 (2026) reported the identification of biallelic hypomorphic variants in WDHD1 gene in 17 patients from 14 families with microcephalic primordial dwarfism (MPD) and a broad spectrum of additional abnormalities including acute liver failure. IUGR and/ or other foetal abnormalities such as microcephaly and oligohydramnios were reported in all cases. Four cases from three families had prenatal death or termination of pregnancy. There is also functional evidence available from patient-derived fibroblasts which supports the disease association.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype (records last accessed 14 April 2026).
Sources: Literature
Severe microcephaly v8.46 WDHD1 Achchuthan Shanmugasundram Classified gene: WDHD1 as Amber List (moderate evidence)
Severe microcephaly v8.46 WDHD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >10 unrelated families reported with severe microcephaly and with biallelic WDHD1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Severe microcephaly v8.46 WDHD1 Achchuthan Shanmugasundram Gene: wdhd1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.45 WDHD1 Achchuthan Shanmugasundram gene: WDHD1 was added
gene: WDHD1 was added to Severe microcephaly. Sources: Literature
Q2_26_promote_green tags were added to gene: WDHD1.
Mode of inheritance for gene: WDHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDHD1 were set to 41962535
Phenotypes for gene: WDHD1 were set to microcephalic osteodysplastic primordial dwarfism, MONDO:0000060
Review for gene: WDHD1 was set to GREEN
Added comment: PMID:41962535 (2026) reported the identification of biallelic hypomorphic variants in WDHD1 gene in 17 patients from 14 families with microcephalic primordial dwarfism (MPD) and a broad spectrum of additional abnormalities including acute liver failure. 12 of these patients had an OFC at a Z-score of -3 or lower at either birth or last examination. There is also functional evidence available from patient-derived fibroblasts which supports the disease association.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype (records last accessed 14 April 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.48 NFU1 Achchuthan Shanmugasundram Classified gene: NFU1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.48 NFU1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are patients from at least nine unrelated families reported with childhood-onset hereditary spastic paraplegia and with biallelic NFU1 variants. Hence, this gene should be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.48 NFU1 Achchuthan Shanmugasundram Gene: nfu1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.47 NFU1 Achchuthan Shanmugasundram gene: NFU1 was added
gene: NFU1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q2_26_promote_green tags were added to gene: NFU1.
Mode of inheritance for gene: NFU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFU1 were set to 36256512
Phenotypes for gene: NFU1 were set to Spastic paraplegia 93, autosomal recessive, OMIM:620938; spastic paraplegia 93, autosomal recessive, MONDO:0975796
Review for gene: NFU1 was set to GREEN
Added comment: PMID:36256512 (2022) reported 19 affected individuals from 10 independent families with nine different biallelic NFU1 missense variants. They are associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Gait acquisition was delayed due to either the insidious onset of limb spasticity in 13/19 individuals or spasticity precipitated by a deterioration in the context of a febrile illness in 4/19 individuals (Fig. 1B). The lower limb spasticity was detected at a mean age of 12 ± 6 months in the cohort. Spasticity was progressive leading to contractures in 13/19 persons and necessitating Achilles' tendon repair surgery in 4/19 affected individuals.

This gene has been associated with relevant phenotype in OMIM (MIM #620938), which was last accessed on 14 April 2026.
Sources: Literature
Likely inborn error of metabolism v8.110 NDUFA5 Achchuthan Shanmugasundram Classified gene: NDUFA5 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.110 NDUFA5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five patients from four unrelated families reported with complex I deficiency and biallelic NDUFA5 variants. There is also functional evidence available from in vitro studies and animal models. Hence, this gene can be promoted to green rating in the next GMS update.
Likely inborn error of metabolism v8.110 NDUFA5 Achchuthan Shanmugasundram Gene: ndufa5 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.29 TRAF3IP1 Ida Ertmanska Tag new-gene-name tag was added to gene: TRAF3IP1.
Limb disorders v7.29 TRAF3IP1 Ida Ertmanska commented on gene: TRAF3IP1
Renal ciliopathies v4.19 TRAF3IP1 Ida Ertmanska Tag new-gene-name tag was added to gene: TRAF3IP1.
Renal ciliopathies v4.19 TRAF3IP1 Ida Ertmanska commented on gene: TRAF3IP1
Likely inborn error of metabolism v8.109 NDUFA5 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA5 were changed from No OMIM phenotype; Isolated complex I deficiency to mitochondrial complex I deficiency, MONDO:0100133
Likely inborn error of metabolism v8.109 NDUFA5 Achchuthan Shanmugasundram Publications for gene: NDUFA5 were set to
Likely inborn error of metabolism v8.108 NDUFA5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: NDUFA5.
Likely inborn error of metabolism v8.108 NDUFA5 Achchuthan Shanmugasundram Mode of inheritance for gene: NDUFA5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.108 NDUFA5 Achchuthan Shanmugasundram Classified gene: NDUFA5 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.108 NDUFA5 Achchuthan Shanmugasundram Gene: ndufa5 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.107 NDUFA5 Achchuthan Shanmugasundram reviewed gene: NDUFA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41859003, 41916321; Phenotypes: mitochondrial complex I deficiency, MONDO:0100133; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ophthalmological ciliopathies v5.22 TRAF3IP1 Ida Ertmanska Tag new-gene-name tag was added to gene: TRAF3IP1.
Ophthalmological ciliopathies v5.22 TRAF3IP1 Ida Ertmanska commented on gene: TRAF3IP1
Rare multisystem ciliopathy disorders v1.180 TRAF3IP1 Ida Ertmanska Tag new-gene-name tag was added to gene: TRAF3IP1.
Rare multisystem ciliopathy disorders v1.180 TRAF3IP1 Ida Ertmanska commented on gene: TRAF3IP1
Retinal disorders v8.120 TRAF3IP1 Ida Ertmanska commented on gene: TRAF3IP1
Retinal disorders v8.120 TRAF3IP1 Ida Ertmanska Tag new-gene-name tag was added to gene: TRAF3IP1.
Fetal anomalies v6.187 TRAF3IP1 Ida Ertmanska commented on gene: TRAF3IP1
Fetal anomalies v6.187 TRAF3IP1 Ida Ertmanska Tag new-gene-name tag was added to gene: TRAF3IP1.
Childhood onset dystonia, chorea or related movement disorder v7.20 TRAF3IP1 Ida Ertmanska commented on gene: TRAF3IP1
Childhood onset dystonia, chorea or related movement disorder v7.20 TRAF3IP1 Ida Ertmanska Tag new-gene-name tag was added to gene: TRAF3IP1.
Early onset or syndromic epilepsy v8.181 RNU6ATAC Ida Ertmanska Phenotypes for gene: RNU6ATAC were changed from neurodevelopmental disorder, MONDO:0700092; Immune dysregulation, HP:0002958; neonatal diabetes mellitus, MONDO:0016391 to Seizure, HP:0001250; neurodevelopmental disorder, MONDO:0700092; Immune dysregulation, HP:0002958; neonatal diabetes mellitus, MONDO:0016391
Ataxia and cerebellar anomalies - narrow panel v8.79 RNU6ATAC Ida Ertmanska Phenotypes for gene: RNU6ATAC were changed from neurodevelopmental disorder, MONDO:0700092; Immune dysregulation, HP:0002958; neonatal diabetes mellitus, MONDO:0016391 to Ataxia, HP:0001251; neurodevelopmental disorder, MONDO:0700092; Immune dysregulation, HP:0002958; neonatal diabetes mellitus, MONDO:0016391
Mitochondrial disorders v9.54 NDUFA5 Achchuthan Shanmugasundram Classified gene: NDUFA5 as Amber List (moderate evidence)
Mitochondrial disorders v9.54 NDUFA5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five patients from four unrelated families reported with complex I deficiency and biallelic NDUFA5 variants. There is also functional evidence available from in vitro studies and animal models. Hence, this gene can be promoted to green rating in the next GMS update.
Mitochondrial disorders v9.54 NDUFA5 Achchuthan Shanmugasundram Gene: ndufa5 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.53 NDUFA5 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA5 were changed from Isolated complex I deficiency; No OMIM phenotype to mitochondrial complex I deficiency, MONDO:0100133
Ataxia and cerebellar anomalies - narrow panel v8.78 RNU6ATAC Ida Ertmanska Classified gene: RNU6ATAC as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.78 RNU6ATAC Ida Ertmanska Added comment: Comment on list classification: There are 2 individuals reported with childhood-onset ataxia and biallelic RNU6ATAC variants. Hence, this gene can only be rated Amber on this panel, until more evidence emerges.
Ataxia and cerebellar anomalies - narrow panel v8.78 RNU6ATAC Ida Ertmanska Gene: rnu6atac has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.52 NDUFA5 Achchuthan Shanmugasundram Publications for gene: NDUFA5 were set to 24154540
Mitochondrial disorders v9.52 NDUFA5 Achchuthan Shanmugasundram Mode of inheritance for gene: NDUFA5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v9.51 NDUFA5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: NDUFA5.
Early onset or syndromic epilepsy v8.180 RNU6ATAC Ida Ertmanska Classified gene: RNU6ATAC as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.180 RNU6ATAC Ida Ertmanska Added comment: Comment on list classification: There are 2 individuals reported with seizures / epilepsy and biallelic RNU6ATAC variants. Hence, this gene can only be rated Amber for Early onset or syndromic epilepsy until more evidence emerges.
Early onset or syndromic epilepsy v8.180 RNU6ATAC Ida Ertmanska Gene: rnu6atac has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.51 NDUFA5 Achchuthan Shanmugasundram reviewed gene: NDUFA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41859003, 41916321; Phenotypes: mitochondrial complex I deficiency, MONDO:0100133; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v3.23 NDUFA5 Achchuthan Shanmugasundram Classified gene: NDUFA5 as Amber List (moderate evidence)
Mitochondrial disorder with complex I deficiency v3.23 NDUFA5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five patients from four unrelated families reported with complex I deficiency and biallelic NDUFA5 variants. There is also functional evidence available from in vitro studies and animal models. Hence, this gene can be promoted to green rating in the next GMS update.
Mitochondrial disorder with complex I deficiency v3.23 NDUFA5 Achchuthan Shanmugasundram Gene: ndufa5 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex I deficiency v3.22 NDUFA5 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA5 were changed from No OMIM phenotype to mitochondrial complex I deficiency, MONDO:0100133
Mitochondrial disorder with complex I deficiency v3.21 NDUFA5 Achchuthan Shanmugasundram Publications for gene: NDUFA5 were set to
Mitochondrial disorder with complex I deficiency v3.20 NDUFA5 Achchuthan Shanmugasundram Mode of inheritance for gene: NDUFA5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v3.19 NDUFA5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: NDUFA5.
Mitochondrial disorder with complex I deficiency v3.19 NDUFA5 Achchuthan Shanmugasundram reviewed gene: NDUFA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41859003, 41916321; Phenotypes: mitochondrial complex I deficiency, MONDO:0100133; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v8.77 RNU6ATAC Ida Ertmanska gene: RNU6ATAC was added
gene: RNU6ATAC was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062; 41864208; 41808409
Phenotypes for gene: RNU6ATAC were set to neurodevelopmental disorder, MONDO:0700092; Immune dysregulation, HP:0002958; neonatal diabetes mellitus, MONDO:0016391
Review for gene: RNU6ATAC was set to AMBER
Added comment: PMID: 41808409 Mendez et al., 2026
Individual A1 - 14-year-old female with intrauterine growth restriction, microcephaly (Z = -2.05 at 13 yrs), refractory epilepsy, cerebral structural anomalies, ataxia, autism, severe intellectual disability, and marked peripheral eosinophilia. Compound het RNU6ATAC variants: n.28C>T & n.36T>G.

Individual B1 - 30-year-old male with immune dysfunction, endocrinopathy, and ectodermal abnormalities (ichthyosis, dystrophic nails, dental anomalies, and alopecia universalis), primary hypothyroidism, failure to thrive, bronchiectasis, chronic inflammatory demyelinating polyneuropathy, and combined variable immunodeficiency (CVID), without neurodevelopmental involvement. Compound het RNU6ATAC variants: n.30C>T & n.64C>G.

Individual C1 - 17-year-old male who presents with microcephaly (no severity stated), growth failure, ID / global developmental delay, immunodeficiency, diabetes mellitus (diagnosed at 9 months), hypothyroidism, and severe skeletal dysplasia. Homozygous for n.43G>A. Parents are first cousins.

PMID: 41864208 Johnson et al., 2026
Identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12).

6/7 individuals had variable additional features of immune dysregulation: sepsis, atopic dermatitis, B cell lymphopenia, low IgA, low IgG, B cell lymphopenia, hypothyroidism (2 sibs), agammaglobulinemia, hypoagammaglobulinemia, immunodeficiency, thyroiditis (2 unrelated patients), alopecia (2 unrelated patients), vitiligo. No microcephaly or developmental delay reported. 3/7 individuals died in early infancy.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

PMID: 40975062 Arriaga et al., 2025
Individual D1 - comp het for RNU6ATAC variants: n.36T>G and n.28C>T. The individual presented with microcephaly, short stature, hypotonia, ID/DD, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus, and oculomotor apraxia. Patient D1 did not have diabetes, hypothyroidism, or immunodeficiency. RNA analysis demonstrated excess minor intron retention.

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 31st Mar 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.179 RNU6ATAC Ida Ertmanska gene: RNU6ATAC was added
gene: RNU6ATAC was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062; 41864208; 41808409
Phenotypes for gene: RNU6ATAC were set to neurodevelopmental disorder, MONDO:0700092; Immune dysregulation, HP:0002958; neonatal diabetes mellitus, MONDO:0016391
Review for gene: RNU6ATAC was set to AMBER
Added comment: PMID: 41808409 Mendez et al., 2026
Individual A1 - 14-year-old female with intrauterine growth restriction, microcephaly (Z = -2.05 at 13 yrs), refractory epilepsy, cerebral structural anomalies, ataxia, autism, severe intellectual disability, and marked peripheral eosinophilia. Compound het RNU6ATAC variants: n.28C>T & n.36T>G.

Individual B1 - 30-year-old male with immune dysfunction, endocrinopathy, and ectodermal abnormalities (ichthyosis, dystrophic nails, dental anomalies, and alopecia universalis), primary hypothyroidism, failure to thrive, bronchiectasis, chronic inflammatory demyelinating polyneuropathy, and combined variable immunodeficiency (CVID), without neurodevelopmental involvement. Compound het RNU6ATAC variants: n.30C>T & n.64C>G.

Individual C1 - 17-year-old male who presents with microcephaly (no severity stated), growth failure, ID / global developmental delay, immunodeficiency, diabetes mellitus (diagnosed at 9 months), hypothyroidism, and severe skeletal dysplasia. Homozygous for n.43G>A. Parents are first cousins.

PMID: 41864208 Johnson et al., 2026
Identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12).

6/7 individuals had variable additional features of immune dysregulation: sepsis, atopic dermatitis, B cell lymphopenia, low IgA, low IgG, B cell lymphopenia, hypothyroidism (2 sibs), agammaglobulinemia, hypoagammaglobulinemia, immunodeficiency, thyroiditis (2 unrelated patients), alopecia (2 unrelated patients), vitiligo. No microcephaly or developmental delay reported. 3/7 individuals died in early infancy.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

PMID: 40975062 Arriaga et al., 2025
Individual D1 - comp het for RNU6ATAC variants: n.36T>G and n.28C>T. The individual presented with microcephaly, short stature, hypotonia, ID/DD, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus, and oculomotor apraxia. Patient D1 did not have diabetes, hypothyroidism, or immunodeficiency. RNA analysis demonstrated excess minor intron retention.

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 31st Mar 2026).
Sources: Literature
Possible mitochondrial disorder - nuclear genes v4.31 NDUFA5 Achchuthan Shanmugasundram Classified gene: NDUFA5 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v4.31 NDUFA5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Sarah Graham, there are five patients from four unrelated families reported with complex I deficiency and biallelic NDUFA5 variants. There is also functional evidence available from in vitro studies and animal models. Hence, this gene can be promoted to green rating in the next GMS update.
Possible mitochondrial disorder - nuclear genes v4.31 NDUFA5 Achchuthan Shanmugasundram Gene: ndufa5 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v4.30 NDUFA5 Achchuthan Shanmugasundram Phenotypes for gene: NDUFA5 were changed from No OMIM phenotype to mitochondrial complex I deficiency, MONDO:0100133
Possible mitochondrial disorder - nuclear genes v4.29 NDUFA5 Achchuthan Shanmugasundram Publications for gene: NDUFA5 were set to
Intellectual disability v9.380 RNU6ATAC Ida Ertmanska Classified gene: RNU6ATAC as Amber List (moderate evidence)
Intellectual disability v9.380 RNU6ATAC Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals with biallelic RNU6ATAC variants and intellectual disability / global developmental delay. Hence, this gene should be promoted to Green at the next update, with MOI BIALLELIC, autosomal or pseudoautosomal.
Intellectual disability v9.380 RNU6ATAC Ida Ertmanska Gene: rnu6atac has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v4.28 NDUFA5 Achchuthan Shanmugasundram Mode of inheritance for gene: NDUFA5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.27 NDUFA5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: NDUFA5.
Tag Q2_26_NHS_review tag was added to gene: NDUFA5.
Possible mitochondrial disorder - nuclear genes v4.27 NDUFA5 Achchuthan Shanmugasundram reviewed gene: NDUFA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41859003, 41916321; Phenotypes: mitochondrial complex I deficiency, MONDO:0100133; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.379 RNU6ATAC Ida Ertmanska gene: RNU6ATAC was added
gene: RNU6ATAC was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: RNU6ATAC.
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062; 41864208; 41808409
Phenotypes for gene: RNU6ATAC were set to neurodevelopmental disorder, MONDO:0700092; Immune dysregulation, HP:0002958; neonatal diabetes mellitus, MONDO:0016391
Review for gene: RNU6ATAC was set to GREEN
Added comment: PMID: 41808409 Mendez et al., 2026
Individual A1 - 14-year-old female with intrauterine growth restriction, microcephaly (Z = -2.05 at 13 yrs), refractory epilepsy, cerebral structural anomalies, ataxia, autism, severe intellectual disability, and marked peripheral eosinophilia. Compound het RNU6ATAC variants: n.28C>T & n.36T>G.

Individual B1 - 30-year-old male with immune dysfunction, endocrinopathy, and ectodermal abnormalities (ichthyosis, dystrophic nails, dental anomalies, and alopecia universalis), primary hypothyroidism, failure to thrive, bronchiectasis, chronic inflammatory demyelinating polyneuropathy, and combined variable immunodeficiency (CVID), without neurodevelopmental involvement. Compound het RNU6ATAC variants: n.30C>T & n.64C>G.

Individual C1 - 17-year-old male who presents with microcephaly (no severity stated), growth failure, ID / global developmental delay, immunodeficiency, diabetes mellitus (diagnosed at 9 months), hypothyroidism, and severe skeletal dysplasia. Homozygous for n.43G>A. Parents are first cousins.

PMID: 41864208 Johnson et al., 2026
Identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12).

6/7 individuals had variable additional features of immune dysregulation: sepsis, atopic dermatitis, B cell lymphopenia, low IgA, low IgG, B cell lymphopenia, hypothyroidism (2 sibs), agammaglobulinemia, hypoagammaglobulinemia, immunodeficiency, thyroiditis (2 unrelated patients), alopecia (2 unrelated patients), vitiligo. No microcephaly or developmental delay reported. 3/7 individuals died in early infancy.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

PMID: 40975062 Arriaga et al., 2025
Individual D1 - comp het for RNU6ATAC variants: n.36T>G and n.28C>T. The individual presented with microcephaly, short stature, hypotonia, ID/DD, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus, and oculomotor apraxia. Patient D1 did not have diabetes, hypothyroidism, or immunodeficiency. RNA analysis demonstrated excess minor intron retention.

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 31st Mar 2026).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 RNU4ATAC Ida Ertmanska changed review comment from: PMID: 26522830 Merico et al., 2015
6 cases with Roifman syndrome from 4 unrelated families (English, Italian, Lebanese, Albanian). All 6 had history of repeat infections.

PMID: 28623346 Bogaert et al., 2017
Report of two siblings that presented with a phenotype resembling early-onset common variable immunodeficiency - extra-immunological characteristics were not apparent at that time. Additional features were diagnosed later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed c.13 C > T and c.116 A > T RNU4ATAC variants, which is consistent with diagnosis of Roifman syndrome.

PMID: 29391254 Heremans et al., 2018
3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC. All patients have a common phenotype of moderate psychomotor delay and autism spectrum disorder, retinal dystrophy with hypovascularization, severe growth retardation, spondyloepiphysial dysplasia with irregularly shaped vertebral bodies with platyspondyly and flattened proximal femoral epiphyses, pruritic ichthyosis-like skin rash, brachydactyly, hyperlaxity, hypotonia, and hepatosplenomegaly.
All 3 patients have hypogammaglobulinemia and B-cell lymphopenia, and they experience recurrent viral infections, necessitating immunoglobulin substitution therapy. P2 had mucocutaneous Herpes simplex infection, and P3 presented a pneumococcal sepsis on discontinuation of therapy. Study showed abnormal differentiation of B cells and megakaryocytes in the patients.

PMID: 33059947 Hagiwara et al., 2020
18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at age one, resulting in severe psychomotor disabilities. Genetic analysis revealed comp het variants in RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity, and little response to vaccinations.

MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.

RNU4ATAC is associated with multiple AR conditions in OMIM: Lowry-Wood syndrome, MIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, MIM:210710; Roifman syndrome, OMIM:616651. Only Roifman syndrome features immunodeficiency.; to: PMID: 26522830 Merico et al., 2015
6 cases with Roifman syndrome from 4 unrelated families (English, Italian, Lebanese, Albanian). All 6 had history of repeat infections.

PMID: 28623346 Bogaert et al., 2017
Report of two siblings that presented with a phenotype resembling early-onset common variable immunodeficiency - extra-immunological characteristics were not apparent at that time. Additional features were diagnosed later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed c.13 C > T and c.116 A > T RNU4ATAC variants, which is consistent with diagnosis of Roifman syndrome.

PMID: 29391254 Heremans et al., 2018
3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC. All patients have a common phenotype of moderate psychomotor delay and autism spectrum disorder, retinal dystrophy with hypovascularization, severe growth retardation, spondyloepiphysial dysplasia with irregularly shaped vertebral bodies with platyspondyly and flattened proximal femoral epiphyses, pruritic ichthyosis-like skin rash, brachydactyly, hyperlaxity, hypotonia, and hepatosplenomegaly.
All 3 patients have hypogammaglobulinemia and B-cell lymphopenia, and they experience recurrent viral infections, necessitating immunoglobulin substitution therapy. P2 had mucocutaneous Herpes simplex infection, and P3 presented a pneumococcal sepsis on discontinuation of therapy. Study showed abnormal differentiation of B cells and megakaryocytes in the patients.

PMID: 33059947 Hagiwara et al., 2020
18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at age one, resulting in severe delay in psychomotor disabilities. Genetic analysis revealed comp het variants in RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity, and little response to vaccinations.

MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.

RNU4ATAC is associated with multiple AR conditions in OMIM: Lowry-Wood syndrome, MIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, MIM:210710; Roifman syndrome, OMIM:616651. Only Roifman syndrome features immunodeficiency.
Intellectual disability v9.378 SCNM1 Ida Ertmanska changed review comment from: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD, though 2 individuals had delayed speech. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (4/4, 3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature; to: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD, though 2 individuals had delayed speech. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (4/4, 3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.

SCNM1 is associated with AR Orofaciodigital syndrome XIX, OMIM:620107 in OMIM (accessed 14th Apr 2026).
Sources: Literature
Skeletal dysplasia v8.46 SCNM1 Ida Ertmanska changed review comment from: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature; to: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.

SCNM1 is associated with AR Orofaciodigital syndrome XIX, OMIM:620107 in OMIM (accessed 14th Apr 2026).
Sources: Literature
Limb disorders v7.29 SCNM1 Ida Ertmanska changed review comment from: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature; to: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.

SCNM1 is associated with AR Orofaciodigital syndrome XIX, OMIM:620107 in OMIM (accessed 14th Apr 2026).
Sources: Literature
Skeletal ciliopathies v6.12 SCNM1 Ida Ertmanska changed review comment from: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature; to: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.

SCNM1 is associated with AR Orofaciodigital syndrome XIX, OMIM:620107 in OMIM (accessed 14th Apr 2026).
Sources: Literature
Retinal disorders v8.120 LRRC32 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and retinal disease. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now more than 3 unrelated individuals with 3 different homozygous LRRC32 variants and retinal disease. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.378 LRRC32 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and syndromic ID/GDD. Hence, this gene should be promoted to Green on Intellectual disability at the next update.; to: Comment on list classification: There are now more than 3 unrelated individuals with 3 different homozygous LRRC32 variants and syndromic ID/GDD. Hence, this gene should be promoted to Green on Intellectual disability at the next update.
Clefting v6.25 LRRC32 Ida Ertmanska changed review comment from: PMID: 40721351 Shboul et al., 2025
Patient 4 - female fetus, Jordanian ancestry, parents first degree consanguineous; homozygous for LRRC32:c.1630C>T, p.Arg544* mutation; presented with growth delay at 18 weeks gestation; fetal growth retardation, oligohydramnios in addition to both lateral ventricle dilatation and right renal pelvis dilation with ventricular septal defect. At 28 weeks GA, the fetus was terminated - normal female with no external gross anomalies detected. Same variant as in PMID: 30976112 (2 Palestinian families).

https://doi.org/10.1016/j.rare.2025.100101 Kumari et al., 2025
Report of a male proband, Pakistani origin, consanguineous parents. He was homozygous for a stop-gain variant in LRRC32 c.1261C>T (p.Arg421*) - confirmed in trans. Variant is rare in gnomAD v4 (MAF = 0.00004464), no homozygotes. Patient presented with cleft palate, proliferative retinopathy (corneal clouding, congenital blindness), and global developmental delay. He also had extremely dry, scaly skin.

3 other unrelated cases described in previous review by Achchuthan Shanmugasundram (2 of them with a founder variant).; to: PMID: 40721351 Shboul et al., 2025
Patient 4 - female fetus, Jordanian ancestry, parents first degree consanguineous; homozygous for LRRC32:c.1630C>T, p.Arg544* mutation; presented with growth delay at 18 weeks gestation; fetal growth retardation, oligohydramnios in addition to both lateral ventricle dilatation and right renal pelvis dilation with ventricular septal defect. At 28 weeks GA, the fetus was terminated - normal female with no external gross anomalies detected. Same variant as in PMID: 30976112 (2 Palestinian families).

https://doi.org/10.1016/j.rare.2025.100101 Kumari et al., 2025
Report of a male proband, Pakistani origin, consanguineous parents. He was homozygous for a stop-gain variant in LRRC32 c.1261C>T (p.Arg421*) - confirmed in trans. Variant is rare in gnomAD v4 (MAF = 0.00004464), no homozygotes. Patient presented with cleft palate, proliferative retinopathy (corneal clouding, congenital blindness), and global developmental delay. He also had extremely dry, scaly skin.

3 other unrelated cases described in previous review by Achchuthan Shanmugasundram (2 of them with the same founder variant).
Clefting v6.25 LRRC32 Ida Ertmanska changed review comment from: PMID: 40721351 Shboul et al., 2025
Patient 4 - female fetus, Jordanian ancestry, parents first degree consanguineous; homozygous for LRRC32:c.1630C>T, p.Arg544* mutation; presented with growth delay at 18 weeks gestation; fetal growth retardation, oligohydramnios in addition to both lateral ventricle dilatation and right renal pelvis dilation with ventricular septal defect. At 28 weeks GA, the fetus was terminated - normal female with no external gross anomalies detected. Same variant as in PMID: 30976112 (2 Palestinian families).

https://doi.org/10.1016/j.rare.2025.100101 Kumari et al., 2025
Report of a male proband, Pakistani origin, consanguineous parents. He was homozygous for a stop-gain variant in LRRC32 c.1261C>T (p.Arg421*) - confirmed in trans. Variant is rare in gnomAD v4 (MAF = 0.00004464), no homozygotes. Patient presented with cleft palate, proliferative retinopathy (corneal clouding, congenital blindness), and global developmental delay. He also had extremely dry, scaly skin.; to: PMID: 40721351 Shboul et al., 2025
Patient 4 - female fetus, Jordanian ancestry, parents first degree consanguineous; homozygous for LRRC32:c.1630C>T, p.Arg544* mutation; presented with growth delay at 18 weeks gestation; fetal growth retardation, oligohydramnios in addition to both lateral ventricle dilatation and right renal pelvis dilation with ventricular septal defect. At 28 weeks GA, the fetus was terminated - normal female with no external gross anomalies detected. Same variant as in PMID: 30976112 (2 Palestinian families).

https://doi.org/10.1016/j.rare.2025.100101 Kumari et al., 2025
Report of a male proband, Pakistani origin, consanguineous parents. He was homozygous for a stop-gain variant in LRRC32 c.1261C>T (p.Arg421*) - confirmed in trans. Variant is rare in gnomAD v4 (MAF = 0.00004464), no homozygotes. Patient presented with cleft palate, proliferative retinopathy (corneal clouding, congenital blindness), and global developmental delay. He also had extremely dry, scaly skin.

3 other unrelated cases described in previous review by Achchuthan Shanmugasundram (2 of them with a founder variant).
Clefting v6.25 LRRC32 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and clefting. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now more than 3 unrelated individuals with 3 different homozygous LRRC32 variants and clefting. Hence, this gene should be promoted to Green at the next update.
Paediatric disorders - additional genes v7.47 ACVR2B Ida Ertmanska Phenotypes for gene: ACVR2B were changed from Heterotaxy syndrome Heterotaxy, visceral, 4, autosomal, 613751 to Heterotaxy, visceral, 4, autosomal, OMIM:613751; heterotaxy, visceral, 4, autosomal, MONDO:0013403
Laterality disorders and isomerism v4.13 ACVR2B Ida Ertmanska Phenotypes for gene: ACVR2B were changed from Heterotaxy syndrome Heterotaxy, visceral, 4, autosomal, 613751 to Heterotaxy, visceral, 4, autosomal, OMIM:613751; heterotaxy, visceral, 4, autosomal, MONDO:0013403
Laterality disorders and isomerism v4.12 ACVR2B Ida Ertmanska Publications for gene: ACVR2B were set to 9916847
Laterality disorders and isomerism v4.11 ACVR2B Ida Ertmanska Classified gene: ACVR2B as Amber List (moderate evidence)
Laterality disorders and isomerism v4.11 ACVR2B Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals reported with heterotaxy and heterozygous missense variants in ACVR2B. Animal models are supportive of gene-disease association, though in homozygous knockouts only (heterozygous knockout mice are reportedly normal). Additional cases have been reported harbouring the p.Arg40His variant, which is too common to cause dominant disease (not counted). Based on available evidence, this gene should be promoted to Green at the next update.
Laterality disorders and isomerism v4.11 ACVR2B Ida Ertmanska Gene: acvr2b has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v4.10 ACVR2B Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: ACVR2B.
Laterality disorders and isomerism v4.10 ACVR2B Ida Ertmanska reviewed gene: ACVR2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916847, 21864452, 30622330, 35547246; Phenotypes: Heterotaxy, visceral, 4, autosomal, OMIM:613751, heterotaxy, visceral, 4, autosomal, MONDO:0013403; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v7.45 MT-TV Alexander Rossor gene: MT-TV was added
gene: MT-TV was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Publications for gene: MT-TV were set to 32715519: 39468830: 38371303
Phenotypes for gene: MT-TV were set to peripheral neuropathy; spasticity
Mode of pathogenicity for gene: MT-TV 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: MT-TV was set to GREEN
Added comment: Described in 3 unrelated families with neuropathy and spasticity
Sources: Other
Malformations of cortical development v7.52 FBXO31 Ida Ertmanska Classified gene: FBXO31 as Amber List (moderate evidence)
Malformations of cortical development v7.52 FBXO31 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated cases reported in literature with a recurrent de novo heterozygous missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, and cerebral abnormalities on MRI (including CC hypoplasia and white matter abnormalities). There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, this gene can be promoted to Green at the next GMS update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Malformations of cortical development v7.52 FBXO31 Ida Ertmanska Gene: fbxo31 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.51 FBXO31 Ida Ertmanska gene: FBXO31 was added
gene: FBXO31 was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: FBXO31.
Mode of inheritance for gene: FBXO31 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO31 were set to 24623383; 32989326; 33675180; 35019165; 41640354; 41640354
Phenotypes for gene: FBXO31 were set to neurodevelopmental disorder, MONDO:0700092; ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979
Review for gene: FBXO31 was set to GREEN
Added comment: MONOALLELIC CASES:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4). Authors propose the monoallelic disorder could be called "Kruer syndrome".

PMID: 41640354 Schierbaum et al., 2026
13yo patient with with spastic diplegia, ID, and abnormal brain MRI findings: "ears of the lynx", thin corpus callosum, and periventricular white matter changes. Trio WGS showed that he had a de novo FBXO31 NM_024735.5, c.1000G>A, p.(Asp334Asn) variant.

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.46 FBXO31 Ida Ertmanska Publications for gene: FBXO31 were set to 32989326; 33675180
Childhood onset hereditary spastic paraplegia v8.45 FBXO31 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype checked 13th Apr 2026.
Childhood onset hereditary spastic paraplegia v8.45 FBXO31 Ida Ertmanska Phenotypes for gene: FBXO31 were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092; Spasticity, HP:0001257; ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979
Intellectual disability v9.378 FBXO31 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype checked 13th Apr 2026.
Intellectual disability v9.378 FBXO31 Ida Ertmanska Phenotypes for gene: FBXO31 were changed from ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant to ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979
Intellectual disability v9.377 FBXO31 Ida Ertmanska Publications for gene: FBXO31 were set to 24623383; 32989326; 33675180
Intellectual disability v9.376 FBXO31 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBXO31.
Intellectual disability v9.376 FBXO31 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with a recurrent heterozygous missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, there is not enough evidence for the recessive association to be included, and the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with a recurrent heterozygous de novo missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, there is not enough evidence for the recessive association to be included, and the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Intellectual disability v9.376 FBXO31 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with a recurrent de novo heterozygous missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, there is not enough evidence for the recessive association to be included, and the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with a recurrent heterozygous missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, there is not enough evidence for the recessive association to be included, and the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Intellectual disability v9.376 FBXO31 Ida Ertmanska commented on gene: FBXO31: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with a recurrent de novo heterozygous missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, there is not enough evidence for the recessive association to be included, and the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Childhood onset hereditary spastic paraplegia v8.44 FBXO31 Ida Ertmanska edited their review of gene: FBXO31: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979
Childhood onset hereditary spastic paraplegia v8.44 FBXO31 Ida Ertmanska edited their review of gene: FBXO31: Changed publications to: 24623383, 32989326, 33675180, 35019165, 41640354, 41640354
Childhood onset hereditary spastic paraplegia v8.44 FBXO31 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated cases reported in literature with a recurrent de novo heterozygous missense variant in FBXO31, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. Hence, this gene can be promoted to Green at the next GMS update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
; to: Comment on list classification: There are more than 3 unrelated cases reported in literature with a recurrent de novo heterozygous missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, this gene can be promoted to Green at the next GMS update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Childhood onset hereditary spastic paraplegia v8.44 FBXO31 Ida Ertmanska changed review comment from: PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
Sources: Literature; to: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4). Authors propose the monoallelic disorder could be called "Kruer syndrome".

PMID: 41640354 Schierbaum et al., 2026
13yo patient with with spastic diplegia, ID, and abnormal brain MRI findings: "ears of the lynx", thin corpus callosum, and periventricular white matter changes. Trio WGS showed that he had a de novo FBXO31 NM_024735.5, c.1000G>A, p.(Asp334Asn) variant.

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).
Intellectual disability v9.376 FBXO31 Ida Ertmanska changed review comment from: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4). Authors propose the monoallelic disorder could be called "Kruer syndrome".

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).; to: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4). Authors propose the monoallelic disorder could be called "Kruer syndrome".

PMID: 41640354 Schierbaum et al., 2026
13yo patient with with spastic diplegia, ID, and abnormal brain MRI findings: "ears of the lynx", thin corpus callosum, and periventricular white matter changes. Trio WGS showed that he had a de novo FBXO31 NM_024735.5, c.1000G>A, p.(Asp334Asn) variant.

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).
Intellectual disability v9.376 FBXO31 Ida Ertmanska edited their review of gene: FBXO31: Changed publications to: 24623383, 32989326, 33675180, 35019165, 41858232
Severe early-onset obesity v5.21 GNAS Eleanor Williams commented on gene: GNAS
Intellectual disability v9.376 FBXO31 Ida Ertmanska changed review comment from: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4).

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).; to: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4). Authors propose the monoallelic disorder could be called "Kruer syndrome".

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).
Intellectual disability v9.376 FBXO31 Ida Ertmanska changed review comment from: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).; to: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4).

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).
Intellectual disability v9.376 GABRA3 Ida Ertmanska changed review comment from: PMID: 41289009 Johannesen et al., 2025
Cohort of 43 individuals (18 males and 25 females) with GABRA3 variants - some reported previously. Detailed genotype–phenotype analyses showed that pathogenic GABRA3 variants can cause either dominant or recessive X-linked disorders. GOF variants caused severe phenotypes and followed X-linked dominant inheritance, while LOF variants resulted in milder phenotypes and followed an X-linked recessive pattern. 30 individuals are described in detail, others excluded due to family history or neutral impact of variant.

Among the 20 individuals with GOF variants, 85% (17/20) had epilepsy with a median age of onset at 33 months (range 2–252 months). In contrast, only 10% (1/10) with LOF variants had epilepsy, with onset at 4 months. Individuals with GOF variants were more likely to have severe ID (8/20 vs. 0/10 in LOF group). Female carriers of LOF variants were unaffected.

GABRA3 is linked to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, OMIM:301091 (OMIM accessed 10th Mar 2026).
Sources: Literature; to: PMID: 41289009 Johannesen et al., 2025
Cohort of 43 individuals (18 males and 25 females) with GABRA3 variants - some reported previously. Detailed genotype–phenotype analyses showed that pathogenic GABRA3 variants can cause either dominant or recessive X-linked disorders. GOF variants caused severe phenotypes and followed X-linked dominant inheritance, while LOF variants resulted in milder phenotypes and followed an X-linked recessive pattern. 30 individuals are described in detail, others excluded due to family history or neutral impact of variant.

Among the 20 individuals with GOF variants, 85% (17/20) had epilepsy with a median age of onset at 33 months (range 2–252 months). In contrast, only 10% (1/10) with LOF variants had epilepsy, with onset at 4 months. Individuals with GOF variants were more likely to have severe ID (8/20 vs. 0/10 in LOF group). Female carriers of LOF variants were unaffected.

GABRA3 is linked to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, OMIM:301091 (OMIM accessed 10th Mar 2026).
Sources: Literature
Intellectual disability v9.376 FBXO31 Ida Ertmanska edited their review of gene: FBXO31: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979
Intellectual disability v9.376 FBXO31 Ida Ertmanska edited their review of gene: FBXO31: Changed publications to: 32989326, 33675180, 24623383, 35019165; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.376 FBXO31 Ida Ertmanska changed review comment from: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)

FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).; to: Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).
Early onset or syndromic epilepsy v8.178 GTF3C3 Eleanor Williams Phenotypes for gene: GTF3C3 were changed from Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201 to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201; neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MONDO:0978301
Fetal anomalies v6.187 GTF3C3 Eleanor Williams Phenotypes for gene: GTF3C3 were changed from Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201 to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201; neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MONDO:0978301
Severe microcephaly v8.44 GTF3C3 Eleanor Williams Phenotypes for gene: GTF3C3 were changed from Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201 to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201; neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MONDO:0978301
Intellectual disability v9.376 GTF3C3 Eleanor Williams Phenotypes for gene: GTF3C3 were changed from Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201 to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201; neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, MONDO:0978301
Hereditary neuropathy or pain disorder v7.45 FAT3 Alexander Rossor gene: FAT3 was added
gene: FAT3 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: FAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAT3 were set to PMID: 41937739
Phenotypes for gene: FAT3 were set to axonal sensory and motor peripheral neuropathy; cranial neuropathy; scoliosis; respiratory failure; pseudoobstruction
Review for gene: FAT3 was set to GREEN
Added comment: 3 unrelated individuals
Sources: Expert list
Intellectual disability v9.375 SCNM1 Ida Ertmanska Classified gene: SCNM1 as Amber List (moderate evidence)
Intellectual disability v9.375 SCNM1 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with biallelic SCNM1 variants and syndromic GDD / ID. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.375 SCNM1 Ida Ertmanska Gene: scnm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.374 SCNM1 Ida Ertmanska gene: SCNM1 was added
gene: SCNM1 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: SCNM1.
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to 36084634; 41291844
Phenotypes for gene: SCNM1 were set to Orofaciodigital syndrome XIX, OMIM:620107; orofaciodigital syndrome 19, MONDO:0859310
Review for gene: SCNM1 was set to GREEN
Added comment: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD, though 2 individuals had delayed speech. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (4/4, 3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature
Skeletal ciliopathies v6.12 SCNM1 Ida Ertmanska Classified gene: SCNM1 as Amber List (moderate evidence)
Skeletal ciliopathies v6.12 SCNM1 Ida Ertmanska Gene: scnm1 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v6.11 SCNM1 Ida Ertmanska Classified gene: SCNM1 as Red List (low evidence)
Skeletal ciliopathies v6.11 SCNM1 Ida Ertmanska Added comment: Comment on list classification: There are 7 unrelated families reported in literature where individuals harbouring biallelic SCNM1 variants presented with polydactyly, sometimes together with syndactyly and brachydactyly. Functional evidence from patient fibroblasts shows that SCNM1 variants result in abnormal cilia morphology. Hence, this gene should be promoted to Green at the next update.
Skeletal ciliopathies v6.11 SCNM1 Ida Ertmanska Gene: scnm1 has been classified as Red List (Low Evidence).
Skeletal dysplasia v8.46 SCNM1 Ida Ertmanska Classified gene: SCNM1 as Amber List (moderate evidence)
Skeletal dysplasia v8.46 SCNM1 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harbouring biallelic SCNM1 variants presented skeletal dysplasia features, such as mesomelic arm and / or leg shortening. Hence, this gene should be promoted to Green at the next update.
Skeletal dysplasia v8.46 SCNM1 Ida Ertmanska Gene: scnm1 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.29 SCNM1 Ida Ertmanska Classified gene: SCNM1 as Amber List (moderate evidence)
Limb disorders v7.29 SCNM1 Ida Ertmanska Added comment: Comment on list classification: There are 7 unrelated families reported in literature where individuals harbouring biallelic SCNM1 variants presented with polydactyly, sometimes together with syndactyly and brachydactyly. Hence, this gene should be promoted to Green at the next update.
Limb disorders v7.29 SCNM1 Ida Ertmanska Gene: scnm1 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v6.10 SCNM1 Ida Ertmanska gene: SCNM1 was added
gene: SCNM1 was added to Skeletal ciliopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: SCNM1.
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to 36084634; 41291844
Phenotypes for gene: SCNM1 were set to Orofaciodigital syndrome XIX, OMIM:620107; orofaciodigital syndrome 19, MONDO:0859310
Review for gene: SCNM1 was set to GREEN
Added comment: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature
Skeletal dysplasia v8.45 SCNM1 Ida Ertmanska gene: SCNM1 was added
gene: SCNM1 was added to Skeletal dysplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: SCNM1.
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to 36084634; 41291844
Phenotypes for gene: SCNM1 were set to Orofaciodigital syndrome XIX, OMIM:620107; orofaciodigital syndrome 19, MONDO:0859310
Review for gene: SCNM1 was set to GREEN
Added comment: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature
Limb disorders v7.28 SCNM1 Ida Ertmanska gene: SCNM1 was added
gene: SCNM1 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: SCNM1.
Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCNM1 were set to 36084634; 41291844
Phenotypes for gene: SCNM1 were set to Orofaciodigital syndrome XIX, OMIM:620107; orofaciodigital syndrome 19, MONDO:0859310
Review for gene: SCNM1 was set to GREEN
Added comment: PMID: 36084634 Iturrate et al., 2022
4 individuals from 3 unrelated families with orofaciodigital syndrome. All 4 presented with tongue nodules, hypodontia / microdontia, facial dysmorphism, polydactyly, syndactyly of the toes, type A brachydactyly. 1 individual had a cleft palate. Skeletal features (mesomelic leg/arm shortening, short tibia) were present in 4/4 individuals. No ID/GDD. SCNM1 homozygous variants detected: c.187delC, p.Arg63Valfs∗33; c.152C>A, p.Pro51Gln; and c.301_302insAluYc1 insertion.

Functional evidence: Primary fibroblasts containing SCNM1 mutations, as well as SCNM1 knockout and SCNM1 knockdown RPE-1 cells, were also found with abnormally elongated cilia.

PMID: 41291844 Iturrate et al., 2025
Report of five new patients from four unrelated families with bi-allelic variants in SCNM1. Phenotype: bilateral postaxial polydactyly of hands and feet (5/5), dysmorphic features, ID/GDD (3 unrelated individuals), mesomelic leg shortening (2/4), cleft palate (1/4), hypodontia / microdontia (1/3). Molar tooth sign absent on MRI.
Sources: Literature
Skeletal ciliopathies v6.9 RSG1 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic RSG1 and polydactyly. Knockout Rsg1-/- mice have fewer prmary cilia, resulting in polydactyly and early lethality. Hence, this gene should be promoted to Green at the next update. Inclusion on this panel also ensures inclusion on the Rare multisystem ciliopathy Super panel.; to: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic RSG1 and polydactyly. Knockout Rsg1-/- mice have fewer primary cilia, resulting in polydactyly and early lethality. Hence, this gene should be promoted to Green at the next update. Inclusion on this panel also ensures inclusion on the Rare multisystem ciliopathy Super panel.
Skeletal ciliopathies v6.9 RSG1 Ida Ertmanska Classified gene: RSG1 as Amber List (moderate evidence)
Skeletal ciliopathies v6.9 RSG1 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic RSG1 and polydactyly. Knockout Rsg1-/- mice have fewer prmary cilia, resulting in polydactyly and early lethality. Hence, this gene should be promoted to Green at the next update. Inclusion on this panel also ensures inclusion on the Rare multisystem ciliopathy Super panel.
Skeletal ciliopathies v6.9 RSG1 Ida Ertmanska Gene: rsg1 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.27 RSG1 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic RSG1 and polydactyly. Knockout Rsg1-/- mice showed polydactyly and early lethality. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic RSG1 and polydactyly. Knockout Rsg1-/- mice showed polydactyly and early lethality. Hence, this gene should be promoted to Green at the next update. Inclusion on this panel also ensures inclusion on R27 Paediatric disorders panel.
Limb disorders v7.27 RSG1 Ida Ertmanska Classified gene: RSG1 as Amber List (moderate evidence)
Limb disorders v7.27 RSG1 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic RSG1 and polydactyly. Knockout Rsg1-/- mice showed polydactyly and early lethality. Hence, this gene should be promoted to Green at the next update.
Limb disorders v7.27 RSG1 Ida Ertmanska Gene: rsg1 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v6.8 RSG1 Ida Ertmanska gene: RSG1 was added
gene: RSG1 was added to Skeletal ciliopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: RSG1.
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 29038301; 40593758
Phenotypes for gene: RSG1 were set to ciliopathy, MONDO:0005308; polydactyly, MONDO:0021003
Review for gene: RSG1 was set to GREEN
Added comment: PMID 40593758 Vazquez et al., 2025
Three individuals from unrelated families reported with biallelic RSG1 variants: c.226G>C (p.Ala76Pro); c.G353A (p.Gly118Glu); c.562C>T (p.Arg188Trp).
Case 1) Polyhydramnios, bilateral pre-and post-axial polydactyly on hands and feet, hypertelorism, high arched palate.
Case 2) aortic coarctation cardiac septal defect and post-axial polydactyly in one hand and pre-axial polydactyly on both feet.
Case 3) hypoplastic and cystic dysplastic kidneys, oligohydramnios, microcephaly, and IUGR.

Functional evidence:
PMID: 29038301 Agbu et al., 2018 - Rsg1 is essential for ciliogenesis in mice. The Rsg1-/- mice showed completely penetrant polydactyly on all limbs and lethality at embryonic day 12.5. Rsg1 mutant embryos have fewer primary cilia than wild-type embryos.
Sources: Literature
Limb disorders v7.26 RSG1 Ida Ertmanska gene: RSG1 was added
gene: RSG1 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: RSG1.
Mode of inheritance for gene: RSG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSG1 were set to 29038301; 40593758
Phenotypes for gene: RSG1 were set to ciliopathy, MONDO:0005308; polydactyly, MONDO:0021003
Review for gene: RSG1 was set to GREEN
Added comment: PMID 40593758 Vazquez et al., 2025
Three individuals from unrelated families reported with biallelic RSG1 variants: c.226G>C (p.Ala76Pro); c.G353A (p.Gly118Glu); c.562C>T (p.Arg188Trp).
Case 1) Polyhydramnios, bilateral pre-and post-axial polydactyly on hands and feet, hypertelorism, high arched palate.
Case 2) aortic coarctation cardiac septal defect and post-axial polydactyly in one hand and pre-axial polydactyly on both feet.
Case 3) hypoplastic and cystic dysplastic kidneys, oligohydramnios, microcephaly, and IUGR.

Functional evidence:
PMID: 29038301 Agbu et al., 2018 - Rsg1 is essential for ciliogenesis in mice. The Rsg1-/- mice showed completely penetrant polydactyly on all limbs and lethality at embryonic day 12.5. Rsg1 mutant embryos have fewer primary cilia than wild-type embryos.
Sources: Literature
Intellectual disability v9.373 RNU2-2P Ida Ertmanska Tag Q2_26_MOI tag was added to gene: RNU2-2P.
Intellectual disability v9.373 RNU2-2P Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous individuals reported with both mono- and bi-allelic variants causing a neurodevelopmental disorder including early-onset epilepsy. Hence MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.; to: Comment on mode of inheritance: There are numerous individuals reported with both mono- and bi-allelic variants causing a neurodevelopmental disorder including syndromic intellectual disability/ GDD. Hence MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Intellectual disability v9.373 RNU2-2P Ida Ertmanska commented on gene: RNU2-2P: Comment on mode of inheritance: There are numerous individuals reported with both mono- and bi-allelic variants causing a neurodevelopmental disorder including early-onset epilepsy. Hence MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Intellectual disability v9.373 RNU2-2P Ida Ertmanska reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: 41912933; Phenotypes: Developmental and epileptic encephalopathy 119, OMIM:621304; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.177 RNU2-2P Ida Ertmanska edited their review of gene: RNU2-2P: Added comment: Comment on mode of inheritance: There are numerous individuals reported with both mono- and bi-allelic variants causing a neurodevelopmental disorder including early-onset epilepsy. Hence MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.177 RNU2-2P Ida Ertmanska Tag Q2_26_MOI tag was added to gene: RNU2-2P.
Early onset or syndromic epilepsy v8.177 RNU2-2P Ida Ertmanska Publications for gene: RNU2-2P were set to 40210679; 40442284
Early onset or syndromic epilepsy v8.176 RNU2-2P Ida Ertmanska reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: 41912933; Phenotypes: Developmental and epileptic encephalopathy 119, OMIM:621304; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v7.11 PTBP1 Ida Ertmanska Phenotypes for gene: PTBP1 were changed from to Neurodevelopmental disorder, MONDO:0700092; STAD syndrome, OMIM:621495
Retinal disorders v8.120 PTBP1 Ida Ertmanska Phenotypes for gene: PTBP1 were changed from to Neurodevelopmental disorder, MONDO:0700092; STAD syndrome, OMIM:621495
Fetal anomalies v6.186 PTBP1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 10th Apr 2026.
Fetal anomalies v6.186 PTBP1 Ida Ertmanska Phenotypes for gene: PTBP1 were changed from neurodevelopmental disorder with skeletal dysplasia; Neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder with skeletal dysplasia; Neurodevelopmental disorder, MONDO:0700092; STAD syndrome, OMIM:621495
Skeletal dysplasia v8.44 PTBP1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 10th Apr 2026.
Skeletal dysplasia v8.44 PTBP1 Ida Ertmanska Phenotypes for gene: PTBP1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder, MONDO:0700092; STAD syndrome, OMIM:621495
Intellectual disability v9.373 PTBP1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 10th Apr 2026.
Intellectual disability v9.373 PTBP1 Ida Ertmanska Phenotypes for gene: PTBP1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder, MONDO:0700092; STAD syndrome, OMIM:621495
Cystic kidney disease v8.13 PDIA6 Ida Ertmanska Publications for gene: PDIA6 were set to 33495992; 34487921; 35856135; 40974269
Cystic kidney disease v8.12 PDIA6 Ida Ertmanska Classified gene: PDIA6 as Amber List (moderate evidence)
Cystic kidney disease v8.12 PDIA6 Ida Ertmanska Added comment: Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and polycystic kidney disease. Functional evidence from mouse models shows that pdia6 downregulation leads to cilia removal, resulting in abnormal kidney morphology and glomerulosclerosis in the mice. Hence, this gene can be promoted to Green on Cystic kidney disease at the next update.
Cystic kidney disease v8.12 PDIA6 Ida Ertmanska Gene: pdia6 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.19 PDIA6 Ida Ertmanska Publications for gene: PDIA6 were set to 33495992; 34487921; 35856135; 40974269
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PDIA6.
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska changed review comment from: Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and polycystic kidney disease. The disease mechanism is yet to be established, and the ciliopathy association is putative. Hence, this gene can only be rated Amber on Renal ciliopathies for now.; to: Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and polycystic kidney disease. Functional evidence from mouse models shows that pdia6 downregulation leads to cilia removal, resulting in glomerulosclerosis in the mice. Hence, this gene can be promoted to Green on Renal ciliopathies at the next update.
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska edited their review of gene: PDIA6: Changed rating: GREEN
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska edited their review of gene: PDIA6: Changed publications to: 34487921, 35856135, 39044457, 40974269
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska changed review comment from: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.; to: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence:
PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.
PMID: 39044457 Kim et al., 2024
Study involved Pdia6 knockout mice with in a 58 bp deletion in exon 3, and a frameshift mutation in exon 4 Downregulating PDIA6 leads to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 intensifies the ER stress response, while also impairing the regulation of primary cilia in various cell types. Pdia6+/− mice displayed glomerular abnormalities that are suggestive of glomerulosclerosis.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Cystic kidney disease v8.11 PDIA6 Ida Ertmanska edited their review of gene: PDIA6: Changed publications to: 33495992, 34487921, 35856135, 39044457, 40974269
Cystic kidney disease v8.11 PDIA6 Ida Ertmanska gene: PDIA6 was added
gene: PDIA6 was added to Cystic kidney disease. Sources: Literature
Q2_26_promote_green tags were added to gene: PDIA6.
Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDIA6 were set to 33495992; 34487921; 35856135; 40974269
Phenotypes for gene: PDIA6 were set to Polycystic kidney dysplasia, HP:0000113; Diabetes mellitus, HP:0000819; Microcephaly, HP:0000252
Review for gene: PDIA6 was set to GREEN
Added comment: PMID: 33495992 Al-Fadhli et al 2021
Case of a child with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes who had a homozygous frameshift variant in the PDIA6 gene (NM_001282704.1:c.703del (p.Val235fs)) which is in exon 8 (of 15). The parents and unaffected sibling were heterozygous for this variant. The authors state that PDIA6 is not known yet to be involved in the formation or function of the primary cilia but suggest that it could be directly or indirectly interacting or required for proper protein folding of known or unknown ciliopathy protein.

PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence:
PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.
PMID: 39044457 Kim et al., 2024
Study involved Pdia6 knockout mice with in a 58 bp deletion in exon 3, and a frameshift mutation in exon 4 Downregulating PDIA6 leads to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 intensifies the ER stress response, while also impairing the regulation of primary cilia in various cell types. Pdia6+/− mice displayed glomerular abnormalities that are suggestive of glomerulosclerosis

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Sources: Literature
Skeletal dysplasia v8.43 PDIA6 Ida Ertmanska changed review comment from: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_001282704: p.Val235fs variant in a male proband with polycystic kidney disease, infancy-onset diabetes, and microcephaly. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.; to: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Neonatal diabetes v5.26 PDIA6 Ida Ertmanska changed review comment from: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_001282704: p.Val235fs variant in a male proband with polycystic kidney disease, infancy-onset diabetes, and microcephaly. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.; to: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska changed review comment from: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.; to: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska changed review comment from: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_001282704: p.Val235fs variant in a male proband with polycystic kidney disease, infancy-onset diabetes, and microcephaly. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.; to: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Skeletal dysplasia v8.43 PDIA6 Ida Ertmanska changed review comment from: Comment on list classification: There are two reports of unrelated individuals with biallelic PDIA6 variants and thoracic dystrophy. However, PMID: 40974269 states the proband harboured a PDIA6 variant p.Pro653fs*, while the gene transcript is 440 amino acids. Hence, this gene can only be rated Amber on Skeletal dysplasia for now.; to: Comment on list classification: There are two reports of unrelated individuals with biallelic PDIA6 variants and thoracic dystrophy. PMID: 40974269 states the proband harboured a PDIA6 variant p.Pro653fs*, while the gene transcript is 440 amino acids. Hence, this gene can only be rated Amber on Skeletal dysplasia for now.
Skeletal dysplasia v8.43 PDIA6 Ida Ertmanska Phenotypes for gene: PDIA6 were changed from Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes; Polycystic kidney dysplasia, HP:0000113; Diabetes mellitus, HP:0000819; Microcephaly, HP:0000252
Skeletal dysplasia v8.42 PDIA6 Ida Ertmanska Publications for gene: PDIA6 were set to 33495992
Skeletal dysplasia v8.41 PDIA6 Ida Ertmanska Classified gene: PDIA6 as Amber List (moderate evidence)
Skeletal dysplasia v8.41 PDIA6 Ida Ertmanska Added comment: Comment on list classification: There are two reports of unrelated individuals with biallelic PDIA6 variants and thoracic dystrophy. However, PMID: 40974269 states the proband harboured a PDIA6 variant p.Pro653fs*, while the gene transcript is 440 amino acids. Hence, this gene can only be rated Amber on Skeletal dysplasia for now.
Skeletal dysplasia v8.41 PDIA6 Ida Ertmanska Gene: pdia6 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.40 PDIA6 Ida Ertmanska reviewed gene: PDIA6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34487921, 35856135, 40974269; Phenotypes: Polycystic kidney dysplasia, HP:0000113, Diabetes mellitus, HP:0000819, Microcephaly, HP:0000252; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v5.26 PDIA6 Ida Ertmanska Phenotypes for gene: PDIA6 were changed from Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes; Polycystic kidney dysplasia, HP:0000113; Diabetes mellitus, HP:0000819; Microcephaly, HP:0000252
Neonatal diabetes v5.25 PDIA6 Ida Ertmanska Publications for gene: PDIA6 were set to 33495992
Neonatal diabetes v5.24 PDIA6 Ida Ertmanska Classified gene: PDIA6 as Amber List (moderate evidence)
Neonatal diabetes v5.24 PDIA6 Ida Ertmanska Added comment: Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and neonatal diabetes. A knock-in mouse model showed that PDIA6 disruption results in hypoinsulinemic and hyperglycemic mice, due to loss of pancreatic β-cell function and identity. Hence, this gene can only be promoted to Green on Neonatal diabetes.
Neonatal diabetes v5.24 PDIA6 Ida Ertmanska Gene: pdia6 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.23 PDIA6 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PDIA6.
Neonatal diabetes v5.23 PDIA6 Ida Ertmanska reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 34487921, 35856135, 40974269; Phenotypes: Polycystic kidney dysplasia, HP:0000113, Diabetes mellitus, HP:0000819, Microcephaly, HP:0000252; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska edited their review of gene: PDIA6: Changed rating: AMBER
Renal ciliopathies v4.18 PDIA6 Ida Ertmanska Publications for gene: PDIA6 were set to 33495992; 35856135; 40974269
Renal ciliopathies v4.17 PDIA6 Ida Ertmanska edited their review of gene: PDIA6: Changed publications to: 34487921, 35856135, 40974269
Renal ciliopathies v4.17 PDIA6 Ida Ertmanska changed review comment from: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_001282704: p.Val235fs variant in a male proband with polycystic kidney disease, infancy-onset diabetes, and microcephaly. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.; to: PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_001282704: p.Val235fs variant in a male proband with polycystic kidney disease, infancy-onset diabetes, and microcephaly. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence: PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Renal ciliopathies v4.17 PDIA6 Ida Ertmanska changed review comment from: Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and polycystic kidney disease. The disease mechanism is yet to be established, and the ciliopathy association is putative. Hence, this gene can only be rated Amber on Renal ciliopathies for now.; to: Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and polycystic kidney disease. The disease mechanism is yet to be established, and the ciliopathy association is putative. Hence, this gene can only be rated Amber on Renal ciliopathies for now.
Renal ciliopathies v4.17 PDIA6 Ida Ertmanska Classified gene: PDIA6 as Amber List (moderate evidence)
Renal ciliopathies v4.17 PDIA6 Ida Ertmanska Added comment: Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and polycystic kidney disease. The disease mechanism is yet to be established, and the ciliopathy association is putative. Hence, this gene can only be rated Amber on Renal ciliopathies for now.
Renal ciliopathies v4.17 PDIA6 Ida Ertmanska Gene: pdia6 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.16 PDIA6 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: PDIA6.
Renal ciliopathies v4.16 PDIA6 Ida Ertmanska Publications for gene: PDIA6 were set to 33495992
Renal ciliopathies v4.15 PDIA6 Ida Ertmanska Phenotypes for gene: PDIA6 were changed from Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes; Polycystic kidney dysplasia, HP:0000113; Diabetes mellitus, HP:0000819; Microcephaly, HP:0000252
Renal ciliopathies v4.14 PDIA6 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PDIA6.
Renal ciliopathies v4.14 PDIA6 Ida Ertmanska reviewed gene: PDIA6: Rating: GREEN; Mode of pathogenicity: None; Publications: 35856135, 40974269; Phenotypes: Polycystic kidney dysplasia, HP:0000113, Diabetes mellitus, HP:0000819, Microcephaly, HP:0000252; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v4.43 NR6A1 Ida Ertmanska edited their review of gene: NR6A1: Added comment: PMID: 40774958 Rasouly et al., 2025
Large cohort with CAKUT - NR6A1 confirmed as a CAKUT gene - described 13 total cases with predicted pathogenic heterozygous NR6A1 variants identified through exome seq.
Of 13 cases, 4 had both CAKUT and eye structural anomalies (e.g. coloboma), and 1 case had eye anomalies without CAKUT. Mix of LoF and missense variants. No spine anomalies reported in this cohort.

PMID: 41733738 Jacquinet et al., 2026
5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies (3/4 female individuals) and costovertebral defects associated with heterozygous deleterious variants in NR6A1: two inherited missense (c.1175T>G;p.(Met392Arg) and c.196C>T;p.(Arg66Cys)) as well as de novo loss of function c.439C>T, p.Gln147*. No ocular malformations reported in this cohort. Seq method: Trio WES / WES.
Functional evidence: loss of nr6a1 orthologs (a & b) in zebrafish causes skeletal anomalies (missing vertebrae) and abnormal kidney morphology.; Changed rating: GREEN; Changed publications to: 40610405, 40774958, 41733738; Changed phenotypes to: Oculovertebral syndrome, OMIM:621277; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v4.43 NR6A1 Ida Ertmanska Publications for gene: NR6A1 were set to 40610405
Paediatric disorders - additional genes v7.46 NR6A1 Ida Ertmanska Publications for gene: NR6A1 were set to 40610405; 40774958
Paediatric disorders - additional genes v7.45 NR6A1 Ida Ertmanska edited their review of gene: NR6A1: Changed publications to: 40610405, 40774958, 41733738
Structural eye disease v4.42 NR6A1 Ida Ertmanska Phenotypes for gene: NR6A1 were changed from coloboma, MONDO:0001476; microphthalmia, MONDO:0021129; Oculovertebral syndrome, OMIM:621277 to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129; Oculovertebral syndrome, OMIM:621277; oculovertebral syndrome, MONDO:0979866
Paediatric disorders - additional genes v7.45 NR6A1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype checked 10th Apr 2026.
Paediatric disorders - additional genes v7.45 NR6A1 Ida Ertmanska Phenotypes for gene: NR6A1 were changed from Oculovertebral syndrome, OMIM:621277; oculovertebral syndrome, MONDO:0979866 to Oculovertebral syndrome, OMIM:621277; oculovertebral syndrome, MONDO:0979866
Paediatric disorders - additional genes v7.44 NR6A1 Ida Ertmanska Phenotypes for gene: NR6A1 were changed from Oculovertebral syndrome, OMIM:621277 to Oculovertebral syndrome, OMIM:621277; oculovertebral syndrome, MONDO:0979866
Paediatric disorders - additional genes v7.43 NR6A1 Ida Ertmanska Classified gene: NR6A1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.43 NR6A1 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported with heterozygous variants in NR6A1 and oculo-vertebral-renal syndrome, presenting with eye structural anomalies, abnormal kidney morphology (often renal agenesis), uterine anomalies, and missing vertebrae. Similar congenital skeletal and kidney malformations were seen in a knockout zebrafish model, supportive of this gene-disease association. Hence, this gene should be promoted to Green on Paediatric disorders - additional genes.
Paediatric disorders - additional genes v7.43 NR6A1 Ida Ertmanska Gene: nr6a1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v4.41 NR6A1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 10th Apr 2026.
Structural eye disease v4.41 NR6A1 Ida Ertmanska Phenotypes for gene: NR6A1 were changed from coloboma, MONDO:0001476; microphthalmia, MONDO:0021129 to coloboma, MONDO:0001476; microphthalmia, MONDO:0021129; Oculovertebral syndrome, OMIM:621277
Paediatric disorders - additional genes v7.42 NR6A1 Ida Ertmanska gene: NR6A1 was added
gene: NR6A1 was added to Paediatric disorders - additional genes. Sources: Literature
Q2_26_promote_green tags were added to gene: NR6A1.
Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR6A1 were set to 40610405; 40774958
Phenotypes for gene: NR6A1 were set to Oculovertebral syndrome, OMIM:621277
Review for gene: NR6A1 was set to GREEN
Added comment: PMID: 40610405 Neelathi et al., 2025
Report of six unrelated families with heterozygous rare variants in NR6A1 gene presenting with an autosomal dominant oculo-vertebral-renal (OVR) syndrome characterised by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities. Spina bifida and scoliosis were also present in some individuals. The variants showed incomplete penetrance and variable expressivity.
Functional evidence from in silico, cellular, and zebrafish experiments showed that reported variants were either pathogenic or likely pathogenic for OVR syndrome.

PMID: 40774958 Rasouly et al., 2025
Large cohort with CAKUT - NR6A1 confirmed as a CAKUT gene - described 13 total cases with predicted pathogenic heterozygous NR6A1 variants identified through exome seq.
Of 13 cases, 4 had both CAKUT and eye structural anomalies (e.g. coloboma), and 1 case had eye anomalies without CAKUT. Mix of LoF and missense variants. No spine anomalies reported in this cohort.

PMID: 41733738 Jacquinet et al., 2026
5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies (3/4 female individuals) and costovertebral defects associated with heterozygous deleterious variants in NR6A1: two inherited missense (c.1175T>G;p.(Met392Arg) and c.196C>T;p.(Arg66Cys)) as well as de novo loss of function c.439C>T, p.Gln147*. No ocular malformations reported in this cohort. Seq method: Trio WES / WES.
Functional evidence: loss of nr6a1 orthologs (a & b) in zebrafish causes skeletal anomalies (missing vertebrae) and abnormal kidney morphology.
Sources: Literature
Intellectual disability v9.372 LRRC32 Ida Ertmanska Publications for gene: LRRC32 were set to 30976112; 35656379
Intellectual disability v9.371 LRRC32 Ida Ertmanska Classified gene: LRRC32 as Amber List (moderate evidence)
Intellectual disability v9.371 LRRC32 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and syndromic ID/GDD. Hence, this gene should be promoted to Green on Intellectual disability at the next update.
Intellectual disability v9.371 LRRC32 Ida Ertmanska Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.370 LRRC32 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LRRC32.
Intellectual disability v9.370 LRRC32 Ida Ertmanska reviewed gene: LRRC32: Rating: GREEN; Mode of pathogenicity: None; Publications: 40721351, https://doi.org/10.1016/j.rare.2025.100101; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.119 LRRC32 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LRRC32.
Retinal disorders v8.119 LRRC32 Ida Ertmanska Publications for gene: LRRC32 were set to 40721351; https://doi.org/10.1016/j.rare.2025.100101
Retinal disorders v8.118 LRRC32 Ida Ertmanska Publications for gene: LRRC32 were set to 30976112; 35656379
Retinal disorders v8.117 LRRC32 Ida Ertmanska Classified gene: LRRC32 as Amber List (moderate evidence)
Retinal disorders v8.117 LRRC32 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and retinal disease. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v8.117 LRRC32 Ida Ertmanska Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.116 LRRC32 Ida Ertmanska reviewed gene: LRRC32: Rating: GREEN; Mode of pathogenicity: None; Publications: 40721351, https://doi.org/10.1016/j.rare.2025.100101; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v6.25 LRRC32 Ida Ertmanska changed review comment from: PMID: 40721351 Shboul et al., 2025
Patient 4 - female fetus, Jordanian ancestry, parents first degree consanguineous; homozygous for LRRC32:c.1630C>T, p.Arg544* mutation; presented with growth delay at 18 weeks gestation; fetal growth retardation, oligohydramnios in addition to both lateral ventricle dilatation and right renal pelvis dilation with ventricular septal defect. At 28 weeks GA, the fetus was terminated - normal female with no external gross anomalies detected.

https://doi.org/10.1016/j.rare.2025.100101 Kumari et al., 2025
Report of a male proband, Pakistani origin, consanguineous parents. He was homozygous for a stop-gain variant in LRRC32 c.1261C>T (p.Arg421*) - confirmed in trans. Variant is rare in gnomAD v4 (MAF = 0.00004464), no homozygotes. Patient presented with cleft palate, proliferative retinopathy (corneal clouding, congenital blindness), and global developmental delay. He also had extremely dry, scaly skin.; to: PMID: 40721351 Shboul et al., 2025
Patient 4 - female fetus, Jordanian ancestry, parents first degree consanguineous; homozygous for LRRC32:c.1630C>T, p.Arg544* mutation; presented with growth delay at 18 weeks gestation; fetal growth retardation, oligohydramnios in addition to both lateral ventricle dilatation and right renal pelvis dilation with ventricular septal defect. At 28 weeks GA, the fetus was terminated - normal female with no external gross anomalies detected. Same variant as in PMID: 30976112 (2 Palestinian families).

https://doi.org/10.1016/j.rare.2025.100101 Kumari et al., 2025
Report of a male proband, Pakistani origin, consanguineous parents. He was homozygous for a stop-gain variant in LRRC32 c.1261C>T (p.Arg421*) - confirmed in trans. Variant is rare in gnomAD v4 (MAF = 0.00004464), no homozygotes. Patient presented with cleft palate, proliferative retinopathy (corneal clouding, congenital blindness), and global developmental delay. He also had extremely dry, scaly skin.
Clefting v6.25 LRRC32 Ida Ertmanska Classified gene: LRRC32 as Amber List (moderate evidence)
Clefting v6.25 LRRC32 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with 3 different homozygous LRRC32 variants and clefting. Hence, this gene should be promoted to Green at the next update.
Clefting v6.25 LRRC32 Ida Ertmanska Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Clefting v6.24 LRRC32 Ida Ertmanska Publications for gene: LRRC32 were set to 30976112; 35656379
Clefting v6.23 LRRC32 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LRRC32.
Clefting v6.23 LRRC32 Ida Ertmanska reviewed gene: LRRC32: Rating: GREEN; Mode of pathogenicity: None; Publications: 40721351, https://doi.org/10.1016/j.rare.2025.100101; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bardet Biedl syndrome v2.16 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs (consanguineous family) with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy no excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Bardet Biedl syndrome v2.16 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs (consanguineous family) with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. All homozygous for IFT57 p.Lys259Lys - leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.; to: PMID: 27060890 Thevenon et al., 2016
3 sibs (consanguineous family) with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Bardet Biedl syndrome v2.16 IFT57 Ida Ertmanska Phenotypes for gene: IFT57 were changed from Bardet-Biedl syndrome, MONDO:0015229 to Bardet-Biedl syndrome, MONDO:0015229; ?Orofaciodigital syndrome XVIII, OMIM:617927
Bardet Biedl syndrome v2.15 IFT57 Ida Ertmanska Publications for gene: IFT57 were set to 40273360
Bardet Biedl syndrome v2.14 IFT57 Ida Ertmanska Classified gene: IFT57 as Amber List (moderate evidence)
Bardet Biedl syndrome v2.14 IFT57 Ida Ertmanska Added comment: Comment on list classification: As there are 2 unrelated families with ciliopathy reported in literature, together with supportive functional evidence, this gene should now be promoted to Green on Bardet Biedl syndrome.
Bardet Biedl syndrome v2.14 IFT57 Ida Ertmanska Gene: ift57 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v2.13 IFT57 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: IFT57.
Bardet Biedl syndrome v2.13 IFT57 Ida Ertmanska reviewed gene: IFT57: Rating: GREEN; Mode of pathogenicity: None; Publications: 27060890; Phenotypes: ?Orofaciodigital syndrome XVIII, OMIM:617927; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Tubulointerstitial kidney disease v3.32 NEK8 Ida Ertmanska Phenotypes for gene: NEK8 were changed from ?Nephronopthisis 9 MIM 613824 to ?Nephronophthisis 9 MIM 613824
Tubulointerstitial kidney disease v3.31 GLIS2 Ida Ertmanska Phenotypes for gene: GLIS2 were changed from Nephronopthisis 7 MIM 611498 to Nephronophthisis 7 MIM 611498
Tubulointerstitial kidney disease v3.30 DCDC2 Ida Ertmanska Phenotypes for gene: DCDC2 were changed from Sclerosing cholangitis, neonatal MIM 617394; ?Deafness, autosomal recessive 66 MIM 610212; Nephronopthisis 19 MIM 616217 to Sclerosing cholangitis, neonatal MIM 617394; ?Deafness, autosomal recessive 66 MIM 610212; Nephronophthisis 19 MIM 616217
Tubulointerstitial kidney disease v3.29 WDR19 Ida Ertmanska Phenotypes for gene: WDR19 were changed from Nephronopthisis 13 MIM 614377; ?Cranioectodermal dysplasia 4, MIM 614378; ?Short-rib thoracic dysplasia 5 with or without polydactyly, MIM 614376; Senior-Loken syndrome 8, MIM 616307 to Nephronophthisis 13 MIM 614377; ?Cranioectodermal dysplasia 4, MIM 614378; ?Short-rib thoracic dysplasia 5 with or without polydactyly, MIM 614376; Senior-Loken syndrome 8, MIM 616307
Tubulointerstitial kidney disease v3.28 TTC21B Ida Ertmanska Phenotypes for gene: TTC21B were changed from Nephronopthisis 12, OMIM:613820 to Nephronophthisis 12, OMIM:613820
Tubulointerstitial kidney disease v3.27 TMEM67 Ida Ertmanska Phenotypes for gene: TMEM67 were changed from ?RHYNS syndrome MIM 602152; COACH syndrome 216360 AR 3; {Bardet-Biedl syndrome 14, modifier of} MIM 615991; ?RHYNS syndrome 602152 AR 3; COACH syndrome, MIM 216306; Joubert syndrome 6, MIM 610688; Nephronopthisis 11 MIM 613550; Meckel syndrome 3, MIM 607361 to ?RHYNS syndrome MIM 602152; COACH syndrome 216360 AR 3; {Bardet-Biedl syndrome 14, modifier of} MIM 615991; ?RHYNS syndrome 602152 AR 3; COACH syndrome, MIM 216306; Joubert syndrome 6, MIM 610688; Nephronophthisis 11 MIM 613550; Meckel syndrome 3, MIM 607361
Tubulointerstitial kidney disease v3.26 NPHP3 Ida Ertmanska Phenotypes for gene: NPHP3 were changed from Renal-hepatic-pancreatic dysplasia 1, MIM 208540; Meckel syndrome 7, MIM 267010; Nephronopthisis 3 MIM 604387 to Nephronophthisis 3, OMIM:604387; nephronophthisis 3, MONDO:0011456; Renal-hepatic-pancreatic dysplasia 1, OMIM:208540; renal-hepatic-pancreatic dysplasia 1, MONDO:0008833; Meckel syndrome 7, OMIM:267010; NPHP3-related Meckel-like syndrome, MONDO:0009966
Tubulointerstitial kidney disease v3.25 NPHP1 Ida Ertmanska Phenotypes for gene: NPHP1 were changed from Joubert syndrome 4 MIM 609583; Senior-Loken syndrome-1 MIM 266900; Nephronopthisis 1, juvenile MIM 256100 to Nephronophthisis 1, juvenile, OMIM:256100; nephronophthisis 1, MONDO:0009728; Senior-Loken syndrome-1, OMIM:266900; Senior-Loken syndrome 1, MONDO:0009962; Joubert syndrome 4, OMIM:609583; Joubert syndrome with renal defect, MONDO:0012308
Tubulointerstitial kidney disease v3.24 NPHP4 Ida Ertmanska Phenotypes for gene: NPHP4 were changed from Senior-Loken syndrome 4 MIM 606996; Nephronopthisis 4 MIM 606966 to Nephronophthisis 4, OMIM:606966; nephronophthisis 4, MONDO:0011752; Senior-Loken syndrome 4, OMIM:606996; Senior-Loken syndrome 4, MONDO:0011756
Tubulointerstitial kidney disease v3.23 MAPKBP1 Ida Ertmanska Phenotypes for gene: MAPKBP1 were changed from Nephronopthisis 20 MIM 6175271 to Nephronophthisis 20, OMIM:617271; nephronophthisis 20, MONDO:0014997
Tubulointerstitial kidney disease v3.22 INVS Ida Ertmanska Phenotypes for gene: INVS were changed from Nephronopthisis 2, infantile MIM 602088 to Nephronophthisis 2, infantile, OMIM:602088; nephronophthisis 2, MONDO:0011190
Tubulointerstitial kidney disease v3.21 GATM Ida Ertmanska Phenotypes for gene: GATM were changed from Fanconi renotubular syndrome 1, OMIM:134600 to Fanconi renotubular syndrome 1, OMIM:134600; Fanconi renotubular syndrome 1, MONDO:0024525
Tubulointerstitial kidney disease v3.20 CEP83 Ida Ertmanska Phenotypes for gene: CEP83 were changed from Nephronopthisis 18 MIM 615862 to Nephronophthisis 18, OMIM:615862; nephronophthisis 18, MONDO:0014374
Tubulointerstitial kidney disease v3.19 CEP164 Ida Ertmanska Phenotypes for gene: CEP164 were changed from Nephronopthisis 15 MIM 614845 to Nephronophthisis 15, OMIM:614845; nephronophthisis 15, MONDO:0013917
Tubulointerstitial kidney disease v3.18 ANKS6 Ida Ertmanska Phenotypes for gene: ANKS6 were changed from Nephronopthisis 16 MIM 615382 to Nephronophthisis 16, OMIM:615382; nephronophthisis 16, MONDO:0014158
Tubulointerstitial kidney disease v3.17 TMEM72 Ida Ertmanska Classified gene: TMEM72 as Amber List (moderate evidence)
Tubulointerstitial kidney disease v3.17 TMEM72 Ida Ertmanska Added comment: Comment on list classification: There are 6 families reported in literature with biallelic TMEM72 variants and a nephronophthisis phenotype. Kidney failure occurred at 21-41 years in 5 families; 1 case had prenatal-onset kidney failure. Based on available evidence, this gene should be promoted to Green for Tubulointerstitial kidney disease.
Tubulointerstitial kidney disease v3.17 TMEM72 Ida Ertmanska Gene: tmem72 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v8.10 TMEM72 Ida Ertmanska Classified gene: TMEM72 as Amber List (moderate evidence)
Cystic kidney disease v8.10 TMEM72 Ida Ertmanska Added comment: Comment on list classification: There are 6 families reported in literature with biallelic TMEM72 variants and a nephronophthisis phenotype. Kidney failure occurred at 21-41 years in 5 families; 1 case had prenatal-onset kidney failure. Based on available evidence, this gene should be promoted to Green for Cystic kidney disease.
Cystic kidney disease v8.10 TMEM72 Ida Ertmanska Gene: tmem72 has been classified as Amber List (Moderate Evidence).
Tubulointerstitial kidney disease v3.16 TMEM72 Ida Ertmanska gene: TMEM72 was added
gene: TMEM72 was added to Tubulointerstitial kidney disease. Sources: Literature
Q1_26_promote_green tags were added to gene: TMEM72.
Mode of inheritance for gene: TMEM72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM72 were set to 41308066
Phenotypes for gene: TMEM72 were set to nephronophthisis, MONDO:0019005
Review for gene: TMEM72 was set to GREEN
Added comment: PMID: 41308066 Claus et al., 2025
Study identified biallelic TMEM72 variants in 9 patients from six families with a phenotype suggestive of nephronophthisis. Five families presented with kidney failure at 21-41years. Kidney ultrasound showed small-to-normal-sized kidneys, increased echogenicity and loss of corticomedullary differentiation. One patient (Family F) had a different phenotype with prenatal onset of kidney failure, as well as epilepsy and intra-uterine oligohydramnios; she died at age 2 years.
Patients in families A-E were homozygous for frameshift/truncating TMEM72 variants, while proband in family F was homozygous for a missense variant c.370G>A p.(Gly124Ser).
Functional evidence: in human-derived tubuloids, authors showed that TMEM72 localizes to the cilium; affinity proteomics approach showed an association of TMEM72 ciliary function in selective ciliary cholesterol transport.

TMEM72 has not yet been associated with disease in OMIM or Gene2Phenotype (accessed 9th March 2026).
Sources: Literature
Cystic kidney disease v8.9 TMEM72 Ida Ertmanska gene: TMEM72 was added
gene: TMEM72 was added to Cystic kidney disease. Sources: Literature
Q1_26_promote_green tags were added to gene: TMEM72.
Mode of inheritance for gene: TMEM72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM72 were set to 41308066
Phenotypes for gene: TMEM72 were set to nephronophthisis, MONDO:0019005
Review for gene: TMEM72 was set to GREEN
Added comment: PMID: 41308066 Claus et al., 2025
Study identified biallelic TMEM72 variants in 9 patients from six families with a phenotype suggestive of nephronophthisis. Five families presented with kidney failure at 21-41years. Kidney ultrasound showed small-to-normal-sized kidneys, increased echogenicity and loss of corticomedullary differentiation. One patient (Family F) had a different phenotype with prenatal onset of kidney failure, as well as epilepsy and intra-uterine oligohydramnios; she died at age 2 years.
Patients in families A-E were homozygous for frameshift/truncating TMEM72 variants, while proband in family F was homozygous for a missense variant c.370G>A p.(Gly124Ser).
Functional evidence: in human-derived tubuloids, authors showed that TMEM72 localizes to the cilium; affinity proteomics approach showed an association of TMEM72 ciliary function in selective ciliary cholesterol transport.

TMEM72 has not yet been associated with disease in OMIM or Gene2Phenotype (accessed 9th March 2026).
Sources: Literature
Differences in sex development v4.20 TACR3 Ida Ertmanska Publications for gene: TACR3 were set to PMID: 22031817; 20332248; 40101754
Differences in sex development v4.19 TACR3 Ida Ertmanska Phenotypes for gene: TACR3 were changed from HYPOGONADOTROPIC HYPOGONADISM 11 WITH OR WITHOUT ANOSMIA; HH11 (OMIM: 614840) to Hypogonadotropic hypogonadism 11 with or without anosmia, OMIM:614840; hypogonadotropic hypogonadism 11 with or without anosmia, MONDO:0013913
Differences in sex development v4.18 TACR3 Ida Ertmanska Classified gene: TACR3 as Red List (low evidence)
Differences in sex development v4.18 TACR3 Ida Ertmanska Gene: tacr3 has been classified as Red List (Low Evidence).
Differences in sex development v4.17 TACR3 Ida Ertmanska reviewed gene: TACR3: Rating: RED; Mode of pathogenicity: None; Publications: 40101754, 22031817, 20332248; Phenotypes: Hypogonadotropic hypogonadism 11 with or without anosmia, OMIM:614840, hypogonadotropic hypogonadism 11 with or without anosmia, MONDO:0013913; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.176 OLA1 Ida Ertmanska Phenotypes for gene: OLA1 were changed from Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder,MONDO:0700092; microcephaly, MONDO:0001149 to Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Early onset or syndromic epilepsy v8.175 OLA1 Ida Ertmanska Classified gene: OLA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.175 OLA1 Ida Ertmanska Added comment: Comment on list classification: There are 6 unrelated individuals reported with biallelic OLA1 variants and early onset seizures. Hence, this gene should be promoted to Green on Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.175 OLA1 Ida Ertmanska Gene: ola1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.174 OLA1 Ida Ertmanska gene: OLA1 was added
gene: OLA1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_26_promote_green tags were added to gene: OLA1.
Mode of inheritance for gene: OLA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OLA1 were set to 41887223
Phenotypes for gene: OLA1 were set to Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder,MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: OLA1 was set to GREEN
Added comment: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in 6 unrelated individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v4.8 OLA1 Ida Ertmanska changed review comment from: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature; to: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in 6 unrelated individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature
Monogenic diabetes v3.17 ZNF808 Ida Ertmanska commented on gene: ZNF808: Comment on list classification: There are 3 unrelated patients with biallelic ZNF808 variants and diabetes diagnosed at 10-23 years old, which fits into the scope of this panel. Hence, this gene should be rated Green on Monogenic diabetes.
Primary lymphoedema v4.23 PLXNB2 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals reported in literature with biallelic PLXNB2 variants and primary lymphoedema. Hence, this gene can only be rated Amber with the current evidence.; to: Comment on list classification: There are 3 individuals from 2 families reported in literature with biallelic PLXNB2 variants and primary lymphoedema. Hence, this gene can only be rated Amber with the current evidence.
Childhood onset dystonia, chorea or related movement disorder v7.20 UROD Sharon Whatley reviewed gene: UROD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria cutanea tarda OMIM:176100, Hepatoerythropoietic porphyria OMIM:176100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.107 UROD Sharon Whatley reviewed gene: UROD: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 30683557, 6112327, 30514647, 38940544, 24175354, 9211196, 7398998, 3821794, 21668429, 7706766, 20479301, 8644733, 18462440, 7971555, 9296199; Phenotypes: Porphyria cutanea tarda OMIM:176100, Hepatoerythropoietic porphyria OMIM:176100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cutaneous photosensitivity with a likely genetic cause v3.16 UROD Sharon Whatley reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38940544, 38813949, 39644053, 30683557, 12735639, 24780981, 33085356, 19233912, 26789143, 12735639, 6112327, 24175354, 40534320; Phenotypes: Porphyria cutanea tarda OMIM:176100, Hepatoerythropoietic porphyria OMIM:176100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Non-acute porphyrias v1.35 UROD Sharon Whatley reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38940544, 39644053, 30683557, 12735639, 24780981, 19233912, 26789143, 6112327, 30514647, 24175354, 40534320; Phenotypes: Porphyria cutanea tarda OMIM:176100, Hepatoerythropoietic porphyria OMIM:176100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neonatal diabetes v5.23 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270; diabetes mellitus, MONDO:0005015
Familial diabetes v1.69 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome; MEGALOBLASTIC ANEMIA, THIAMINE-RESPONSIVE, WITH DIABETES MELLITUS AND SENSORINEURAL DEAFNESS ROGERS SYNDROME to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270; diabetes mellitus, MONDO:0005015
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.69 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome; MEGALOBLASTIC ANEMIA, THIAMINE-RESPONSIVE, WITH DIABETES MELLITUS AND SENSORINEURAL DEAFNESS ROGERS SYNDROME to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270; diabetes mellitus, MONDO:0005015
Pyruvate dehydrogenase (PDH) deficiency v1.39 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME OMIM:249270; thiamine-responsive megaloblastic anemia syndrome MONDO:0009575 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Cytopenias and congenital anaemias v1.124 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-Responsive Megaloblastic Anemia syndrome 249270 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Likely inborn error of metabolism v8.107 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome, 249270; Thiamine-responsive megaloblastic anemia syndrome (Disorders of thiamine metabolism) to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Unexplained kidney failure in young people v1.125 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-Responsive Megaloblastic Anemia; Thiamine-responsive megaloblastic anemia syndrome, 249270; (originally on the Imerslund-Grasbeck syndrome gene panel) to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Rare anaemia v3.23 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from 249270 Thiamine-responsive megaloblastic anemia syndrome; 249270 Thiamine-Responsive Megaloblastic Anemia syndrome; Thiamine-Responsive Megaloblastic Anemia syndrome, 249270 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Undiagnosed metabolic disorders v1.645 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome (Disorders of thiamine metabolism); Thiamine-responsive megaloblastic anemia syndrome, 249270 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Possible mitochondrial disorder - nuclear genes v4.27 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME, 249270 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Mitochondrial disorders v9.51 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome, 249270 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Proteinuric renal disease v5.10 SLC19A2 Arina Puzriakova Phenotypes for gene: SLC19A2 were changed from Thiamine-Responsive Megaloblastic Anemia; Thiamine-responsive megaloblastic anemia syndrome, 249270; (originally on the Imerslund-Grasbeck syndrome gene panel) to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Monogenic hearing loss v5.64 SLC19A2 Arina Puzriakova Mode of inheritance for gene: SLC19A2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.370 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from Congenital disorder of glycosylation, type If, 609180; CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type If, OMIM:609180
Likely inborn error of metabolism v8.106 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from Congenital disorder of glycosylation, type If 609180; Lec35 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type If, OMIM:609180; Lec35 deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Early onset or syndromic epilepsy v8.173 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from Congenital disorder of glycosylation, type If, 609180; seizures to Congenital disorder of glycosylation, type If, OMIM:609180
Skeletal dysplasia v8.40 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from Congenital disorder of glycosylation, type If 609180 to Congenital disorder of glycosylation, type If, OMIM:609180
Fetal anomalies v6.185 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type If, OMIM:609180
Undiagnosed metabolic disorders v1.644 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from Lec35 deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type If 609180; Lec35 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type If, OMIM:609180; Lec35 deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Congenital disorders of glycosylation v7.16 MPDU1 Arina Puzriakova Phenotypes for gene: MPDU1 were changed from Congenital disorder of glycosylation, type If 609180; Lec35 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type If, OMIM:609180; Lec35 deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Possible mitochondrial disorder - nuclear genes v4.26 NDUFA5 Sarah Graham reviewed gene: NDUFA5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 41859003, 41916321; Phenotypes: Mitochondrial complex I deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.369 MYCBP2 Arina Puzriakova Publications for gene: MYCBP2 were set to 36200388; 41200582; 41543631
Intellectual disability v9.368 MYCBP2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MYCBP2.
Malformations of cortical development v7.50 MYCBP2 Ida Ertmanska Classified gene: MYCBP2 as Amber List (moderate evidence)
Malformations of cortical development v7.50 MYCBP2 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with corpus callosum malformations and biallelic MYCBP2 variants. Hence, this gene can be promoted to Green at the next update.
Malformations of cortical development v7.50 MYCBP2 Ida Ertmanska Gene: mycbp2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.49 MYCBP2 Ida Ertmanska gene: MYCBP2 was added
gene: MYCBP2 was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: MYCBP2.
Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYCBP2 were set to 33875846; 36200388; 41200582; 41543631
Phenotypes for gene: MYCBP2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: MYCBP2 was set to GREEN
Added comment: PMID: 33875846 Bertoli-Avella et al., 2021
Large WES/WGS cohort. Study detected three de novo variants (one likely affecting splicing and two missense) in three patients with NDD, microcephaly, and seizures. One case presented bilateral bifid thumbs, talipes, and scoliosis, without vaginal or uterine anomalies. No variants details.

PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done.

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).
Sources: Literature
Intellectual disability v9.368 MYCBP2 Ida Ertmanska edited their review of gene: MYCBP2: Changed publications to: 33875846, 36200388, 41200582, 41543631
Intellectual disability v9.368 MYCBP2 Ida Ertmanska Publications for gene: MYCBP2 were set to 36200388; 41543631; 41200582
Intellectual disability v9.367 MYCBP2 Ida Ertmanska Publications for gene: MYCBP2 were set to 41200582; 36200388; 41543631
Intellectual disability v9.366 MYCBP2 Ida Ertmanska changed review comment from: PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done.

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).; to: PMID: 33875846 Bertoli-Avella et al., 2021
Large WES/WGS cohort. Study detected three de novo variants (one likely affecting splicing and two missense) in three patients with NDD, microcephaly, and seizures. One case presented bilateral bifid thumbs, talipes, and scoliosis, without vaginal or uterine anomalies. No variants details.

PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done.

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).
Intellectual disability v9.366 MYCBP2 Ida Ertmanska edited their review of gene: MYCBP2: Changed publications to: 36200388, 41200582, 41543631
Intellectual disability v9.366 MYCBP2 Ida Ertmanska Phenotypes for gene: MYCBP2 were changed from to neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.365 MYCBP2 Ida Ertmanska Classified gene: MYCBP2 as Amber List (moderate evidence)
Intellectual disability v9.365 MYCBP2 Ida Ertmanska Added comment: Comment on list classification: There are now more than 10 unrelated patients with heterozygous MYCBP2 variants and a neurodevelopmental disorder, with ID/GDD being the most consistent feature. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.365 MYCBP2 Ida Ertmanska Gene: mycbp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.364 MYCBP2 Ida Ertmanska changed review comment from: PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother).

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).; to: PMID: 36200388 AlAbdi et al., 2023
Eight patients (7 male, 1 female) with de novo MYCBP2 variants. Phenotypic spectrum: ID (4/8, moderate to severe), GDD (7/8), corpus callosum thinning / dysgenesis / agenesis (4/5). 2 patients had seizures and 1 had abnormal EEG; 1 patient diagnosed with cone dystrophy, one with retinopathy; 2 patients had hearing loss.

PMID: 41200582 Kostovska et al., 2025
Family with three affected members (mother and 2 sons aged 3yrs and 9 mo) carrying a novel heterozygous MYCBP2 variant NM_015057.5 c.7311del, p.(Leu2438Trpfs*3). Phenotypes: mild intellectual disability, dev delay, speech impairment, facial dysmorphism, microcephaly, seizures (only in the mother). Brain MRI not done.

PMID: 41543631 Pham et al., 2026
Proband with a maternally inherited c.4409dup (p.Leu1470Phefs*7), presented with global developmental delay, autism spectrum disorder (ASD), chronic constipation, sleep disturbances, and aggressive behaviors. Brain MRI showed normal corpus callosum. Mother had generally intact cognition (FSIQ = 103).

MYCBP2 is not yet associated with disease in OMIM (accessed 1st Apr 2026).
Intellectual disability v9.364 MYCBP2 Ida Ertmanska reviewed gene: MYCBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36200388; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 SLC19A1 Ida Ertmanska Classified gene: SLC19A1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 SLC19A1 Ida Ertmanska Added comment: Comment on list classification: There are now 5 individuals from 4 unrelated families (1 distantly related) with biallelic variants in SLC19A1 and folate-dependent disease. 3 individuals had megaloblastic anemia, and 4 presented with immunodeficiency. 2 patients also noted to have chronic diarrhea. Slc19a1-null mice die early on due to failure of hematopoietic organs. Based on available evidence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 SLC19A1 Ida Ertmanska Gene: slc19a1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.98 SLC19A1 Ida Ertmanska gene: SLC19A1 was added
gene: SLC19A1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Q2_26_promote_green tags were added to gene: SLC19A1.
Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A1 were set to 32276275; 36517554; 36745868
Phenotypes for gene: SLC19A1 were set to ?Megaloblastic anemia, folate-responsive, OMIM:601775; Immunodeficiency 114, folate-responsive, OMIM:620603
Review for gene: SLC19A1 was set to GREEN
Added comment: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemia was at 15 yrs old with hemoglobin [Hb], 5 g/dL. Responded well to treatment with cyanocobalamin and folate.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia (low Igg, reduced B cells and lymphocyte counts), high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

Functional evidence: PMID: 11266438 Zhao et al., 2001 - SLC19A1-null mice died in utero, and survived until about 12 days if folic acid supplementation was given to the SLC19A1 +/- mother. The knockout mice showed a marked absence of erythropoiesis in bone marrow, spleen, and liver along with lymphoid depletion in the splenic white pulp and thymus.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.
Sources: Literature
Rare anaemia v3.22 SLC19A1 Ida Ertmanska changed review comment from: Comment on list classification: There are now 5 individuals from 4 unrelated families (1 distantly related) with biallelic variants in SLC19A1 and folate-dependent disease. 3 individuals had megaloblastic anemia, and 4 presented with immunodeficiency. Slc19a1-null mice die early on due to failure of hematopoietic organs. Based on available evidence, this gene should be promoted to Green on Rare anaemia.; to: Comment on list classification: There are now 5 individuals from 4 unrelated families (1 distantly related) with biallelic variants in SLC19A1 and folate-dependent disease. 3 individuals had megaloblastic anemia, and 4 presented with immunodeficiency. Slc19a1-null mice die early on due to failure of hematopoietic organs. Based on available evidence, this gene should be promoted to Green on Rare anaemia.
Rare anaemia v3.22 SLC19A1 Ida Ertmanska Classified gene: SLC19A1 as Amber List (moderate evidence)
Rare anaemia v3.22 SLC19A1 Ida Ertmanska Added comment: Comment on list classification: There are now 5 individuals from 4 unrelated families (1 distantly related) with biallelic variants in SLC19A1 and folate-dependent disease. 3 individuals had megaloblastic anemia, and 4 presented with immunodeficiency. Slc19a1-null mice die early on due to failure of hematopoietic organs. Based on available evidence, this gene should be promoted to Green on Rare anaemia.
Rare anaemia v3.22 SLC19A1 Ida Ertmanska Gene: slc19a1 has been classified as Amber List (Moderate Evidence).
Rare anaemia v3.21 SLC19A1 Ida Ertmanska Phenotypes for gene: SLC19A1 were changed from Megaloblastic anemia, folate-responsive, OMIM:601775 to ?Megaloblastic anemia, folate-responsive, OMIM:601775; Immunodeficiency 114, folate-responsive, OMIM:620603
Rare anaemia v3.20 SLC19A1 Ida Ertmanska Publications for gene: SLC19A1 were set to 32276275
Rare anaemia v3.19 SLC19A1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: SLC19A1.
Rare anaemia v3.19 SLC19A1 Ida Ertmanska changed review comment from: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia (low Igg, reduced B cells and lymphocyte counts), high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

Functional evidence: PMID: 11266438 Zhao et al., 2001 - SLC19A1-null mice died in utero, and survived until about 12 days if folic acid supplementation was given to the SLC19A1 +/- mother. The knockout mice showed a marked absence of erythropoiesis in bone marrow, spleen, and liver along with lymphoid depletion in the splenic white pulp and thymus.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.; to: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemia was at 15 yrs old with hemoglobin [Hb], 5 g/dL. Responded well to treatment with cyanocobalamin and folate.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia (low Igg, reduced B cells and lymphocyte counts), high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

Functional evidence: PMID: 11266438 Zhao et al., 2001 - SLC19A1-null mice died in utero, and survived until about 12 days if folic acid supplementation was given to the SLC19A1 +/- mother. The knockout mice showed a marked absence of erythropoiesis in bone marrow, spleen, and liver along with lymphoid depletion in the splenic white pulp and thymus.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.
Rare anaemia v3.19 SLC19A1 Ida Ertmanska changed review comment from: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia, high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

Functional evidence: PMID: 11266438 Zhao et al., 2001 - SLC19A1-null mice died in utero, and survived until about 12 days if folic acid supplementation was given to the SLC19A1 +/- mother. The knockout mice showed a marked absence of erythropoiesis in bone marrow, spleen, and liver along with lymphoid depletion in the splenic white pulp and thymus.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.; to: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia (low Igg, reduced B cells and lymphocyte counts), high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

Functional evidence: PMID: 11266438 Zhao et al., 2001 - SLC19A1-null mice died in utero, and survived until about 12 days if folic acid supplementation was given to the SLC19A1 +/- mother. The knockout mice showed a marked absence of erythropoiesis in bone marrow, spleen, and liver along with lymphoid depletion in the splenic white pulp and thymus.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.
Rare anaemia v3.19 SLC19A1 Ida Ertmanska changed review comment from: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia, high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.; to: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia, high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

Functional evidence: PMID: 11266438 Zhao et al., 2001 - SLC19A1-null mice died in utero, and survived until about 12 days if folic acid supplementation was given to the SLC19A1 +/- mother. The knockout mice showed a marked absence of erythropoiesis in bone marrow, spleen, and liver along with lymphoid depletion in the splenic white pulp and thymus.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.
Rare anaemia v3.19 SLC19A1 Ida Ertmanska changed review comment from: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia, high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues; brain tomography revealed cerebral calcification.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.; to: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia, high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed. Brain tomography revealed cerebral calcification.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.
Rare anaemia v3.19 SLC19A1 Ida Ertmanska changed review comment from: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia, high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.; to: PMID: 32276275 Svaton et al., 2020
Case of recurrent severe megaloblastic anemia in a male patient with a homozygous SLC19A1 mutation c.634_636delTTC, p.Phe212del. First episode of severe anemai was at 15 yrs old with hemoglobin [Hb], 5 g/dL.

PMID: 36517554 Gök et al., 2023
Report of two cousins carrying a homozygous pathogenic variant c.1042 G>A, p.G348R in SLC19A1, with symptoms of immunodeficiency associated with defects of folate transport. Patients benefited from folinic acid supplementation.
Case 1 - hospitalised at 15 days with lower respiratory tract infection and mouth sores; cytopenia, high ferritin, low fibrinogen, and high triglycerides were noted. His sibling died at 3.5 months due to pneumonia.
Case 2 - cousin, presented with immunological and neurological issues; brain tomography revealed cerebral calcification.

PMID: 36745868 Shiraishi et al., 2023
2 patients with primary immunodeficiency caused by a homozygous missense mutation in SLC19A1 NM_194255:c.1042G>A (p.G348R).
P1 - 9yo boy with recurrent respiratory infections, chronic diarrhea, oral lesions, atopic dermatitis, recurrent fever and vomiting; brian MRI showed extensive periventricular white matter hyperintensities (lesions) and undeveloped myelinization for his age
P2 - 5yo boy, distant relative of P1; he had repeated episodes of oral lesions, fever, respiratory infections, and chronic diarrhea. Epilepsy and delayed development were also diagnosed.
Both patients had anemia (megaloblastic), thrombocytopenia, hypogammaglobulinemia, and lymphopenia, as well as sparse gray hair.
Folic acid supplementation was beneficial and improved most symptoms.

The relationship between SCL19A1 and immunodeficiency 114, folate-responsive has been classified as Limited by the Primary Immune Regulatory Disorders GCEP in September 2025.
Rare anaemia v3.19 SLC19A1 Ida Ertmanska reviewed gene: SLC19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32276275, 36517554, 36745868; Phenotypes: ?Megaloblastic anemia, folate-responsive, OMIM:601775, Immunodeficiency 114, folate-responsive, OMIM:620603; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.97 TAPBP Ida Ertmanska changed review comment from: PMID: 38989814 Ramalingam et al., 2024
Case 2 - 10yo boy with recurrent respiratory infections for 2 years, presented with wheezing and hypoxia; homozygous for TAPBP c.312del, p.Lys104AsnfsTer6. Consanguineous family. Patient was diagnosed with MHC class 1 deficiency, underwent a hematopoietic stem cell transplant.

PMID: 38866210 Elsayed et al., 2024
Identified a homozygous deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Patient was a Turkish male, 39yo at time of report.

PMID: 12149238 Yabe et al., 2002
54-year-old woman with tapasin deficiency and MHC1D3 and a homozygous Alu-mediated 7.4-kb deletion encompassing exons 4 through 7 of the TAPBP gene. Western blot analysis of patient lymphocytes showed absence of the TAPBP protein.; to: PMID: 38989814 Ramalingam et al., 2024
Case 2 - 10yo boy with recurrent respiratory infections for 2 years, presented with wheezing and hypoxia; homozygous for TAPBP c.312del, p.Lys104AsnfsTer6. Consanguineous family. Patient was diagnosed with MHC class 1 deficiency, underwent a hematopoietic stem cell transplant.

PMID: 38866210 Elsayed et al., 2024
Identified a homozygous deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Patient was a Turkish male, 39yo at time of report.

PMID: 12149238 Yabe et al., 2002
54-year-old woman with tapasin deficiency and MHC1D3 and a homozygous Alu-mediated 7.4-kb deletion encompassing exons 4 through 7 of the TAPBP gene. Western blot analysis of patient lymphocytes showed absence of the TAPBP protein.

Functional evidence: PMID: 10973281 Garbi et al., 2000 - tapasin deficient mice have impaired immune response
Primary immunodeficiency or monogenic inflammatory bowel disease v8.97 TAPBP Ida Ertmanska Classified gene: TAPBP as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.97 TAPBP Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic TAPBP variants (1 deletion and 2 cases with the same homozygous nonsense variant), which presented with recurrent infections due to tapasin deficiency. Hence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.97 TAPBP Ida Ertmanska Gene: tapbp has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.96 TAPBP Ida Ertmanska Phenotypes for gene: TAPBP were changed from ?MHC class I deficiency 3, OMIM:620814 to ?MHC class I deficiency 3, OMIM:620814; MHC class I deficiency 3, MONDO:0971012
Primary immunodeficiency or monogenic inflammatory bowel disease v8.95 TAPBP Ida Ertmanska Publications for gene: TAPBP were set to 32086639; 12149238; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v8.94 TAPBP Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TAPBP.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.94 TAPBP Ida Ertmanska edited their review of gene: TAPBP: Added comment: PMID: 38989814 Ramalingam et al., 2024
Case 2 - 10yo boy with recurrent respiratory infections for 2 years, presented with wheezing and hypoxia; homozygous for TAPBP c.312del, p.Lys104AsnfsTer6. Consanguineous family. Patient was diagnosed with MHC class 1 deficiency, underwent a hematopoietic stem cell transplant.

PMID: 38866210 Elsayed et al., 2024
Identified a homozygous deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Patient was a Turkish male, 39yo at time of report.

PMID: 12149238 Yabe et al., 2002
54-year-old woman with tapasin deficiency and MHC1D3 and a homozygous Alu-mediated 7.4-kb deletion encompassing exons 4 through 7 of the TAPBP gene. Western blot analysis of patient lymphocytes showed absence of the TAPBP protein.; Changed rating: GREEN; Changed publications to: 38866210, 38989814; Changed phenotypes to: ?MHC class I deficiency 3, OMIM:620814, MHC class I deficiency 3, MONDO:0971012; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v8.94 TAPBP Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 1st Apr 2026.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.94 TAPBP Ida Ertmanska Phenotypes for gene: TAPBP were changed from Vasculitis, pyoderma gangrenosum; Bare lymphocyte syndrome, type I 604571; HLA class I deficiency; Immunodeficiencies affecting cellular and humoral immunity; Vasculitis,pyoderma gangrenosum to ?MHC class I deficiency 3, OMIM:620814
Ataxia and cerebellar anomalies - narrow panel v8.76 COQ5 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated families reported where 4 individuals with biallelic COQ5 variants presented with cerebellar ataxia (1 case with confirmed cerebellar atrophy). Based on available evidence, this gene can only be rated Amber on Ataxia and cerebellar anomalies - narrow panel.; to: Comment on list classification: There are 2 unrelated families reported where 4 individuals with biallelic COQ5 variants presented with childhood-onset cerebellar ataxia (1 case with confirmed cerebellar atrophy). Based on available evidence, this gene can only be rated Amber on Ataxia and cerebellar anomalies - narrow panel.
Ataxia and cerebellar anomalies - narrow panel v8.76 COQ5 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated families reported where 4 individuals with biallelic COQ5 variants presented with cerebellar ataxia (1 case with confirmed cerebellar atrophy). Based on available evidence, this gene can only be rated Amber on Early onset or syndromic epilepsy.; to: Comment on list classification: There are 2 unrelated families reported where 4 individuals with biallelic COQ5 variants presented with cerebellar ataxia (1 case with confirmed cerebellar atrophy). Based on available evidence, this gene can only be rated Amber on Ataxia and cerebellar anomalies - narrow panel.
Ataxia and cerebellar anomalies - narrow panel v8.76 COQ5 Ida Ertmanska edited their review of gene: COQ5: Changed rating: AMBER
Ataxia and cerebellar anomalies - narrow panel v8.76 COQ5 Ida Ertmanska Classified gene: COQ5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.76 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated families reported where 4 individuals with biallelic COQ5 variants presented with cerebellar ataxia (1 case with confirmed cerebellar atrophy). Based on available evidence, this gene can only be rated Amber on Early onset or syndromic epilepsy.
Ataxia and cerebellar anomalies - narrow panel v8.76 COQ5 Ida Ertmanska Gene: coq5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.75 COQ5 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: COQ5.
Early onset or syndromic epilepsy v8.172 COQ5 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated families reported where 5 individuals with biallelic COQ5 variants presented with multifocal epileptiform discharges and seizures. Seizures may be a result of brain atrophy and strokes noted in these patients. Based on avaiable evidence, this gene can only be rated Amber on Early onset or syndromic epilepsy.; to: Comment on list classification: There are 2 unrelated families reported where 5 individuals with biallelic COQ5 variants presented with multifocal epileptiform discharges and seizures. Seizures may be a result of brain atrophy and strokes noted in these patients. Based on available evidence, this gene can only be rated Amber on Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.172 COQ5 Ida Ertmanska Classified gene: COQ5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.172 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated families reported where 5 individuals with biallelic COQ5 variants presented with multifocal epileptiform discharges and seizures. Seizures may be a result of brain atrophy and strokes noted in these patients. Based on avaiable evidence, this gene can only be rated Amber on Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.172 COQ5 Ida Ertmanska Gene: coq5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.171 COQ5 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: COQ5.
Early onset or syndromic epilepsy v8.171 COQ5 Ida Ertmanska edited their review of gene: COQ5: Changed rating: AMBER
Early onset or syndromic epilepsy v8.171 COQ5 Ida Ertmanska changed review comment from: PMID: 29044765 Malicdan et al., 2018
Report of 3 female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. WES/WGS identified biallelic duplications in the COQ5 gene [Chr12(GRCh37):120940098–120949687]. Sequencing of the cDNA from fibroblasts of patient III.4 shows an abnormal 3′UTR because of an abnormal splicing event, leading to LoF.
Study showed reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement. Retinal examination not mentioned in report.

PMID: 36266294 Jurkute et al., 2022
2 families, 2 affected individuals with biallelic COQ5 variants and RP
Family 11: 56yo patient with isolated RP (onset at 49 years) - harboured COQ5 variants c.682-7 T > G and c.933delC, p.(Tyr311*).
Family 12: 38 yo patient with RP, nystagmus (onset at 14 yrs), Muscular weakness (hyposthenia) with onset at 5 yrs, as well as infantile appearance, hypertelorism, and undeveloped fertile function. Comp het for COQ5 c.367 C > T, p.(Arg123Trp) and c.682-7 T > G.
c.682-7 T > G variant was confirmed to cause mis-splicing, with exon 5 skipping (p.(Gln230*)), as well as exon 4-5 skipping in a small proportion of reads (p.(Leu193Phefs*27)). Muscle biopsy / fibroblast testing was not done.

PMID: 37599337 Dawidziuk et al., 2023
Report of a patient harbouring one novel c.681+1G>A and one recurrent p.Gly118Ser variant within COQ5. Symptoms included reduced COQ10 levels, intellectual disability, encephalopathy, cerebellar ataxia, cerebellar atrophy speech regression/dysarthria, short stature, and developmental delays, as well as rarer features of dysmorphia, microcephaly, and regressive social faculties. Low COQ10 level tests showing 0.6 mg/l (normal range >0.67 mg/l). Ophthalmologic investigation proved normal.

PMID: 41199775 Wongkittichote et al., 2025
Report of two siblings with profound developmental delay, epilepsy, hypotonia, and stroke‐like episodes - diagnosed with COQ5-related primary CoQ10 deficiency. Clinical exome sequencing revealed compound heterozygous variants in COQ5: c.177_178del (p.Ser60Glyfs13) and c.353G>A (p.Gly118Asp) - confirmed in trans. Brain MRI showed abnormal signal hyperintensity in basal ganglia and thalami, and signs of multiple strokes. Ophthalmologic examination of Patient 1 at the age of 4 years revealed ptosis, pale optic discs concerning for optic atrophy, and abnormal electroretinography consistent with retinopathy.

COQ5 is putatively linked to AR ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028 (OMIM accessed 1st Apr 2026). The relationship between COQ5 and mitochondrial disease has been classified as Moderate in ClinGen by Cerebellar Ataxia GCEP in July 2024.
Sources: Literature; to: PMID: 29044765 Malicdan et al., 2018
Report of 3 female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. WES/WGS identified biallelic duplications in the COQ5 gene [Chr12(GRCh37):120940098–120949687]. Sequencing of the cDNA from fibroblasts of patient III.4 shows an abnormal 3′UTR because of an abnormal splicing event, leading to LoF.
Study showed reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement. Retinal examination not mentioned in report.

PMID: 36266294 Jurkute et al., 2022
2 families, 2 affected individuals with biallelic COQ5 variants and RP
Family 11: 56yo patient with isolated RP (onset at 49 years) - harboured COQ5 variants c.682-7 T > G and c.933delC, p.(Tyr311*).
Family 12: 38 yo patient with RP, nystagmus (onset at 14 yrs), Muscular weakness (hyposthenia) with onset at 5 yrs, as well as infantile appearance, hypertelorism, and undeveloped fertile function. Comp het for COQ5 c.367 C > T, p.(Arg123Trp) and c.682-7 T > G.
c.682-7 T > G variant was confirmed to cause mis-splicing, with exon 5 skipping (p.(Gln230*)), as well as exon 4-5 skipping in a small proportion of reads (p.(Leu193Phefs*27)). Muscle biopsy / fibroblast testing was not done.

PMID: 37599337 Dawidziuk et al., 2023
Report of a patient harbouring one novel c.681+1G>A and one recurrent p.Gly118Ser variant within COQ5. Symptoms included reduced COQ10 levels, intellectual disability, encephalopathy, cerebellar ataxia, cerebellar atrophy speech regression/dysarthria, short stature, and developmental delays, as well as rarer features of dysmorphia, microcephaly, and regressive social faculties. Low COQ10 level tests showing 0.6 mg/l (normal range >0.67 mg/l). Ophthalmologic investigation proved normal.

PMID: 41199775 Wongkittichote et al., 2025
Report of two siblings with profound developmental delay, epilepsy, hypotonia, and stroke‐like episodes - diagnosed with COQ5-related primary CoQ10 deficiency. Clinical exome sequencing revealed compound heterozygous variants in COQ5: c.177_178del (p.Ser60Glyfs13) and c.353G>A (p.Gly118Asp) - confirmed in trans. Brain MRI showed abnormal signal hyperintensity in basal ganglia and thalami, and signs of multiple strokes. Ophthalmologic examination of Patient 1 at the age of 4 years revealed ptosis, pale optic discs concerning for optic atrophy, and abnormal electroretinography consistent with retinopathy. Both patients showed multifocal epileptiform discharges and generalized seizures. COQ10 supplementation yielded subjective improvement in social interaction.

COQ5 is putatively linked to AR ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028 (OMIM accessed 1st Apr 2026). The relationship between COQ5 and mitochondrial disease has been classified as Moderate in ClinGen by Cerebellar Ataxia GCEP in July 2024.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.75 COQ5 Ida Ertmanska gene: COQ5 was added
gene: COQ5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_26_promote_green tags were added to gene: COQ5.
Mode of inheritance for gene: COQ5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ5 were set to 29044765; 36266294; 37599337; 41199775
Phenotypes for gene: COQ5 were set to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; mitochondrial disease, MONDO:0044970
Review for gene: COQ5 was set to GREEN
Added comment: PMID: 29044765 Malicdan et al., 2018
Report of 3 female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. WES/WGS identified biallelic duplications in the COQ5 gene [Chr12(GRCh37):120940098–120949687]. Sequencing of the cDNA from fibroblasts of patient III.4 shows an abnormal 3′UTR because of an abnormal splicing event, leading to LoF.
Study showed reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement. Retinal examination not mentioned in report.

PMID: 36266294 Jurkute et al., 2022
2 families, 2 affected individuals with biallelic COQ5 variants and RP
Family 11: 56yo patient with isolated RP (onset at 49 years) - harboured COQ5 variants c.682-7 T > G and c.933delC, p.(Tyr311*).
Family 12: 38 yo patient with RP, nystagmus (onset at 14 yrs), Muscular weakness (hyposthenia) with onset at 5 yrs, as well as infantile appearance, hypertelorism, and undeveloped fertile function. Comp het for COQ5 c.367 C > T, p.(Arg123Trp) and c.682-7 T > G.
c.682-7 T > G variant was confirmed to cause mis-splicing, with exon 5 skipping (p.(Gln230*)), as well as exon 4-5 skipping in a small proportion of reads (p.(Leu193Phefs*27)). Muscle biopsy / fibroblast testing was not done.

PMID: 37599337 Dawidziuk et al., 2023
Report of a patient harbouring one novel c.681+1G>A and one recurrent p.Gly118Ser variant within COQ5. Symptoms included reduced COQ10 levels, intellectual disability, encephalopathy, cerebellar ataxia, cerebellar atrophy speech regression/dysarthria, short stature, and developmental delays, as well as rarer features of dysmorphia, microcephaly, and regressive social faculties. Low COQ10 level tests showing 0.6 mg/l (normal range >0.67 mg/l). Ophthalmologic investigation proved normal.

PMID: 41199775 Wongkittichote et al., 2025
Report of two siblings with profound developmental delay, epilepsy, hypotonia, and stroke‐like episodes - diagnosed with COQ5-related primary CoQ10 deficiency. Clinical exome sequencing revealed compound heterozygous variants in COQ5: c.177_178del (p.Ser60Glyfs13) and c.353G>A (p.Gly118Asp) - confirmed in trans. Brain MRI showed abnormal signal hyperintensity in basal ganglia and thalami, and signs of multiple strokes. Ophthalmologic examination of Patient 1 at the age of 4 years revealed ptosis, pale optic discs concerning for optic atrophy, and abnormal electroretinography consistent with retinopathy.

COQ5 is putatively linked to AR ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028 (OMIM accessed 1st Apr 2026). The relationship between COQ5 and mitochondrial disease has been classified as Moderate in ClinGen by Cerebellar Ataxia GCEP in July 2024.
Sources: Literature
Early onset or syndromic epilepsy v8.171 COQ5 Ida Ertmanska gene: COQ5 was added
gene: COQ5 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_26_promote_green tags were added to gene: COQ5.
Mode of inheritance for gene: COQ5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ5 were set to 29044765; 36266294; 37599337; 41199775
Phenotypes for gene: COQ5 were set to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; mitochondrial disease, MONDO:0044970
Review for gene: COQ5 was set to GREEN
Added comment: PMID: 29044765 Malicdan et al., 2018
Report of 3 female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. WES/WGS identified biallelic duplications in the COQ5 gene [Chr12(GRCh37):120940098–120949687]. Sequencing of the cDNA from fibroblasts of patient III.4 shows an abnormal 3′UTR because of an abnormal splicing event, leading to LoF.
Study showed reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement. Retinal examination not mentioned in report.

PMID: 36266294 Jurkute et al., 2022
2 families, 2 affected individuals with biallelic COQ5 variants and RP
Family 11: 56yo patient with isolated RP (onset at 49 years) - harboured COQ5 variants c.682-7 T > G and c.933delC, p.(Tyr311*).
Family 12: 38 yo patient with RP, nystagmus (onset at 14 yrs), Muscular weakness (hyposthenia) with onset at 5 yrs, as well as infantile appearance, hypertelorism, and undeveloped fertile function. Comp het for COQ5 c.367 C > T, p.(Arg123Trp) and c.682-7 T > G.
c.682-7 T > G variant was confirmed to cause mis-splicing, with exon 5 skipping (p.(Gln230*)), as well as exon 4-5 skipping in a small proportion of reads (p.(Leu193Phefs*27)). Muscle biopsy / fibroblast testing was not done.

PMID: 37599337 Dawidziuk et al., 2023
Report of a patient harbouring one novel c.681+1G>A and one recurrent p.Gly118Ser variant within COQ5. Symptoms included reduced COQ10 levels, intellectual disability, encephalopathy, cerebellar ataxia, cerebellar atrophy speech regression/dysarthria, short stature, and developmental delays, as well as rarer features of dysmorphia, microcephaly, and regressive social faculties. Low COQ10 level tests showing 0.6 mg/l (normal range >0.67 mg/l). Ophthalmologic investigation proved normal.

PMID: 41199775 Wongkittichote et al., 2025
Report of two siblings with profound developmental delay, epilepsy, hypotonia, and stroke‐like episodes - diagnosed with COQ5-related primary CoQ10 deficiency. Clinical exome sequencing revealed compound heterozygous variants in COQ5: c.177_178del (p.Ser60Glyfs13) and c.353G>A (p.Gly118Asp) - confirmed in trans. Brain MRI showed abnormal signal hyperintensity in basal ganglia and thalami, and signs of multiple strokes. Ophthalmologic examination of Patient 1 at the age of 4 years revealed ptosis, pale optic discs concerning for optic atrophy, and abnormal electroretinography consistent with retinopathy.

COQ5 is putatively linked to AR ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028 (OMIM accessed 1st Apr 2026). The relationship between COQ5 and mitochondrial disease has been classified as Moderate in ClinGen by Cerebellar Ataxia GCEP in July 2024.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.93 FADD Nicole Gossan changed review comment from: R117H identified in a heterozygous state in three unrelated patients. Described as a dominant susceptibility variant, shown to cause ALPS in combination with somatic UPD in DN T-cells - Inherited from heterozygous healthy parent in 2/3 cases. Third case parents not tested (PMID: 37793571).; to: R117H identified in a heterozygous state in three unrelated patients. Described as a dominant susceptibility variant, shown to cause ALPS in combination with somatic UPD in DN T-cells - Inherited from heterozygous healthy parent in 2/3 cases. Third case parents not tested (PMID: 37793571).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.93 FADD Nicole Gossan reviewed gene: FADD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37793571; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.364 COQ5 Ida Ertmanska Publications for gene: COQ5 were set to 19377476; 26350204; 21937992; 29044765
Intellectual disability v9.363 COQ5 Ida Ertmanska Phenotypes for gene: COQ5 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; cerebellar ataxia and static encephalomyopathy due to COQ5 C-methyltransferase deficiency to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; mitochondrial disease, MONDO:0044970
Mitochondrial disorders v9.50 COQ5 Ida Ertmanska Phenotypes for gene: COQ5 were changed from No OMIM phenotype to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; mitochondrial disease, MONDO:0044970
Mitochondrial disorders v9.49 COQ5 Ida Ertmanska Publications for gene: COQ5 were set to 29044765
Mitochondrial disorders v9.48 COQ5 Ida Ertmanska changed review comment from: Comment on list classification: There are now more than 3 unrelated families reported with biallelic COQ5 variants and mitchondrial disease (COQ5-related primary CoQ10 deficiency). Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: There are now more than 3 unrelated families reported with biallelic COQ5 variants and mitochondrial disease (COQ5-related primary CoQ10 deficiency). Hence, this gene should be promoted to Green at the next GMS update.
Possible mitochondrial disorder - nuclear genes v4.26 COQ5 Ida Ertmanska changed review comment from: Comment on list classification: There are now more than 3 unrelated families reported with biallelic COQ5 variants and mitchondrial disease (COQ5-related primary CoQ10 deficiency). Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: There are now more than 3 unrelated families reported with biallelic COQ5 variants and mitochondrial disease (COQ5-related primary CoQ10 deficiency). Hence, this gene should be promoted to Green at the next GMS update.
Mitochondrial disorders v9.48 COQ5 Ida Ertmanska Classified gene: COQ5 as Amber List (moderate evidence)
Mitochondrial disorders v9.48 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated families reported with biallelic COQ5 variants and mitchondrial disease (COQ5-related primary CoQ10 deficiency). Hence, this gene should be promoted to Green at the next GMS update.
Mitochondrial disorders v9.48 COQ5 Ida Ertmanska Gene: coq5 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v9.47 COQ5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: COQ5.
Intellectual disability v9.362 COQ5 Ida Ertmanska Classified gene: COQ5 as Amber List (moderate evidence)
Intellectual disability v9.362 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are now 6 individuals from 3 unrelated families with intellectual disability and developmental delay, harbouring biallelic variants in COQ5. Hence, this gene can be promoted to Green at the next GMS update.
Intellectual disability v9.362 COQ5 Ida Ertmanska Gene: coq5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.361 COQ5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: COQ5.
Mitochondrial disorders v9.47 COQ5 Ida Ertmanska reviewed gene: COQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29044765, 36266294, 37599337, 41199775; Phenotypes: ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028, mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.361 COQ5 Ida Ertmanska reviewed gene: COQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29044765, 36266294, 37599337, 41199775; Phenotypes: ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028, mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.116 COQ5 Ida Ertmanska Publications for gene: COQ5 were set to 36266294
Retinal disorders v8.115 COQ5 Ida Ertmanska Classified gene: COQ5 as Amber List (moderate evidence)
Retinal disorders v8.115 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic COQ5 variants and retinopathy due to COQ10 deficiency. Hence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.115 COQ5 Ida Ertmanska Gene: coq5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.114 COQ5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: COQ5.
Retinal disorders v8.114 COQ5 Ida Ertmanska reviewed gene: COQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29044765, 36266294, 37599337, 41199775; Phenotypes: ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028, mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v4.26 COQ5 Ida Ertmanska Phenotypes for gene: COQ5 were changed from No OMIM phenotype to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; mitochondrial disease, MONDO:0044970
Possible mitochondrial disorder - nuclear genes v4.25 COQ5 Ida Ertmanska Publications for gene: COQ5 were set to 29044765
Possible mitochondrial disorder - nuclear genes v4.24 COQ5 Ida Ertmanska Classified gene: COQ5 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v4.24 COQ5 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated families reported with biallelic COQ5 variants and mitchondrial disease (COQ5-related primary CoQ10 deficiency). Hence, this gene should be promoted to Green at the next GMS update.
Possible mitochondrial disorder - nuclear genes v4.24 COQ5 Ida Ertmanska Gene: coq5 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v4.23 COQ5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: COQ5.
Possible mitochondrial disorder - nuclear genes v4.23 COQ5 Ida Ertmanska reviewed gene: COQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29044765, 36266294, 37599337, 41199775; Phenotypes: ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028, mitochondrial disease, MONDO:0044970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v7.48 RDH11 Ida Ertmanska Classified gene: RDH11 as Amber List (moderate evidence)
Malformations of cortical development v7.48 RDH11 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic RDH11 variants and corpus callosum hypoplasia. Hence, this gene should be promoted to Green on Malformations of cortical development at the next update.
Malformations of cortical development v7.48 RDH11 Ida Ertmanska Gene: rdh11 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.47 RDH11 Ida Ertmanska changed review comment from: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Sources: Literature; to: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram. No mention of brain imaging.

PMID: 34988992 Liu et al., 2022
15yo Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly seen, no abnormalities found on MRI. First admitted to the clinic at 7 years old. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly. No brain imaging done.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.41 RDH11 Ida Ertmanska Classified gene: RDH11 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.41 RDH11 Ida Ertmanska Added comment: Comment on list classification: There are 9 individuals from multiple unrelated families reported in literature with biallelic variants in RDH11 and juvenile-onset progressive myopathy. Hence, this gene should be promoted to Green at the next update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.41 RDH11 Ida Ertmanska Gene: rdh11 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v7.10 RDH11 Ida Ertmanska Classified gene: RDH11 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v7.10 RDH11 Ida Ertmanska Added comment: Comment on list classification: There are 15 individuals from multiple unrelated families reported in literature with biallelic variants in RDH11 and juvenile-onset cataracts. Hence, this gene should be promoted to Green at the next update.
Bilateral congenital or childhood onset cataracts v7.10 RDH11 Ida Ertmanska Gene: rdh11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.114 RDH11 Ida Ertmanska Publications for gene: RDH11 were set to 24916380; 15634683; 30731079; 18326732; 41904678
Retinal disorders v8.113 RDH11 Ida Ertmanska Phenotypes for gene: RDH11 were changed from ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118
Intellectual disability v9.361 RDH11 Ida Ertmanska Classified gene: RDH11 as Amber List (moderate evidence)
Intellectual disability v9.361 RDH11 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic variants in RDH11 and syndromic Intellectual disability. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.361 RDH11 Ida Ertmanska Gene: rdh11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.112 RDH11 Ida Ertmanska changed review comment from: Comment on list classification: There are now more than 10 unrelated individuals reported in literature with biallelic variants in RDH11 and retinal disease (RP and progressive night blindness). Hence, this gene should be promoted to Green for Retinal disorders.; to: Comment on list classification: There are now more than 3 unrelated individuals reported in literature with biallelic variants in RDH11 and retinal disease (RP and progressive night blindness). Hence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.112 RDH11 Ida Ertmanska edited their review of gene: RDH11: Changed publications to: 24916380, 34988992, 41459630, 41904678; Changed phenotypes to: ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108, Neurodevelopmental delay, HP:0012758, Juvenile cataract, HP:0001118
Retinal disorders v8.112 RDH11 Ida Ertmanska Classified gene: RDH11 as Amber List (moderate evidence)
Retinal disorders v8.112 RDH11 Ida Ertmanska Added comment: Comment on list classification: There are now more than 10 unrelated individuals reported in literature with biallelic variants in RDH11 and retinal disease (RP and progressive night blindness). Hence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.112 RDH11 Ida Ertmanska Gene: rdh11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.111 RDH11 Ida Ertmanska changed review comment from: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).; to: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life. 70% of cases had some ocular involvement.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Retinal disorders v8.111 RDH11 Ida Ertmanska changed review comment from: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Neurodevelopmental impairment, juvenile-onset cataract, and retinal dystrophy were confirmed as common features. Microcephaly and distinct craniofacial traits were also recurrent.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).; to: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v5.40 RDH11 Ida Ertmanska gene: RDH11 was added
gene: RDH11 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: RDH11.
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 34988992; 41459630; 41904678
Phenotypes for gene: RDH11 were set to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118
Review for gene: RDH11 was set to GREEN
Added comment: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Sources: Literature
Bilateral congenital or childhood onset cataracts v7.9 RDH11 Ida Ertmanska gene: RDH11 was added
gene: RDH11 was added to Bilateral congenital or childhood onset cataracts. Sources: Literature
Q2_26_promote_green tags were added to gene: RDH11.
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 34988992; 41459630; 41904678
Phenotypes for gene: RDH11 were set to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118
Review for gene: RDH11 was set to GREEN
Added comment: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Sources: Literature
Malformations of cortical development v7.47 RDH11 Ida Ertmanska gene: RDH11 was added
gene: RDH11 was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: RDH11.
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 34988992; 41459630; 41904678
Phenotypes for gene: RDH11 were set to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118
Review for gene: RDH11 was set to GREEN
Added comment: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Sources: Literature
Intellectual disability v9.360 RDH11 Ida Ertmanska gene: RDH11 was added
gene: RDH11 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: RDH11.
Mode of inheritance for gene: RDH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH11 were set to 24916380; 34988992; 41459630; 41904678
Phenotypes for gene: RDH11 were set to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118
Review for gene: RDH11 was set to GREEN
Added comment: PMID: 41904678 Radio et al., 2026
Report of 16 affected individuals from 9 unrelated families with biallelic LoF RDH11 variants, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Common features included: neurodevelopmental impairment (16/16), microcephaly (10/16), retinitis pigmentosa (8/16), juvenile-onset cataracts (11/16), myopathy (8/15), progressive night blindness (9/16), hypoplasia of corpus callosum (8/10 assessed by MRI). Microcephaly and distinct craniofacial traits were also recurrent. Short stature was reported in 4/16 patients.
Muscle weakness was reported as slowly progressive, associated with myopathic facies and exercise intolerance with onset in the first or second decade of life.

PMID: 41459630 Stephenson et al., 2025
Report of a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly (<3rd centile) and a novel inherited retinal dystrophy. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram.

PMID: 34988992 Liu et al., 2022
Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy. No microcephaly. Trio WES identified variants in RDH11: c.938T>C (p.Leu313Pro) and c.75-3C>A - confirmed in trans. Splice variant shown to cause exon 2 skipping resulting in (p.Lys26Serfs*38) change. Using immunofluorescence, authors found mislocalization of RDH11 protein in muscle cells of the patient.

PMID: 24916380 Xie et al., 2014
3 sibs aged 8-19 years (Italian-American family) with juvenile cataracts (onset at 8-10 years old), issues with night vision, and retinitis pigmentosa, as well as other syndromic features: facial dysmorphologies, psychomotor developmental delays, learning disabilities and short stature. WES detected comp het RDH11 mutations c.C199T:p.R67* and c.C322T:p.R108*. No mention of muscle weakness or microcephaly.

RDH11 is putatively associated in OMIM with AR Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108 (accessed 1st Apr 2026).
Sources: Literature
Retinal disorders v8.111 RDH11 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: RDH11.
Retinal disorders v8.111 RDH11 Ida Ertmanska Publications for gene: RDH11 were set to 24916380; 15634683; 30731079; 18326732
Retinal disorders v8.110 RDH11 Ida Ertmanska reviewed gene: RDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 41904678; Phenotypes: ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.359 ATG12 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with intellectual disability / psychomotor delay. Hence, this gene should be upgraded to Green for Intellectual disability.; to: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with intellectual disability / psychomotor delay. This association is supported by a zebrafish model, where atg12 knockout results in developmental delay and impaired brain funciton. Hence, this gene should be upgraded to Green for Intellectual disability.
Intellectual disability v9.359 ATG12 Ida Ertmanska changed review comment from: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature; to: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proband with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.74 ATG12 Ida Ertmanska changed review comment from: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature; to: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proband with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Malformations of cortical development v7.46 ATG12 Ida Ertmanska changed review comment from: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proband with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature; to: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proband with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Malformations of cortical development v7.46 ATG12 Ida Ertmanska Classified gene: ATG12 as Amber List (moderate evidence)
Malformations of cortical development v7.46 ATG12 Ida Ertmanska Added comment: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with corpus callosum hypoplasia and hypoplasia of the cerebellar vermis on brain MRI, along with other less consistent cortical findings. Hence, this gene should be upgraded to Green for Malformations of cortical development.
Malformations of cortical development v7.46 ATG12 Ida Ertmanska Gene: atg12 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.45 ATG12 Ida Ertmanska changed review comment from: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature; to: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proband with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.74 ATG12 Ida Ertmanska changed review comment from: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature; to: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

Functional: Loss of atg12 function in zebrafish causes developmental delay, impaired brain function, and pre-adult lethality.

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.74 ATG12 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with hypoplasia of the cerebellar vermis on MRI. Ataxia was diagnosed in 1 patient (walking with support at 17yo), with 2 other cases that were nonambulant. Based on available evidence, this gene should be promoted to Green on Ataxia and cerebellar anomalies - narrow panel.; to: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with hypoplasia of the cerebellar vermis on MRI. Ataxia was diagnosed in 1 patient (walking with support at 17yo), while 2 other individuals were nonambulant. Based on available evidence, this gene should be promoted to Green on Ataxia and cerebellar anomalies - narrow panel.
Ataxia and cerebellar anomalies - narrow panel v8.74 ATG12 Ida Ertmanska changed review comment from: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with hypoplasia of the cerebellar vermis on MRI. Ataxia was diagnosed in 1 patient, with 2 other cases that were nonambulant. Based on available evidence, this gene should be promoted to Green on Ataxia and cerebellar anomalies - narrow panel.; to: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with hypoplasia of the cerebellar vermis on MRI. Ataxia was diagnosed in 1 patient (walking with support at 17yo), with 2 other cases that were nonambulant. Based on available evidence, this gene should be promoted to Green on Ataxia and cerebellar anomalies - narrow panel.
Ataxia and cerebellar anomalies - narrow panel v8.74 ATG12 Ida Ertmanska Classified gene: ATG12 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.74 ATG12 Ida Ertmanska Added comment: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with hypoplasia of the cerebellar vermis on MRI. Ataxia was diagnosed in 1 patient, with 2 other cases that were nonambulant. Based on available evidence, this gene should be promoted to Green on Ataxia and cerebellar anomalies - narrow panel.
Ataxia and cerebellar anomalies - narrow panel v8.74 ATG12 Ida Ertmanska Gene: atg12 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.73 ATG12 Ida Ertmanska Deleted their comment
Ataxia and cerebellar anomalies - narrow panel v8.73 ATG12 Ida Ertmanska commented on gene: ATG12: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with hypoplasia of the cerebellar vermis on MRI. Ataxia was diagnosed in 1 patient, with 2 other cases that were nonambulant. Based on available evidence, this gene should be promoted to Green on Ataxia and cerebellar anomalies - narrow panel.
Intellectual disability v9.359 ATG12 Ida Ertmanska Classified gene: ATG12 as Amber List (moderate evidence)
Intellectual disability v9.359 ATG12 Ida Ertmanska Added comment: Comment on list classification: There are 5 unrelated families reported in literature with individuals harbouring biallelic ATG12 variants and presenting with intellectual disability / psychomotor delay. Hence, this gene should be upgraded to Green for Intellectual disability.
Intellectual disability v9.359 ATG12 Ida Ertmanska Gene: atg12 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.45 ATG12 Ida Ertmanska gene: ATG12 was added
gene: ATG12 was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: ATG12.
Mode of inheritance for gene: ATG12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG12 were set to 41895291
Phenotypes for gene: ATG12 were set to neurodevelopmental disorder, MONDO:0700092; Hypoplasia of the corpus callosum, HP:0002079; Cerebellar hypoplasia, HP:0001321
Review for gene: ATG12 was set to GREEN
Added comment: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.73 ATG12 Ida Ertmanska gene: ATG12 was added
gene: ATG12 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_26_promote_green tags were added to gene: ATG12.
Mode of inheritance for gene: ATG12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG12 were set to 41895291
Phenotypes for gene: ATG12 were set to neurodevelopmental disorder, MONDO:0700092; Hypoplasia of the corpus callosum, HP:0002079; Cerebellar hypoplasia, HP:0001321
Review for gene: ATG12 was set to GREEN
Added comment: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Intellectual disability v9.358 ATG12 Ida Ertmanska gene: ATG12 was added
gene: ATG12 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: ATG12.
Mode of inheritance for gene: ATG12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG12 were set to 41895291
Phenotypes for gene: ATG12 were set to neurodevelopmental disorder, MONDO:0700092; Hypoplasia of the corpus callosum, HP:0002079; Cerebellar hypoplasia, HP:0001321
Review for gene: ATG12 was set to GREEN
Added comment: PMID: 41895291 Lambton et al, 2026
Homozygous and compound heterozygous variants in ATG12 reported in 6 individuals from five unrelated families with neurodevelopmental disorder with hypotonia, seizures (all 6 individuals with variable severity), ataxia, developmental delay and / or intellectual disability (seen in all 5 families), corpus callosum hypoplasia (4/5 individuals) and hypoplasia of the cerebellar vermis (5/5 individuals assessed). Other less consistent MRI findings: reduced white and gray matter, polymicrogyria, cerebellocerebral atrophy, thinning of pons, brainstem hypomyelination, and more. 4/6 individuals died before age 5 years.

Family 1: 2 sibs with ATG12 variants c.359A>C, p.Tyr120Ser and c.363+3A>T (demonstrated to cause exon 3 skipping)
Family 2: proband with a homozygous variant c.413C>T, p.Ala138Val
Family 3 : proband with a homozygous variant c.359A>C p.Tyr.120Ser
Family 4: proband S5 comp het for ATG12 variants c.235C>T (p.Arg79∗) & c.359A>C p.Tyr.120Ser
Family 5: proabdn with homozygous missense variant c.324T>G (p.Phe108Leu)

This gene has no disease association in OMIM (accessed 1st Apr 2026).
Sources: Literature
Intellectual disability v9.357 OLA1 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: OLA1.
Tag Q2_26_promote_green tag was added to gene: OLA1.
Ehlers Danlos syndrome with a likely monogenic cause v4.8 OLA1 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: OLA1.
Tag Q2_26_promote_green tag was added to gene: OLA1.
Severe microcephaly v8.43 OLA1 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: OLA1.
Tag Q2_26_promote_green tag was added to gene: OLA1.
Severe microcephaly v8.43 OLA1 Ida Ertmanska changed review comment from: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Severe / borderline severe microcephaly was noted in 6 individuals from 4 unrelated families (severity details: -4.49 SD, -4.6SD, -2.5SD, -2.54SD, and 2 microcephalic sibs in Family 8 with HC 46cm at 10 years & HC 45cm at 9 years)

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature; to: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Severe / borderline severe microcephaly was noted in 6 individuals from 4 unrelated families (severity details: -4.49 SD, -4.6SD, -2.5SD, -2.54SD, and 2 microcephalic sibs in Family 8 with HC 46cm at 10 years & HC 45cm at 9 years - both estimated to be under -3SD based on PMID: 20304425)

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.

OLA1 is not yet associated with a phenotype in OMIM (accessed 1st April 2026).
Sources: Literature
Severe microcephaly v8.43 OLA1 Ida Ertmanska Classified gene: OLA1 as Amber List (moderate evidence)
Severe microcephaly v8.43 OLA1 Ida Ertmanska Added comment: Comment on list classification: In a cohort of 14 patients with biallelic OLA1 variants, there are 2 patients reported with severe microcephaly, 2 with likely severe microcephaly, and 2 others with borderline severe microcephaly. Hence, this gene should be promoted to Green at the next update.
Severe microcephaly v8.43 OLA1 Ida Ertmanska Gene: ola1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.42 OLA1 Ida Ertmanska changed review comment from: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature; to: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Severe / borderline severe microcephaly was noted in 6 individuals from 4 unrelated families (severity details: -4.49 SD, -4.6SD, -2.5SD, -2.54SD, and 2 microcephalic sibs in Family 8 with HC 46cm at 10 years & HC 45cm at 9 years)

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v4.8 OLA1 Ida Ertmanska Classified gene: OLA1 as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v4.8 OLA1 Ida Ertmanska Added comment: Comment on list classification: There are 13 individuals reported from 9 unrelated families with biallelic variants in OLA1 and joint hypermobility, with additional features of skin laxity (5 cases) and scoliosis (6 cases), suggestive of EDS diagnosis. Hence, this gene should be promoted to Green at the next update.
Ehlers Danlos syndrome with a likely monogenic cause v4.8 OLA1 Ida Ertmanska Gene: ola1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.357 OLA1 Ida Ertmanska Classified gene: OLA1 as Amber List (moderate evidence)
Intellectual disability v9.357 OLA1 Ida Ertmanska Added comment: Comment on list classification: There are 14 individuals reported from 9 unrelated families with biallelic variants in OLA1 and syndromic intellectual disability / psychomotor delay. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.357 OLA1 Ida Ertmanska Gene: ola1 has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v4.7 OLA1 Ida Ertmanska gene: OLA1 was added
gene: OLA1 was added to Ehlers Danlos syndrome with a likely monogenic cause. Sources: Literature
Q1_26_promote_green tags were added to gene: OLA1.
Mode of inheritance for gene: OLA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OLA1 were set to 41887223
Phenotypes for gene: OLA1 were set to Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder,MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: OLA1 was set to GREEN
Added comment: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature
Severe microcephaly v8.42 OLA1 Ida Ertmanska gene: OLA1 was added
gene: OLA1 was added to Severe microcephaly. Sources: Literature
Q1_26_promote_green tags were added to gene: OLA1.
Mode of inheritance for gene: OLA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OLA1 were set to 41887223
Phenotypes for gene: OLA1 were set to Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder,MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: OLA1 was set to GREEN
Added comment: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature
Intellectual disability v9.356 OLA1 Ida Ertmanska gene: OLA1 was added
gene: OLA1 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: OLA1.
Mode of inheritance for gene: OLA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OLA1 were set to 41887223
Phenotypes for gene: OLA1 were set to Ehlers-Danlos syndrome, hypermobility type, MONDO:0007523; neurodevelopmental disorder,MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: OLA1 was set to GREEN
Added comment: PMID: 41887223 Alabdi et al., 2026
14 individuals from 9 families reported with homozygous loss of function variants in OLA1 with a phenotype characterised by a neurodevelopmental condition with connective tissue disorder.
All 14 individuals presented with intellectual disability / psychomotor delay. Seizures were reported in unrelated 6 individuals. Joint hypermobility was noted in 13/13 patients, 5 of them had skin laxity. 6 individuals had scoliosis or kyphoscoliosis. Several patients were diagnosed with Ehlers-Danos syndrome.
Microcephaly was noted in 4 individuals from unrelated families (severity details: -4.49 SD, -3SD, -4.6SD, and "HC 45cm at 9 years")

Functional evidence: C. elegans model with knock-in protein-truncating variants showed behavioural abnormalities (reduced bending, no response to touch), and reduced axon numbers in GABAergic neurons.
Variant in family 1 (p.Arg143Ter) was shown to cause complete loss of OLA1 protein on Western blot; RT-PCR was supportive of NMD taking place. Splice variant seen in Family 8 (c.728+5G>A) was demonstrated to cause exon 7 skipping.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.93 RNU6ATAC Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU6ATAC.
Neonatal diabetes v5.22 RNU4ATAC Ida Ertmanska Publications for gene: RNU4ATAC were set to MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
Neonatal diabetes v5.21 RNU4ATAC Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: RNU4ATAC.
Neonatal diabetes v5.21 RNU4ATAC Ida Ertmanska edited their review of gene: RNU4ATAC: Added comment: Comment on list classification: As the article PMID: 41864208 Johnson et al., 2026 is now published, this gene is tagged for promotion to Green at the next GMS update.; Changed publications to: 41864208
Primary immunodeficiency or monogenic inflammatory bowel disease v8.93 RNU6ATAC Ida Ertmanska Classified gene: RNU6ATAC as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.93 RNU6ATAC Ida Ertmanska Added comment: Comment on list classification: There are 6 individuals reported in literature with biallelic RNU6ATAC variants and immune dysregulation features, including low immunoglobulins, hypothyroidism / thyroiditis, hypoagammaglobulinemia, immunodeficiency, and more. Based on available evidence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.93 RNU6ATAC Ida Ertmanska Gene: rnu6atac has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v5.21 RNU6ATAC Ida Ertmanska edited their review of gene: RNU6ATAC: Added comment: PMID: 40975062 Arriaga et al., 2025
Individual D1 - comp het for RNU6ATAC variants: n.36T>G and n.28C>T. The individual presented with microcephaly, short stature, hypotonia, ID/DD, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus, and oculomotor apraxia. Patient D1 did not have diabetes, hypothyroidism, or immunodeficiency. RNA analysis demonstrated excess minor intron retention.; Changed publications to: 40975062, 41864208
Primary immunodeficiency or monogenic inflammatory bowel disease v8.92 RNU6ATAC Ida Ertmanska gene: RNU6ATAC was added
gene: RNU6ATAC was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Q1_26_promote_green tags were added to gene: RNU6ATAC.
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062; 41864208
Phenotypes for gene: RNU6ATAC were set to hypothyroidism, MONDO:0005420; Immune dysregulation, HP:0002958; thyroiditis, MONDO:0004126; alopecia, MONDO:0004907
Review for gene: RNU6ATAC was set to GREEN
Added comment: PMID: 41864208 Johnson et al., 2026
Identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12).

6/7 individuals had variable additional features of immune dysregulation: sepsis, atopic dermatitis, B cell lymphopenia, low IgA, low IgG, B cell lymphopenia, hypothyroidism (2 sibs), agammaglobulinemia, hypoagammaglobulinemia, immunodeficiency, thyroiditis (2 unrelated patients), alopecia (2 unrelated patients), vitiligo. No microcephaly or developmental delay reported. 3/7 individuals died in early infancy.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

PMID: 40975062 Arriaga et al., 2025
Individual D1 - comp het for RNU6ATAC variants: n.36T>G and n.28C>T. The individual presented with microcephaly, short stature, hypotonia, ID/DD, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus, and oculomotor apraxia. Patient D1 did not have diabetes, hypothyroidism, or immunodeficiency. RNA analysis demonstrated excess minor intron retention.

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 31st Mar 2026).
Sources: Literature
Neonatal diabetes v5.21 RNU6ATAC Ida Ertmanska changed review comment from: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 6/7 individuals had variable additional features of immune dysregulation: sepsis, atopic dermatitis, B cell lymphopenia, low IgA, low IgG, hypothyroidism B cell lymphopenia, hypothyroidism (2 sibs), agammaglobulinemia, hypoagammaglobulinemia, immunodeficiency, thyroiditis (2 unrelated patients), alopecia (2 unrelated patients), vitiligo. No microcephaly or developmental delay reported. 3/7 individuals died in early infancy.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).; to: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12).

6/7 individuals had variable additional features of immune dysregulation: sepsis, atopic dermatitis, B cell lymphopenia, low IgA, low IgG, B cell lymphopenia, hypothyroidism (2 sibs), agammaglobulinemia, hypoagammaglobulinemia, immunodeficiency, thyroiditis (2 unrelated patients), alopecia (2 unrelated patients), vitiligo. No microcephaly or developmental delay reported. 3/7 individuals died in early infancy.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).
Neonatal diabetes v5.21 RNU6ATAC Ida Ertmanska Publications for gene: RNU6ATAC were set to MedRxiv preprint Johnson et al., 2025 https://doi.org/10.1101/2025.09.12.25335567
Neonatal diabetes v5.20 RNU6ATAC Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: RNU6ATAC.
Neonatal diabetes v5.20 RNU6ATAC Ida Ertmanska changed review comment from: Comment on list classification: There are 7 individuals from 4 unrelated families with biallelic RNU6ATAC variants and early-onset diabetes (article not yet peer-reviewed). Hence, this gene will be recommended for promotion to Green on Neonatal diabetes panel once the article is published.; to: Comment on list classification: There are 7 individuals from 4 unrelated families with biallelic RNU6ATAC variants and early-onset diabetes (article not yet peer-reviewed). Hence, this gene will be recommended for promotion to Green on Neonatal diabetes panel once the article is published.
Neonatal diabetes v5.20 RNU6ATAC Ida Ertmanska edited their review of gene: RNU6ATAC: Changed publications to: 41864208
Neonatal diabetes v5.20 RNU6ATAC Ida Ertmanska commented on gene: RNU6ATAC: Comment on list classification: As the article PMID: 41864208 Johnson et al., 2026 is now published, this gene is tagged for promotion to Green at the next GMS update.
Neonatal diabetes v5.20 RNU6ATAC Ida Ertmanska changed review comment from: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).; to: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 6/7 individuals had variable additional features of immune dysregulation: sepsis, atopic dermatitis, B cell lymphopenia, low IgA, low IgG, hypothyroidism B cell lymphopenia, hypothyroidism (2 sibs), agammaglobulinemia, hypoagammaglobulinemia, immunodeficiency, thyroiditis (2 unrelated patients), alopecia (2 unrelated patients), vitiligo. No microcephaly or developmental delay reported. 3/7 individuals died in early infancy.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).
Neonatal diabetes v5.20 RNU6ATAC Ida Ertmanska changed review comment from: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).; to: MedRxiv preprint Johnson et al., 2025 doi: https://doi.org/10.1101/2025.09.12.25335567
identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinical features who had biallelic pathogenic variants in the novel disease gene RNU6ATAC (n=7) or in RNU4ATAC (n=12). 12/19 had additional immune features of immune dysregulation.
Around 60% of patients also had microcephaly and developmental delay.

Among the 4 families with biallelic RNU6ATAC variants, the variants reported were: n.4T>C, n.6G>A, n.43G>A, n.68C>A, n.71C>T (homozygous or compound het).

RNU6ATAC has not yet been linked to any phenotypes in OMIM (accessed 29th Dec 2025).
Monogenic hearing loss v5.63 FOXI1 Ida Ertmanska reviewed gene: FOXI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41833579; Phenotypes: Enlarged vestibular aqueduct, OMIM:600791, hearing loss disorder, MONDO:0005365; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v5.63 FOXI1 Ida Ertmanska Phenotypes for gene: FOXI1 were changed from Nonsyndromic Hearing Loss, Mixed; #600791:Enlarged vestibular aqueduct; hearing loss to Enlarged vestibular aqueduct, OMIM:600791; hearing loss disorder, MONDO:0005365
Monogenic hearing loss v5.62 FOXI1 Ida Ertmanska Publications for gene: FOXI1 were set to PMID:12642503; 15173882; 16932748; 17503324; 7957066; 8825632; 9843211; 29242249
Monogenic hearing loss v5.61 FOXI1 Ida Ertmanska Tag Q1_26_NHS_review was removed from gene: FOXI1.
Tag Q1_26_expert_review tag was added to gene: FOXI1.
Monogenic hearing loss v5.61 FOXI1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FOXI1.
Tag Q1_26_NHS_review tag was added to gene: FOXI1.
Monogenic hearing loss v5.61 FOXI1 Ida Ertmanska Tag watchlist_moi was removed from gene: FOXI1.
Neurological ciliopathies v6.17 CEP76 Ida Ertmanska Classified gene: CEP76 as Amber List (moderate evidence)
Neurological ciliopathies v6.17 CEP76 Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed cortical anomalies including molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene should be promoted to Green for Neurological ciliopathies.
Neurological ciliopathies v6.17 CEP76 Ida Ertmanska Gene: cep76 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.110 CEP76 Ida Ertmanska Classified gene: CEP76 as Amber List (moderate evidence)
Retinal disorders v8.110 CEP76 Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 7 patients had an ocular phenotype, of which 2 presented with isolated retinitis pigmentosa. Functional evidence shows that cep76 knockout in zebrafish results in retinal degeneration. Based on available evidence, this gene should be promoted to Green for Retinal disorders.
Retinal disorders v8.110 CEP76 Ida Ertmanska Gene: cep76 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.16 CEP76 Ida Ertmanska gene: CEP76 was added
gene: CEP76 was added to Neurological ciliopathies. Sources: Literature
Q1_26_promote_green tags were added to gene: CEP76.
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP76 were set to 41105778
Phenotypes for gene: CEP76 were set to retinitis pigmentosa, MONDO:0019200; Joubert syndrome, MONDO:0018772; Bardet-Biedl syndrome, MONDO:0015229
Review for gene: CEP76 was set to GREEN
Added comment: PMID: 41105778 Khan et al., 2025
Report of 8 patients with biallelic variants in CEP76 and syndromic ciliopathy diagnosis, presenting with neurodevelopmental, ocular, and variable additional multisystem features.
Eye abnormalities were the most common feature in the cohort (7/8), including childhood-onset retinal degeneration, oculomotor apraxia, and nystagmus - 3 patients diagnosed with Joubert syndrome, 1 with Bardet-Biedl Syndrome, and 2 patients had isolated retinitis pigmentosa. Neuroanatomical anomalies were seen in 5/8 patients - molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Muscular hypotonia was seen in 4/8 patients, ID/DD in 3/8, obesity in 3/8.

Functional evidence: Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits. Zebrafish cep76 mutants recapitulate key clinical phenotypes: retinal degeneration and visual function deficits, diminished locomotor activity
Sources: Literature
Retinal disorders v8.109 CEP76 Ida Ertmanska gene: CEP76 was added
gene: CEP76 was added to Retinal disorders. Sources: Literature
Q1_26_promote_green tags were added to gene: CEP76.
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP76 were set to 41105778
Phenotypes for gene: CEP76 were set to retinitis pigmentosa, MONDO:0019200; Joubert syndrome, MONDO:0018772; Bardet-Biedl syndrome, MONDO:0015229
Review for gene: CEP76 was set to GREEN
Added comment: PMID: 41105778 Khan et al., 2025
Report of 8 patients with biallelic variants in CEP76 and syndromic ciliopathy diagnosis, presenting with neurodevelopmental, ocular, and variable additional multisystem features.
Eye abnormalities were the most common feature in the cohort (7/8), including childhood-onset retinal degeneration, oculomotor apraxia, and nystagmus - 3 patients diagnosed with Joubert syndrome, 1 with Bardet-Biedl Syndrome, and 2 patients had isolated retinitis pigmentosa. Neuroanatomical anomalies were seen in 5/8 patients - molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Muscular hypotonia was seen in 4/8 patients, ID/DD in 3/8, obesity in 3/8.

Functional evidence: Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits. Zebrafish cep76 mutants recapitulate key clinical phenotypes: retinal degeneration and visual function deficits, diminished locomotor activity
Sources: Literature
Malformations of cortical development v7.44 CEP76 Ida Ertmanska Classified gene: CEP76 as Amber List (moderate evidence)
Malformations of cortical development v7.44 CEP76 Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed cortical anomalies including molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene should be promoted to Green for Malformations of cortical development.
Malformations of cortical development v7.44 CEP76 Ida Ertmanska Gene: cep76 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.43 CEP76 Ida Ertmanska Phenotypes for gene: CEP76 were changed from ciliopathy, MONDO:0005308 to ciliopathy, MONDO:0005308; Joubert syndrome, MONDO:0018772; Bardet-Biedl syndrome, MONDO:0015229
Ophthalmological ciliopathies v5.22 CEP76 Ida Ertmanska Phenotypes for gene: CEP76 were changed from ciliopathy, MONDO:0005308 to ciliopathy, MONDO:0005308; Joubert syndrome, MONDO:0018772; Bardet-Biedl syndrome, MONDO:0015229
Malformations of cortical development v7.42 CEP76 Ida Ertmanska Mode of pathogenicity for gene: CEP76 was changed from None to None
Malformations of cortical development v7.41 CEP76 Ida Ertmanska Added comment: Comment on phenotypes: This gene is not yet associated with a phenotype in OMIM - accessed 30th Mar 2026.
Malformations of cortical development v7.41 CEP76 Ida Ertmanska Phenotypes for gene: CEP76 were changed from to ciliopathy, MONDO:0005308
Ophthalmological ciliopathies v5.21 CEP76 Ida Ertmanska Added comment: Comment on phenotypes: This gene is not yet associated with a phenotype in OMIM - accessed 30th Mar 2026.
Ophthalmological ciliopathies v5.21 CEP76 Ida Ertmanska Phenotypes for gene: CEP76 were changed from to ciliopathy, MONDO:0005308
Ophthalmological ciliopathies v5.20 CEP76 Ida Ertmanska edited their review of gene: CEP76: Changed phenotypes to: ciliopathy, MONDO:0005308
Ophthalmological ciliopathies v5.20 CEP76 Ida Ertmanska changed review comment from: PMID: 41105778 Khan et al., 2025
Report of 8 patients with biallelic variants in CEP76 and syndromic ciliopathy diagnosis, presenting with neurodevelopmental, ocular, and variable additional multisystem features.
Eye abnormalities were the most common feature in the cohort (7/8), including childhood-onset retinal degeneration, oculomotor apraxia, and nystagmus - 3 patients diagnosed with Joubert syndrome and 1 with Bardet-Biedl Syndrome. Neuroanatomical anomalies were seen in 5/8 patients - molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Muscular hypotonia was seen in 4/8 patients, ID/DD in 3/8, obesity in 3/8.

Functional evidence: Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits. Zebrafish cep76 mutants recapitulate key clinical phenotypes: retinal degeneration and visual function deficits, diminished locomotor activity
Sources: Literature; to: PMID: 41105778 Khan et al., 2025
Report of 8 patients with biallelic variants in CEP76 and syndromic ciliopathy diagnosis, presenting with neurodevelopmental, ocular, and variable additional multisystem features.
Eye abnormalities were the most common feature in the cohort (7/8), including childhood-onset retinal degeneration, oculomotor apraxia, and nystagmus - 3 patients diagnosed with Joubert syndrome and 1 with Bardet-Biedl Syndrome. Neuroanatomical anomalies were seen in 5/8 patients - molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Muscular hypotonia was seen in 4/8 patients, ID/DD in 3/8, obesity in 3/8.

Functional evidence: Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits. Zebrafish cep76 mutants recapitulate key clinical phenotypes: retinal degeneration and visual function deficits, diminished locomotor activity
Sources: Literature
Ophthalmological ciliopathies v5.20 CEP76 Ida Ertmanska Classified gene: CEP76 as Amber List (moderate evidence)
Ophthalmological ciliopathies v5.20 CEP76 Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. Functional evidence shows that cep76 knockout in zebrafish results in retinal degeneration. Based on available evidence, this gene should be promoted to Green for Ophthalmological ciliopathies.
Ophthalmological ciliopathies v5.20 CEP76 Ida Ertmanska Gene: cep76 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.40 CEP76 Ida Ertmanska gene: CEP76 was added
gene: CEP76 was added to Malformations of cortical development. Sources: Literature
Q1_26_promote_green tags were added to gene: CEP76.
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP76 were set to 41105778
Review for gene: CEP76 was set to GREEN
Added comment: PMID: 41105778 Khan et al., 2025
Report of 8 patients with biallelic variants in CEP76 and syndromic ciliopathy diagnosis, presenting with neurodevelopmental, ocular, and variable additional multisystem features.
Eye abnormalities were the most common feature in the cohort (7/8), including childhood-onset retinal degeneration, oculomotor apraxia, and nystagmus - 3 patients diagnosed with Joubert syndrome and 1 with Bardet-Biedl Syndrome. Neuroanatomical anomalies were seen in 5/8 patients - molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Muscular hypotonia was seen in 4/8 patients, ID/DD in 3/8, obesity in 3/8.

Functional evidence: Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits. Zebrafish cep76 mutants recapitulate key clinical phenotypes: retinal degeneration and visual function deficits, diminished locomotor activity
Sources: Literature
Ophthalmological ciliopathies v5.19 CEP76 Ida Ertmanska gene: CEP76 was added
gene: CEP76 was added to Ophthalmological ciliopathies. Sources: Literature
Q1_26_promote_green tags were added to gene: CEP76.
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP76 were set to 41105778
Review for gene: CEP76 was set to GREEN
Added comment: PMID: 41105778 Khan et al., 2025
Report of 8 patients with biallelic variants in CEP76 and syndromic ciliopathy diagnosis, presenting with neurodevelopmental, ocular, and variable additional multisystem features.
Eye abnormalities were the most common feature in the cohort (7/8), including childhood-onset retinal degeneration, oculomotor apraxia, and nystagmus - 3 patients diagnosed with Joubert syndrome and 1 with Bardet-Biedl Syndrome. Neuroanatomical anomalies were seen in 5/8 patients - molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Muscular hypotonia was seen in 4/8 patients, ID/DD in 3/8, obesity in 3/8.

Functional evidence: Proband-derived fibroblasts and CEP76-depleted RPE1 cells display ciliary deficits. Zebrafish cep76 mutants recapitulate key clinical phenotypes: retinal degeneration and visual function deficits, diminished locomotor activity
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.91 BRF2 Ida Ertmanska edited their review of gene: BRF2: Changed rating: AMBER
Intestinal failure or congenital diarrhoea v3.11 PSMB10 Arina Puzriakova Phenotypes for gene: PSMB10 were changed from Immunodeficiency 121 with autoinflammation, OMIM:620807; Proteasome-associated autoinflammatory syndrome 5, OMIM:619175 to Immunodeficiency 121 with autoinflammation, OMIM:620807
Intellectual disability v9.355 BRF2 Ida Ertmanska changed review comment from: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Sources: Literature; to: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families with biallelic BRF2 variants and multiple congenital anomalies (+ multiple Icelandic families with a founder splice variant). The findings are not consistent and include facial dysmorphism, immunodeficiency, ID, skin rashes, contractures, polydactyly, and more. The gene has been tagged for promotion on Intellectual disability, which ensures inclusion on R27. Hence, added a curated_removed tag.; to: Comment on list classification: There are at least 4 unrelated families with biallelic BRF2 variants and multiple congenital anomalies (+ multiple Icelandic families with a founder splice variant). The findings are not consistent and include facial dysmorphism, immunodeficiency, ID, skin rashes, contractures, polydactyly, and more. The gene has been tagged for promotion to Green on Intellectual disability, which ensures inclusion on R27. Hence, added a curated_removed tag and rated Grey on this panel.
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska reviewed gene: BRF2: Rating: ; Mode of pathogenicity: None; Publications: 40229899, 40781771; Phenotypes: multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska Deleted their review
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska Deleted their comment
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska Deleted their comment
Intellectual disability v9.355 BRF2 Ida Ertmanska Classified gene: BRF2 as Amber List (moderate evidence)
Intellectual disability v9.355 BRF2 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families with biallelic BRF2 variants and syndromic congenital anomalies, including intellectual disability and developmental delay. Hence, this gene can be promoted to Green at the next udpate, which also ensures inclusion on R27 Paediatric disorders.
Intellectual disability v9.355 BRF2 Ida Ertmanska Gene: brf2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: BRF2.
Tag curated_removed tag was added to gene: BRF2.
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska Classified gene: BRF2 as No list
Paediatric disorders - additional genes v7.41 BRF2 Ida Ertmanska Gene: brf2 has been removed from the panel.
Paediatric disorders - additional genes v7.40 BRF2 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 4 unrelated families with biallelic BRF2 variants and multiple congenital anomalies (+ multiple Icelandic families with a founder splice variant). The findings are not consistent and include facial dysmorphism, immunodeficiency, ID, skin rashes, contractures, polydactyly, and more. Based on the syndromic, non-specific, congenital presentation, this gene should be promoted to Green on Paediatric disorders - additional genes.; to: Comment on list classification: There are at least 4 unrelated families with biallelic BRF2 variants and multiple congenital anomalies (+ multiple Icelandic families with a founder splice variant). The findings are not consistent and include facial dysmorphism, immunodeficiency, ID, skin rashes, contractures, polydactyly, and more. The gene has been tagged for promotion on Intellectual disability, which ensures inclusion on R27. Hence, added a curated_removed tag.
Paediatric disorders - additional genes v7.40 BRF2 Ida Ertmanska edited their review of gene: BRF2: Changed phenotypes to: multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042
Intellectual disability v9.354 BRF2 Ida Ertmanska gene: BRF2 was added
gene: BRF2 was added to Intellectual disability. Sources: Literature
Q1_26_promote_green tags were added to gene: BRF2.
Mode of inheritance for gene: BRF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRF2 were set to 40229899; 40781771
Phenotypes for gene: BRF2 were set to multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042; intellectual disability, MONDO:0001071
Review for gene: BRF2 was set to GREEN
Added comment: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.91 BRF2 Ida Ertmanska Phenotypes for gene: BRF2 were changed from to multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042
Primary immunodeficiency or monogenic inflammatory bowel disease v8.90 BRF2 Ida Ertmanska Classified gene: BRF2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v8.90 BRF2 Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 2 unrelated families with biallelic BRF2 variants and multiple non-specific congential anomalies, including primary immunodeficiency leading to early death. Early lethality was also seen in several Icelandic families with a BRF2 founder variant, though cause of death was not ascertained in those cases. Based on available evidence, this gene can only be rated Amber on this panel.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.90 BRF2 Ida Ertmanska Gene: brf2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v8.89 BRF2 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: BRF2.
Paediatric disorders - additional genes v7.40 BRF2 Ida Ertmanska Phenotypes for gene: BRF2 were changed from to multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042
Paediatric disorders - additional genes v7.39 BRF2 Ida Ertmanska Classified gene: BRF2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v7.39 BRF2 Ida Ertmanska Added comment: Comment on list classification: There are at least 4 unrelated families with biallelic BRF2 variants and multiple congenital anomalies (+ multiple Icelandic families with a founder splice variant). The findings are not consistent and include facial dysmorphism, immunodeficiency, ID, skin rashes, contractures, polydactyly, and more. Based on the syndromic, non-specific, congenital presentation, this gene should be promoted to Green on Paediatric disorders - additional genes.
Paediatric disorders - additional genes v7.39 BRF2 Ida Ertmanska Gene: brf2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v7.38 BRF2 Ida Ertmanska changed review comment from: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report - girl with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs
Sources: Literature; to: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.89 BRF2 Ida Ertmanska gene: BRF2 was added
gene: BRF2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Q1_26_promote_green tags were added to gene: BRF2.
Mode of inheritance for gene: BRF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRF2 were set to 40229899; 40781771
Review for gene: BRF2 was set to GREEN
Added comment: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report - girl with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs
Sources: Literature
Paediatric disorders - additional genes v7.38 BRF2 Ida Ertmanska gene: BRF2 was added
gene: BRF2 was added to Paediatric disorders - additional genes. Sources: Literature
Q1_26_promote_green tags were added to gene: BRF2.
Mode of inheritance for gene: BRF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRF2 were set to 40229899; 40781771
Review for gene: BRF2 was set to GREEN
Added comment: PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report - girl with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs
Sources: Literature
Retinal disorders v8.108 BBIP1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: BBIP1.
Bardet Biedl syndrome v2.13 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM entry states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Renal ciliopathies v4.14 BBIP1 Ida Ertmanska Phenotypes for gene: BBIP1 were changed from ?Bardet-Biedl syndrome 18, 615995 to Bardet-Biedl syndrome 18, OMIM:615995
Renal ciliopathies v4.13 BBIP1 Ida Ertmanska Publications for gene: BBIP1 were set to 24026985; 32055034
Renal ciliopathies v4.12 BBIP1 Ida Ertmanska Classified gene: BBIP1 as Amber List (moderate evidence)
Renal ciliopathies v4.12 BBIP1 Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Renal dysfunction was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including bilateral cystic dilations of the pronephros. Hence, this gene should be promoted to Green at the next update.
Renal ciliopathies v4.12 BBIP1 Ida Ertmanska Gene: bbip1 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.11 BBIP1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: BBIP1.
Renal ciliopathies v4.11 BBIP1 Ida Ertmanska reviewed gene: BBIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24026985, 32055034, 37239474; Phenotypes: Bardet-Biedl syndrome 18, OMIM:615995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.108 BBIP1 Ida Ertmanska Phenotypes for gene: BBIP1 were changed from Bardet-Biedl syndrome 18, OMIM:615995 to Bardet-Biedl syndrome 18, OMIM:615995; Bardet-Biedl syndrome 18, MONDO:0014446
Ophthalmological ciliopathies v5.18 BBIP1 Ida Ertmanska Phenotypes for gene: BBIP1 were changed from ?Bardet-Biedl syndrome 18, 615995 to Bardet-Biedl syndrome 18, OMIM:615995
Ophthalmological ciliopathies v5.17 BBIP1 Ida Ertmanska Publications for gene: BBIP1 were set to 24026985
Ophthalmological ciliopathies v5.16 BBIP1 Ida Ertmanska Classified gene: BBIP1 as Amber List (moderate evidence)
Ophthalmological ciliopathies v5.16 BBIP1 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Ophthalmological ciliopathies v5.16 BBIP1 Ida Ertmanska Gene: bbip1 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v5.15 BBIP1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: BBIP1.
Ophthalmological ciliopathies v5.15 BBIP1 Ida Ertmanska reviewed gene: BBIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24026985, 32055034, 37239474; Phenotypes: Bardet-Biedl syndrome 18, OMIM:615995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.107 BBIP1 Ida Ertmanska Phenotypes for gene: BBIP1 were changed from Genetic Retinal Degeneration Conditions to Bardet-Biedl syndrome 18, OMIM:615995
Retinal disorders v8.106 BBIP1 Ida Ertmanska Publications for gene: BBIP1 were set to PMID: 24026985 - Scheidecker et al (2014) Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet. 2014 Feb; 51(2):132-6. - Report a novel homozygous nonsense mutation, c.173T>G, p.Leu58Ter. Het in father; mother and sibling's samples not available for testing. Three functional assays confirm that this mutation has a major biological effect underlying the phenotype observed in the patient. PMID: 1908107 - publication describing function of the protein.
Retinal disorders v8.105 BBIP1 Ida Ertmanska Mode of inheritance for gene: BBIP1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.104 BBIP1 Ida Ertmanska Classified gene: BBIP1 as Amber List (moderate evidence)
Retinal disorders v8.104 BBIP1 Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v8.104 BBIP1 Ida Ertmanska Gene: bbip1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.103 BBIP1 Ida Ertmanska reviewed gene: BBIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24026985, 32055034, 37239474; Phenotypes: Bardet-Biedl syndrome 18, OMIM:615995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v7.25 BBIP1 Ida Ertmanska Phenotypes for gene: BBIP1 were changed from ?Bardet-Biedl syndrome 18, 615995 to Bardet-Biedl syndrome 18, OMIM:615995
Limb disorders v7.24 BBIP1 Ida Ertmanska Publications for gene: BBIP1 were set to 24026985
Limb disorders v7.23 BBIP1 Ida Ertmanska Classified gene: BBIP1 as Amber List (moderate evidence)
Limb disorders v7.23 BBIP1 Ida Ertmanska Added comment: Comment on list classification: 2 patients reported in literature with BBS and biallelic BBIP1 variants had polydactyly / brachydactyly. Hence, this gene can only be rated Amber on Limb disorders given available evidence.
Limb disorders v7.23 BBIP1 Ida Ertmanska Gene: bbip1 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.22 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. No phenotypic details provided.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Limb disorders v7.22 BBIP1 Ida Ertmanska reviewed gene: BBIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24026985, 32055034, 37239474; Phenotypes: Bardet-Biedl syndrome 18, OMIM:615995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bardet Biedl syndrome v2.13 BBIP1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated on 27 Mar 2026.
Bardet Biedl syndrome v2.13 BBIP1 Ida Ertmanska Phenotypes for gene: BBIP1 were changed from Bardet-Biedl syndrome 18, OMIM:615995; Bardet-Biedl syndrome 18, MONDO:0014446 to Bardet-Biedl syndrome 18, OMIM:615995; Bardet-Biedl syndrome 18, MONDO:0014446
Bardet Biedl syndrome v2.12 BBIP1 Ida Ertmanska Phenotypes for gene: BBIP1 were changed from ?Bardet-Biedl syndrome 18, 615995 to Bardet-Biedl syndrome 18, OMIM:615995; Bardet-Biedl syndrome 18, MONDO:0014446
Bardet Biedl syndrome v2.11 BBIP1 Ida Ertmanska Publications for gene: BBIP1 were set to 24026985
Bardet Biedl syndrome v2.10 BBIP1 Ida Ertmanska Classified gene: BBIP1 as Amber List (moderate evidence)
Bardet Biedl syndrome v2.10 BBIP1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic BBIP1 variants and Bardet Biedl syndrome diagnosis. Hence, this gene should be promoted to Green at the next update.
Bardet Biedl syndrome v2.10 BBIP1 Ida Ertmanska Gene: bbip1 has been classified as Amber List (Moderate Evidence).
Bardet Biedl syndrome v2.9 BBIP1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: BBIP1.
Bardet Biedl syndrome v2.9 BBIP1 Ida Ertmanska reviewed gene: BBIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24026985, 32055034, 37239474; Phenotypes: Bardet-Biedl syndrome 18, OMIM:615995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v5.54 NRDC Ida Ertmanska Classified gene: NRDC as Amber List (moderate evidence)
Optic neuropathy v5.54 NRDC Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals reported with optic atrophy and biallelic NRDC variants. Hence, this gene should be promoted to Green at the next update.
Optic neuropathy v5.54 NRDC Ida Ertmanska Gene: nrdc has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.41 NRDC Ida Ertmanska Classified gene: NRDC as Amber List (moderate evidence)
Severe microcephaly v8.41 NRDC Ida Ertmanska Added comment: Comment on list classification: There are 13 individuals reported with biallelic NRDC variants and microcephaly. While severity is not stated, this is a consistent feature in all patients. Hence, NRDC should be promoted to Green for Severe microcephaly, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Severe microcephaly v8.41 NRDC Ida Ertmanska Gene: nrdc has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.53 NRDC Ida Ertmanska gene: NRDC was added
gene: NRDC was added to Optic neuropathy. Sources: Literature
Q1_26_promote_green tags were added to gene: NRDC.
Mode of inheritance for gene: NRDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRDC were set to 41734767
Phenotypes for gene: NRDC were set to microcephaly, MONDO:0001149; neurodevelopmental disorder, MONDO:0700092; Optic neuropathy, HP:0001138
Review for gene: NRDC was set to GREEN
Added comment: PMID: 41734767 Pehlivan et al., 2026
Report of 14 individuals from nine unrelated families carrying homozygous NRDC pathogenic variants (some reported previously). Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), eye/visual abnormalities (5/7 - 3 with optic atrophy, 1 with nystagmus, and 1 case of visual inattentiveness), and abnormal brain imaging studies ranging from diffuse atrophy to lissencephaly (8/11). The identified variants include two splice, three frameshift, and three missense variants.

NRDC is not yet associated with a phenotype in OMIM (accessed 9th Mar 2026).
Sources: Literature
Severe microcephaly v8.40 NRDC Ida Ertmanska gene: NRDC was added
gene: NRDC was added to Severe microcephaly. Sources: Literature
Q1_26_promote_green tags were added to gene: NRDC.
Mode of inheritance for gene: NRDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRDC were set to 41734767
Phenotypes for gene: NRDC were set to microcephaly, MONDO:0001149; neurodevelopmental disorder, MONDO:0700092; Optic neuropathy, HP:0001138
Review for gene: NRDC was set to GREEN
Added comment: PMID: 41734767 Pehlivan et al., 2026
Report of 14 individuals from nine unrelated families carrying homozygous NRDC pathogenic variants (some reported previously). Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), eye/visual abnormalities (5/7 - 3 with optic atrophy, 1 with nystagmus, and 1 case of visual inattentiveness), and abnormal brain imaging studies ranging from diffuse atrophy to lissencephaly (8/11). The identified variants include two splice, three frameshift, and three missense variants.

NRDC is not yet associated with a phenotype in OMIM (accessed 9th Mar 2026).
Sources: Literature
Severe microcephaly v8.39 TYW1 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 sibs reported in literature with a biallelic TYW1 variant and severe microcephaly (more than -3 SD). Based on available evidence, this gene can only be rated Red on this panel.; to: Comment on list classification: There are 2 sibs reported in literature with a biallelic TYW1 variant and severe microcephaly (more than -3 SD). Mouse and zebrafish knockout models showed microcephaly, supportive of the disease association. Based on available evidence, this gene can only be rated Amber on this panel.
Severe microcephaly v8.39 TYW1 Ida Ertmanska Classified gene: TYW1 as Amber List (moderate evidence)
Severe microcephaly v8.39 TYW1 Ida Ertmanska Gene: tyw1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.38 TYW1 Ida Ertmanska changed review comment from: PMID: 34077496 Li et al., 2021
2 Chinese sibs (non-consanguineous parents) reported with comp het TYW1 variants: NM_018264: c.616C>T, p.R206C & c.1166G>A, p. R389Q.
Proband CP_012_1, male - Wechsler Preschool and Primary Scale of Intelligence IQ = 40 at 7 years old (moderate ID); head circumference at 6yrs: 47.5 cm (−3.26 SD).
CP_012_2, older sister - diagnosed with mixed type cerebral palsy (spasticity, dyskinesia), IQ <50 (moderate ID). Head circumference was 49 cm at 14yrs (−3.64 SD).
Parents confirmed heterozygous for 1 variant each. TYW1:c.616C>T - MAF in gnomADv4 = 0.0004900, including 1 homozygote. TYW1:c.1166G>A MAF in gnomAD v4 = 0.0001559, no homozygotes.

Functional evidence: TYW1 protein levels dramatically reduced in proband compared to controls; tyw1 deficiency in zebrafish resulted in ectopic neuronal cell migration in the brain and undifferentiated motor neuronal cells in the spinal cord - this was rescued by WT human and zebrafish tyw1 mRNA, but not by mRNA with patients' mutations. In addition, tyw1 knockdown zebrafish showed recuded swimming capacity. Kncokout tyw1-/- mice showed impaired motor function and reduced cognition in behavioural tests.

PMID: 38706838 Sun et al., 2024
Fucntional evidence: Study used brain organoid model and human embryonic stem cells to show that translation efficiency of UUU codon was compromised in TYW1−/− cells. Also, neuron differentiation was impaired when TYW1 was depleted.

TYW1 is not yet associated with a phenotype in OMIM, ClinGen or G2P (accessed 17 Mar 2026).
Sources: Literature; to: PMID: 34077496 Li et al., 2021
2 Chinese sibs (non-consanguineous parents) reported with comp het TYW1 variants: NM_018264: c.616C>T, p.R206C & c.1166G>A, p. R389Q.
Proband CP_012_1, male - Wechsler Preschool and Primary Scale of Intelligence IQ = 40 at 7 years old (moderate ID); head circumference at 6yrs: 47.5 cm (−3.26 SD).
CP_012_2, older sister - diagnosed with mixed type cerebral palsy (spasticity, dyskinesia), IQ <50 (moderate ID). Head circumference was 49 cm at 14yrs (−3.64 SD).
Parents confirmed heterozygous for 1 variant each. TYW1:c.616C>T - MAF in gnomADv4 = 0.0004900, including 1 homozygote. TYW1:c.1166G>A MAF in gnomAD v4 = 0.0001559, no homozygotes.

Functional evidence: TYW1 protein levels dramatically reduced in proband compared to controls; tyw1 deficiency in zebrafish resulted in ectopic neuronal cell migration in the brain and undifferentiated motor neuronal cells in the spinal cord - this was rescued by WT human and zebrafish tyw1 mRNA, but not by mRNA with patients' mutations. In addition, tyw1 knockdown zebrafish showed recuded swimming capacity. Kncokout tyw1-/- mice showed impaired motor function and reduced cognition in behavioural tests. Microcephaly and neurological manifestation were observed in both mice and zebrafish.

PMID: 38706838 Sun et al., 2024
Fucntional evidence: Study used brain organoid model and human embryonic stem cells to show that translation efficiency of UUU codon was compromised in TYW1−/− cells. Also, neuron differentiation was impaired when TYW1 was depleted.

TYW1 is not yet associated with a phenotype in OMIM, ClinGen or G2P (accessed 17 Mar 2026).
Sources: Literature
Severe microcephaly v8.38 TYW1 Ida Ertmanska changed review comment from: Comment on list classification: There are 2 sibs reported in literature with a biallelic TYW1 variant and severe microcephaly (more than -3 SD). Based on available evidence, this gene can only be rated Red.; to: Comment on list classification: There are 2 sibs reported in literature with a biallelic TYW1 variant and severe microcephaly (more than -3 SD). Based on available evidence, this gene can only be rated Red on this panel.
Severe microcephaly v8.38 TYW1 Ida Ertmanska Tag watchlist was removed from gene: TYW1.
Severe microcephaly v8.38 TYW1 Ida Ertmanska Classified gene: TYW1 as Red List (low evidence)
Severe microcephaly v8.38 TYW1 Ida Ertmanska Added comment: Comment on list classification: There are 2 sibs reported in literature with a biallelic TYW1 variant and severe microcephaly (more than -3 SD). Based on available evidence, this gene can only be rated Red.
Severe microcephaly v8.38 TYW1 Ida Ertmanska Gene: tyw1 has been classified as Red List (Low Evidence).
Severe microcephaly v8.37 TYW1 Ida Ertmanska gene: TYW1 was added
gene: TYW1 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: TYW1.
Mode of inheritance for gene: TYW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TYW1 were set to 34077496
Phenotypes for gene: TYW1 were set to cerebral palsy, MONDO:0006497; microcephaly, MONDO:0001149
Review for gene: TYW1 was set to AMBER
Added comment: PMID: 34077496 Li et al., 2021
2 Chinese sibs (non-consanguineous parents) reported with comp het TYW1 variants: NM_018264: c.616C>T, p.R206C & c.1166G>A, p. R389Q.
Proband CP_012_1, male - Wechsler Preschool and Primary Scale of Intelligence IQ = 40 at 7 years old (moderate ID); head circumference at 6yrs: 47.5 cm (−3.26 SD).
CP_012_2, older sister - diagnosed with mixed type cerebral palsy (spasticity, dyskinesia), IQ <50 (moderate ID). Head circumference was 49 cm at 14yrs (−3.64 SD).
Parents confirmed heterozygous for 1 variant each. TYW1:c.616C>T - MAF in gnomADv4 = 0.0004900, including 1 homozygote. TYW1:c.1166G>A MAF in gnomAD v4 = 0.0001559, no homozygotes.

Functional evidence: TYW1 protein levels dramatically reduced in proband compared to controls; tyw1 deficiency in zebrafish resulted in ectopic neuronal cell migration in the brain and undifferentiated motor neuronal cells in the spinal cord - this was rescued by WT human and zebrafish tyw1 mRNA, but not by mRNA with patients' mutations. In addition, tyw1 knockdown zebrafish showed recuded swimming capacity. Kncokout tyw1-/- mice showed impaired motor function and reduced cognition in behavioural tests.

PMID: 38706838 Sun et al., 2024
Fucntional evidence: Study used brain organoid model and human embryonic stem cells to show that translation efficiency of UUU codon was compromised in TYW1−/− cells. Also, neuron differentiation was impaired when TYW1 was depleted.

TYW1 is not yet associated with a phenotype in OMIM, ClinGen or G2P (accessed 17 Mar 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.44 TYW1 Ida Ertmanska changed review comment from: Comment on list classification: There is one pedigree reported in literature linking biallelic TYW1 variants to cerebral palsy with intellectual disability. There is also good functional evidence in zebrafish, mouse, and human brain organoids supporting TYW1 role in motor function and cognition. Based on available evidence, this gene can only be rated Amber for now.; to: Comment on list classification: There is one pedigree reported in literature linking biallelic TYW1 variants to cerebral palsy with intellectual disability. There is also good functional evidence in zebrafish, mouse, and human brain organoids supporting TYW1 role in motor function and cognition. Based on available evidence, this gene can only be rated Amber for now. The gene should be tagged for expert review if sufficient evidence arises to promote to green, to get views if HSP is the right panel for cerebral palsy cases.
Intestinal failure or congenital diarrhoea v3.10 PSMB10 Ida Ertmanska edited their review of gene: PSMB10: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intestinal failure or congenital diarrhoea v3.10 PSMB10 Ida Ertmanska Classified gene: PSMB10 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v3.10 PSMB10 Ida Ertmanska Added comment: Comment on list classification: There are at least 6 individuals reported in literature with monoallelic PSMB10 variants and SCID-Omenn syndrome, which includes congential diarrhea. Hence, this gene should be promoted to Green at the next update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Intestinal failure or congenital diarrhoea v3.10 PSMB10 Ida Ertmanska Gene: psmb10 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v3.9 PSMB10 Ida Ertmanska Mode of inheritance for gene: PSMB10 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v2.39 PSMB10 Ida Ertmanska Classified gene: PSMB10 as Amber List (moderate evidence)
Autoinflammatory disorders v2.39 PSMB10 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 cases reported with both mono- and bi- allelic PSMB10 variants - presenting with a proteasome-associated autoinflammatory syndrome (with or without recurrent infections and chronic diarrhea). Hence, the MOI should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Autoinflammatory disorders v2.39 PSMB10 Ida Ertmanska Gene: psmb10 has been classified as Amber List (Moderate Evidence).
Intestinal failure or congenital diarrhoea v3.8 PSMB10 Ida Ertmanska gene: PSMB10 was added
gene: PSMB10 was added to Intestinal failure or congenital diarrhoea. Sources: Literature
Q1_26_promote_green tags were added to gene: PSMB10.
Mode of inheritance for gene: PSMB10 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PSMB10 were set to 31783057; 36250618; 37600812; 38503300; 39734035
Phenotypes for gene: PSMB10 were set to Immunodeficiency 121 with autoinflammation, OMIM:620807; Proteasome-associated autoinflammatory syndrome 5, OMIM:619175
Review for gene: PSMB10 was set to GREEN
Added comment: MONOALLELIC CASES:
PMID: 36250618 Hebert et al., 2022
Patient 1 - severe combined immunodeficiency (SCID), ectodermal dysplasia, alopecia, hypodontia and anonychia; het de novo PSMB10 NM_002801.3: c.601G>A p.(Gly201Arg) variant.

PMID: 38503300 van der Made et al., 2024
Identified de novo PSMB10 mutations in 6 infants with SCID-Omenn syndrome. The syndromic presentation includes severe combined immunodeficiency (SCID), as well as diarrhea (6/6), alopecia (4/5), and desquamating erythematous rash (6/6). Reported variants: PSMB10: c.166G>C, p.Asp56His and c.601G>A/c.601G>C, p.Gly201Arg.

PMID: 39734035 Kuehn et al., 2025
Case report: white female with SCID, failure to thrive, diarrhea, and pruritic rash - symptom onset at 5-9 months. Trio WES identified a de novo PSMB10 variant in the proband: c.601G>A, p.Gly201Arg.

https://doi.org/10.70962/jhi.20250096 Fournier et al., 2025
Report of 3 patients with WES detected de novo heterozygous PSMB10 variants: c.614A>C p.Asp205Ala for PI and c.623C>T p.Ser208Phe for PII and PIII. Presentation: combined immunodeficiency (3/3), generalized erythroderma with desquamation (1/3), chronic diarrhea (2/3), severe liver disease (2/3).
Functional evidence: PSMB10 constructs were expressed in HEK293T cells prior to SDS-PAGE/western blotting analysis. The p.Asp205Ala and p.Ser208Phe PSMB10 variants were shown to impair proteasome assembly and exert dominant-negative effects on PSMB9 expression.

BIALLELIC CASES:
PMID: 31783057 Sarrabay et al., 2020
3yo girl with a proteasome-associated autoinflammatory syndrome, homozygous for a PSMB10 c.41T>C, p.Phe14Ser variant. She presented with failure to thrive, cutaneous rash, and hepatosplenomegaly. No immunodeficiency.

PMID: 37600812 Papendorf et al., 2023
Three unrelated Brazilian patients present with four novel PSMB10 variants. All share the p.Phe14del variant plus a different novel variant: p.Gly167Asp, p.Cys83Leufs*123, and c.710+1G>C. All 3 patients had skin lesions, recurrent fevers, failure to thrive; microcytic anemia ascertained in 2/3.

PSMB10 is now associated with AD Immunodeficiency 121 with autoinflammation, MIM:620807 & AR Proteasome-associated autoinflammatory syndrome 5, MIM:619175 (OMIM accessed 10th Mar 2026).
Sources: Literature
Autoinflammatory disorders v2.38 PSMB10 Ida Ertmanska gene: PSMB10 was added
gene: PSMB10 was added to Autoinflammatory disorders. Sources: Literature
Q1_26_promote_green tags were added to gene: PSMB10.
Mode of inheritance for gene: PSMB10 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PSMB10 were set to 31783057; 36250618; 37600812; 38503300; 39734035
Phenotypes for gene: PSMB10 were set to Immunodeficiency 121 with autoinflammation, OMIM:620807; Proteasome-associated autoinflammatory syndrome 5, OMIM:619175
Review for gene: PSMB10 was set to GREEN
Added comment: MONOALLELIC CASES:
PMID: 36250618 Hebert et al., 2022
Patient 1 - severe combined immunodeficiency (SCID), ectodermal dysplasia, alopecia, hypodontia and anonychia; het de novo PSMB10 NM_002801.3: c.601G>A p.(Gly201Arg) variant.

PMID: 38503300 van der Made et al., 2024
Identified de novo PSMB10 mutations in 6 infants with SCID-Omenn syndrome. The syndromic presentation includes severe combined immunodeficiency (SCID), as well as diarrhea (6/6), alopecia (4/5), and desquamating erythematous rash (6/6). Reported variants: PSMB10: c.166G>C, p.Asp56His and c.601G>A/c.601G>C, p.Gly201Arg.

PMID: 39734035 Kuehn et al., 2025
Case report: white female with SCID, failure to thrive, diarrhea, and pruritic rash - symptom onset at 5-9 months. Trio WES identified a de novo PSMB10 variant in the proband: c.601G>A, p.Gly201Arg.

https://doi.org/10.70962/jhi.20250096 Fournier et al., 2025
Report of 3 patients with WES detected de novo heterozygous PSMB10 variants: c.614A>C p.Asp205Ala for PI and c.623C>T p.Ser208Phe for PII and PIII. Presentation: combined immunodeficiency (3/3), generalized erythroderma with desquamation (1/3), chronic diarrhea (2/3), severe liver disease (2/3).
Functional evidence: PSMB10 constructs were expressed in HEK293T cells prior to SDS-PAGE/western blotting analysis. The p.Asp205Ala and p.Ser208Phe PSMB10 variants were shown to impair proteasome assembly and exert dominant-negative effects on PSMB9 expression.

BIALLELIC CASES:
PMID: 31783057 Sarrabay et al., 2020
3yo girl with a proteasome-associated autoinflammatory syndrome, homozygous for a PSMB10 c.41T>C, p.Phe14Ser variant. She presented with failure to thrive, cutaneous rash, and hepatosplenomegaly. No immunodeficiency.

PMID: 37600812 Papendorf et al., 2023
Three unrelated Brazilian patients present with four novel PSMB10 variants. All share the p.Phe14del variant plus a different novel variant: p.Gly167Asp, p.Cys83Leufs*123, and c.710+1G>C. All 3 patients had skin lesions, recurrent fevers, failure to thrive; microcytic anemia ascertained in 2/3.

PSMB10 is now associated with AD Immunodeficiency 121 with autoinflammation, MIM:620807 & AR Proteasome-associated autoinflammatory syndrome 5, MIM:619175 (OMIM accessed 10th Mar 2026).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v8.88 PSMB10 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are now more than 3 cases reported with both mono- and bi- allelic PSMB10 variants - presenting with a proteasome-associated autoinflammatory syndrome (with or without recurrent infections and chronic diarrhea). Hence, the MOI should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are now more than 3 cases reported with both mono- and bi- allelic PSMB10 variants - presenting with a proteasome-associated autoinflammatory syndrome (with or without recurrent infections and chronic diarrhea). Hence, the MOI should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ectodermal dysplasia v4.27 PSMB10 Ida Ertmanska Classified gene: PSMB10 as Red List (low evidence)
Ectodermal dysplasia v4.27 PSMB10 Ida Ertmanska Gene: psmb10 has been classified as Red List (Low Evidence).
Ectodermal dysplasia v4.26 PSMB10 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: PSMB10.
Ectodermal dysplasia v4.26 PSMB10 Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic variants in PSMB10 have been reported to cause ectodermal dysplasia (alopecia, hypodontia, anonychia) in at least 5 unrelated individuals. Biallelic PSMB10 variants have not been linked to ectodermal dysplasia. Hence, the gene should be promoted to Green at the next update, with MOI MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on list classification: Monoallelic variants in PSMB10 have been reported to cause ectodermal dysplasia (alopecia, hypodontia, anonychia) in at least 5 unrelated individuals. However, inclusion criteria for this panel state at least two structures need to be affected (alopecia only is not sufficient. Biallelic PSMB10 variants have not been linked to ectodermal dysplasia. Hence, the gene can only be rated Red with current evidence, as only 1 case meets inclusion criteria (PMID: 36250618).
Ectodermal dysplasia v4.26 PSMB10 Ida Ertmanska edited their review of gene: PSMB10: Changed rating: RED
Primary lymphoedema v4.23 PLXNB2 Ida Ertmanska Tag watchlist tag was added to gene: PLXNB2.
Primary lymphoedema v4.23 PLXNB2 Ida Ertmanska Phenotypes for gene: PLXNB2 were changed from amelogenesis imperfecta; hearing loss; intellectual disability; lymphoedema to amelogenesis imperfecta, MONDO:0019507; sensorineural hearing loss disorder, MONDO:0020678; intellectual disability, MONDO:0001071
Primary lymphoedema v4.22 PLXNB2 Ida Ertmanska Classified gene: PLXNB2 as Amber List (moderate evidence)
Primary lymphoedema v4.22 PLXNB2 Ida Ertmanska Added comment: Comment on list classification: There are 3 individuals reported in literature with biallelic PLXNB2 variants and primary lymphoedema. Hence, this gene can only be rated Amber with the current evidence.
Primary lymphoedema v4.22 PLXNB2 Ida Ertmanska Gene: plxnb2 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v4.21 PLXNB2 Ida Ertmanska reviewed gene: PLXNB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 38458752; Phenotypes: amelogenesis imperfecta, MONDO:0019507, sensorineural hearing loss disorder, MONDO:0020678, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic diabetes v3.17 APPL1 Arina Puzriakova Tag Q1_26_NHS_review tag was added to gene: APPL1.
Ectodermal dysplasia v4.26 PSMB10 Arina Puzriakova Phenotypes for gene: PSMB10 were changed from Immunodeficiency 121 with autoinflammation, OMIM:620807; Proteasome-associated autoinflammatory syndrome 5, OMIM:619175 to Immunodeficiency 121 with autoinflammation, OMIM:620807
Monogenic hearing loss v5.61 SLC19A2 Ida Ertmanska Classified gene: SLC19A2 as Amber List (moderate evidence)
Monogenic hearing loss v5.61 SLC19A2 Ida Ertmanska Added comment: Comment on list classification: There are numerous patients reported with Thiamine-Responsive Megaloblastic Anemia (TRMA) syndrome, caused by biallelic variants in the SLC19A2 gene, which typically presents with a triad of megaloblastic anemia, diabetes mellitus, and sensorineural hearing loss. Hearing loss can be the main presenting feature. Hence, this gene should be promoted to Green for monogenic hearing loss, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Monogenic hearing loss v5.61 SLC19A2 Ida Ertmanska Gene: slc19a2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v5.60 SLC19A2 Ida Ertmanska Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270 to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270; thiamine-responsive megaloblastic anemia syndrome, MONDO:0009575
Monogenic hearing loss v5.59 SLC19A2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: SLC19A2.
Monogenic hearing loss v5.59 SLC19A2 Ida Ertmanska Phenotypes for gene: SLC19A2 were changed from to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270
Monogenic hearing loss v5.58 SLC19A2 Ida Ertmanska Publications for gene: SLC19A2 were set to
Monogenic hearing loss v5.57 SLC19A2 Ida Ertmanska reviewed gene: SLC19A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38037112, 40220483; Phenotypes: Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic diabetes v3.17 SLC19A2 Ida Ertmanska Phenotypes for gene: SLC19A2 were changed from Thiamine-responsive megaloblastic anemia syndrome; MEGALOBLASTIC ANEMIA, THIAMINE-RESPONSIVE, WITH DIABETES MELLITUS AND SENSORINEURAL DEAFNESS ROGERS SYNDROME to Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270; diabetes mellitus, MONDO:0005015
Monogenic diabetes v3.16 SLC19A2 Ida Ertmanska Publications for gene: SLC19A2 were set to 26549656; 26839896
Monogenic diabetes v3.15 SLC19A2 Ida Ertmanska Tag curated_removed was removed from gene: SLC19A2.
Tag Q1_26_promote_green tag was added to gene: SLC19A2.
Tag Q1_26_NHS_review tag was added to gene: SLC19A2.
Monogenic diabetes v3.15 SLC19A2 Ida Ertmanska Classified gene: SLC19A2 as Amber List (moderate evidence)
Monogenic diabetes v3.15 SLC19A2 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Kevin Colclough, patients with biallelic SLC19A2 variants are often diagnosed with diabetes after 9 months of age, which is in scope of this panel. Hence, SLC19A2 should be promoted to Green for Monogenic diabetes at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Monogenic diabetes v3.15 SLC19A2 Ida Ertmanska Gene: slc19a2 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.14 SLC19A2 Ida Ertmanska reviewed gene: SLC19A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thiamine-responsive megaloblastic anemia syndrome, OMIM:249270, diabetes mellitus, MONDO:0005015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.184 FGFR1 Ida Ertmanska commented on gene: FGFR1: Comment on mode of inheritance: There are more than 3 individuals reported with biallelic FGFR1 variants and Hypogonadotropic hypogonadism. Individuals consistently presented with ectrodactyly, CC agenesis, and holoprosencephaly - disease features relevant to Fetal anomalies, as these would be detected on a prenatal scan. Hence, MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Fetal anomalies v6.184 FGFR1 Ida Ertmanska Phenotypes for gene: FGFR1 were changed from IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; OSTEOGLOPHONIC DYSPLASIA; PFEIFFER SYNDROME; KALLMANN SYNDROME TYPE 2; Hartsfield syndrome; Encephalocraniocutaneous lipomatosis to Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465
Fetal anomalies v6.183 FGFR1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR1.
Fetal anomalies v6.183 FGFR1 Ida Ertmanska changed review comment from: PMID: 27055092 Mazen et al., 2016
Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease.

PMID: 25394172 Villanueva et al., 2015
7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous.
P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members.
In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance.

PMID: 23812909 Simonis et al., 2013
6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing.

PMID: 23154428 Jarzabek et al., 2012
5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations.
P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).

FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026).; to: PMID: 27055092 Mazen et al., 2016
Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease.

PMID: 25394172 Villanueva et al., 2015
7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous.
P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members.
In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance.

PMID: 23812909 Simonis et al., 2013
6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). Fetal case (patient 7) had no FGFR1 mutation detected.


PMID: 23154428 Jarzabek et al., 2012
5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations.
P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).

FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026).
Fetal anomalies v6.183 FGFR1 Ida Ertmanska reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23154428, 23812909, 25394172, 27055092; Phenotypes: Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950, Hartsfield syndrome, OMIM:615465; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Differences in sex development v4.17 FGFR1 Ida Ertmanska Phenotypes for gene: FGFR1 were changed from Hypogonadotropic hypogonadism 2 with out without anosmia to Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465
Differences in sex development v4.16 FGFR1 Ida Ertmanska Publications for gene: FGFR1 were set to (PMID: 41108094; 34589657; 32853167)
Differences in sex development v4.15 FGFR1 Ida Ertmanska Classified gene: FGFR1 as Red List (low evidence)
Differences in sex development v4.15 FGFR1 Ida Ertmanska Added comment: Comment on list classification: There is only one individual reported in literature with a biallelic FGFR1 variant and a diagnosed difference in sex development (ambiguous genitalia - PMID: 27055092). Other reported cases are more aligned with diagnosis of Hypogonadotropic hypogonadism (FGFR1 is already Green on that panel). Hence, this gene can only be rated Red on Differences in sex development given the evidence available.
Differences in sex development v4.15 FGFR1 Ida Ertmanska Gene: fgfr1 has been classified as Red List (Low Evidence).
Differences in sex development v4.14 FGFR1 Ida Ertmanska edited their review of gene: FGFR1: Changed rating: RED; Changed publications to: 23154428, 23812909, 25394172, 27055092, 32853167, 34589657, 41108094; Changed phenotypes to: Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950, Hartsfield syndrome, OMIM:615465
Differences in sex development v4.14 FGFR1 Ida Ertmanska commented on gene: FGFR1
Optic neuropathy v5.52 INTS11 Ida Ertmanska Classified gene: INTS11 as Amber List (moderate evidence)
Optic neuropathy v5.52 INTS11 Ida Ertmanska Added comment: Comment on list classification: There are 5 individuals from 4 families reported with biallelic INTS11 variants and optic atrophy. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Optic neuropathy v5.52 INTS11 Ida Ertmanska Gene: ints11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.103 INTS11 Ida Ertmanska Phenotypes for gene: INTS11 were changed from Retinal dystrophy to Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, OMIM:620428
Retinal disorders v8.102 INTS11 Ida Ertmanska Publications for gene: INTS11 were set to PMID: 41810893
Optic neuropathy v5.51 INTS11 Ida Ertmanska gene: INTS11 was added
gene: INTS11 was added to Optic neuropathy. Sources: Literature
Q1_26_promote_green tags were added to gene: INTS11.
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to 37054711; 41810893
Phenotypes for gene: INTS11 were set to Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, OMIM:620428
Review for gene: INTS11 was set to GREEN
Added comment: PMID: 41810893 Lin et al., 2026
Report of four affected individuals with biallelic INTS11 variants from two unrelated families.
Retinal phenotype: mild optic disc pallor; severe thinning of the inner retinal layers with preserved outer retinal layers, generalized rod and cone system dysfunction localized to the inner retina or post-phototransduction.
Individuals A-1 and A-2 were compound heterozygous for missense INTS11 variants c.34G > A; p.(Gly12Ser) and c.1219C > T; p.(Pro407Ser), as previously described. Novel compound het INTS11 variants (c.721G > A, p.(Ala241Thr) and c.983T > A, p.(Leu328Gln)) were identified in individuals B-3 and B-4.

PMID: 37054711 Tepe et al., 2023
15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. 5 patients were noted to have optic atrophy, and 2 had retinal dystrophy. Less specific ocular findings included myopia, astigmatism, and strabismus.
Sources: Literature
Retinal disorders v8.101 INTS11 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: INTS11.
Tag Q1_26_NHS_review tag was added to gene: INTS11.
Retinal disorders v8.101 INTS11 Ida Ertmanska Classified gene: INTS11 as Amber List (moderate evidence)
Retinal disorders v8.101 INTS11 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated families with individuals harbouring biallelic INTS11 variants affected by retinal disease. Hence, this gene should be updated to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Retinal disorders v8.101 INTS11 Ida Ertmanska Gene: ints11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.100 INTS11 Ida Ertmanska changed review comment from: PMID: 41810893 Lin et al., 2026
Report of four affected individuals with biallelic INTS11 variants from two unrelated families.
Retinal phenotype: mild optic disc pallor; severe thinning of the inner retinal layers with preserved outer retinal layers, generalized rod and cone system dysfunction localized to the inner retina or post-phototransduction.
Individuals A-1 and A-2 were compound heterozygous for missense INTS11 variants c.34G > A; p.(Gly12Ser) and c.1219C > T; p.(Pro407Ser), as previously described. Novel compound het INTS11 variants (c.721G > A, p.(Ala241Thr) and c.983T > A, p.(Leu328Gln)) were identified in individuals B-3 and B-4.

PMID: 37054711 Tepe et al., 2023
15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. 5 patients were noted to have optic atrophy, and 2 had retinal dystrophy.; to: PMID: 41810893 Lin et al., 2026
Report of four affected individuals with biallelic INTS11 variants from two unrelated families.
Retinal phenotype: mild optic disc pallor; severe thinning of the inner retinal layers with preserved outer retinal layers, generalized rod and cone system dysfunction localized to the inner retina or post-phototransduction.
Individuals A-1 and A-2 were compound heterozygous for missense INTS11 variants c.34G > A; p.(Gly12Ser) and c.1219C > T; p.(Pro407Ser), as previously described. Novel compound het INTS11 variants (c.721G > A, p.(Ala241Thr) and c.983T > A, p.(Leu328Gln)) were identified in individuals B-3 and B-4.

PMID: 37054711 Tepe et al., 2023
15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. 5 patients were noted to have optic atrophy, and 2 had retinal dystrophy. Less specific ocular findings included myopia, astigmatism, and strabismus.
Retinal disorders v8.100 INTS11 Ida Ertmanska reviewed gene: INTS11: Rating: GREEN; Mode of pathogenicity: None; Publications: 37054711, 41810893; Phenotypes: Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, OMIM:620428; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v5.50 FSD1L Ida Ertmanska Classified gene: FSD1L as Amber List (moderate evidence)
Optic neuropathy v5.50 FSD1L Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature with biallelic FSD1L variants and optic nerve atrophy/hypoplasia. Hence, this gene can be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Optic neuropathy v5.50 FSD1L Ida Ertmanska Gene: fsd1l has been classified as Amber List (Moderate Evidence).
Optic neuropathy v5.49 FSD1L Ida Ertmanska gene: FSD1L was added
gene: FSD1L was added to Optic neuropathy. Sources: Literature
Q1_26_promote_green tags were added to gene: FSD1L.
Mode of inheritance for gene: FSD1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FSD1L were set to 41720098; 41720099
Phenotypes for gene: FSD1L were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: FSD1L was set to GREEN
Added comment: PMID: 41720098 Serpieri et al., 2026
Report of eleven individuals (including five fetuses) from six unrelated families harbouring biallelic FSD1L variants. Seq method: exome sequencing. Consanguinity was confirmed in 4/6 families, and suspected in the fifth.
Phenotype spectrum: severe intellectual disability (5/5 assessed from 3 families), epilepsy (5 individuals from 3 families), severe hydrocephalus (3 families), vision deficit due to optic nerve hypoplasia/atrophy (3 families), spastic tetraparesis (2 families) corpus callosum hypoplasia/agenesis on MRI (5/5 families assessed),

Variants detected - largely nonsense type:
Family A - homozygous c.409T>G (p.Leu137Val);
Family B - 3 affected fetuses homozygous for c.1411C>T (p.Gln471Ter);
Family C - sibs compound het for c.1228T>G (p.Phe410Val) and c.1251_1252insTAA (p.Thr418Ter);
Family D - affected individuals (1 fetal case) homozygous for c.1366G>C (p.Asp456His) - shown to impact splicing (r.406_442del), resulting in predicted p.Ser136LeufsTer19 change;
Family E - affected child with homozygous c.835C>T (p.Arg279Ter) change;
Family F - fetus homozygous for c.1260G>A (p.Trp420Ter);

Functional evidence: Fsd1l depletion in mouse embryos recapitulated the ventricular dilation observed in affected fetuses.

PMID 41720099 Lin et al., 2026
Report of 6 affected individuals from 4 families with retinitis pigmentosa. One individual underwent a full neurological evaluation, including brain neuroimaging, which revealed no evidence of central nervous system involvement.
FSD1L variants detected:
Family A: 2 sibs compound het for c.1049G>A (p.Arg350Gln) and c.1428del (p.Phe476Leufs∗22)
Family B: individual comp het for c.488G>A (p.Arg163His), c.488G>A & c.745C>T (p.Arg249∗)
Family C: 2 sibs compound het for c.488G>A (p.Arg163His) & c.226_227del (p.Ser77Argfs∗4)
Family D: individual compound het for c.1037_1038delinsT (p.Pro346Leufs∗8) and c.1025+624_1025+649del
Sibs from family A had mild neurological involvement (mild ID, spastic diplegia in one sibling).
Authors note that "specific combination and functional severity of the two alleles likely determines the clinical outcome", with non-LoF variants causing a milder effect (e.g., isolated retinal phenotype).

FSD1L is not yet associated with a phenotype in OMIM or Gene2Phenotype.
Sources: Literature
Fetal anomalies v6.183 FSD1L Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: FSD1L.
Fetal anomalies v6.183 FSD1L Ida Ertmanska Classified gene: FSD1L as Amber List (moderate evidence)
Fetal anomalies v6.183 FSD1L Ida Ertmanska Added comment: Comment on list classification: There are at least three unrelated fetal cases reported in literature with biallelic FSD1L variants. Based on available evidence, FSD1L should be promoted to Green at the next update.
Fetal anomalies v6.183 FSD1L Ida Ertmanska Gene: fsd1l has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.37 PTPN1 Ida Ertmanska changed review comment from: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. Several patients responded well to immune suppression treatment. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.; to: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. Several patients responded well to immune suppression treatment. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Autoinflammatory disorders v2.37 PTPN1 Ida Ertmanska changed review comment from: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. Several patients responded to immune suppression treatment. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.; to: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. Several patients responded well to immune suppression treatment. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Autoinflammatory disorders v2.37 PTPN1 Ida Ertmanska Classified gene: PTPN1 as Amber List (moderate evidence)
Autoinflammatory disorders v2.37 PTPN1 Ida Ertmanska Added comment: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. Several patients responded to immune suppression treatment. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Autoinflammatory disorders v2.37 PTPN1 Ida Ertmanska Gene: ptpn1 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v2.36 PTPN1 Ida Ertmanska gene: PTPN1 was added
gene: PTPN1 was added to Autoinflammatory disorders. Sources: Literature
Q1_26_promote_green, Q1_26_expert_review tags were added to gene: PTPN1.
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 10066179; 39986310
Phenotypes for gene: PTPN1 were set to Encephalopathy, HP:0001298; dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Review for gene: PTPN1 was set to GREEN
Added comment: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.

Brain MRI findings: Cerebral atrophy (9/12 patients), non-specific white matter changes (8/12), intracranial calcification (2/12). In 8 cases, the brain abnormalities resolved.Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

Functional evidence: PMID: 10066179 Elchebly et al., 1999 - Ptpn1 knock-out (KO) mice are both viable and healthy, demonstrating enhanced insulin sensitivity and resistance to metabolic syndrome.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Ichthyosis and erythrokeratoderma v4.12 MPDU1 Ida Ertmanska Phenotypes for gene: MPDU1 were changed from Ichthyosis to Congenital disorder of glycosylation, type If, OMIM:609180; MPDU1-congenital disorder of glycosylation, MONDO:0012211; ichthyosis, MONDO:0019269
Ichthyosis and erythrokeratoderma v4.11 MPDU1 Ida Ertmanska Publications for gene: MPDU1 were set to 11733556
Ichthyosis and erythrokeratoderma v4.10 MPDU1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: MPDU1.
Tag Q1_26_NHS_review tag was added to gene: MPDU1.
Ichthyosis and erythrokeratoderma v4.10 MPDU1 Ida Ertmanska Classified gene: MPDU1 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v4.10 MPDU1 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic MPDU1 variants and syndromic ichthyosis / erythrokeratoderma. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Ichthyosis and erythrokeratoderma v4.10 MPDU1 Ida Ertmanska Gene: mpdu1 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v4.9 MPDU1 Ida Ertmanska reviewed gene: MPDU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11733564, 29721919, 35279850, 36755425, 38831602; Phenotypes: Congenital disorder of glycosylation, type If, OMIM:609180; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v4.3 RHOBTB2 Ida Ertmanska Publications for gene: RHOBTB2 were set to 33504645
Paroxysmal central nervous system disorders v4.2 RHOBTB2 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: RHOBTB2.
Paroxysmal central nervous system disorders v4.2 RHOBTB2 Ida Ertmanska commented on gene: RHOBTB2: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with movement disorders, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Intellectual disability v9.353 RHOBTB2 Ida Ertmanska changed review comment from: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with epilepsy, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.; to: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with syndromic ID/DD, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Paroxysmal central nervous system disorders v4.2 RHOBTB2 Ida Ertmanska reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37165955; Phenotypes: Developmental and epileptic encephalopathy 64, OMIM:618004, developmental and epileptic encephalopathy, 64, MONDO:0033373; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.353 RHOBTB2 Ida Ertmanska Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508
Intellectual disability v9.352 RHOBTB2 Ida Ertmanska Phenotypes for gene: RHOBTB2 were changed from Epileptic encephalopathy, early infantile, 64, 618004; Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly to Developmental and epileptic encephalopathy 64, OMIM:618004; developmental and epileptic encephalopathy, 64, MONDO:0033373
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska changed review comment from: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.; to: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (8/10), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.
Early onset or syndromic epilepsy v8.170 RHOBTB2 Ida Ertmanska changed review comment from: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.; to: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (8/10), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: RHOBTB2.
Early onset or syndromic epilepsy v8.170 RHOBTB2 Ida Ertmanska changed review comment from: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants.; to: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska changed review comment from: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants.; to: PMID: 37165955 Langhammer et al., 2023
Report of 13 individuals from 9 families with bilallelic loss of function RHOBTB2 variants with a variable neurodevelopmental disorder including intellectual disability and seizures. 7/9 families were confirmed as consanguineous. Phenotypic spectrum: DD/ID ranging from learning difficulties to moderate ID (11/13 individuals), epilepsy, seizures, and/or abnormal EEG (11/13), microcephaly (5/9 individuals assessed, 2 with more than -3 SD), ataxia & gait disturbances (7/13), MRI anomalies seen in 2 patients. Study also reported 6 new cases with de novo heterozygous missense variants in RHOBTB2.
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska commented on gene: RHOBTB2: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with epilepsy, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Intellectual disability v9.351 RHOBTB2 Ida Ertmanska reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37165955; Phenotypes: Developmental and epileptic encephalopathy 64, OMIM:618004, developmental and epileptic encephalopathy, 64, MONDO:0033373; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.170 RHOBTB2 Ida Ertmanska edited their review of gene: RHOBTB2: Changed phenotypes to: Developmental and epileptic encephalopathy 64, OMIM:618004, developmental and epileptic encephalopathy, 64, MONDO:0033373
Early onset or syndromic epilepsy v8.170 RHOBTB2 Ida Ertmanska commented on gene: RHOBTB2: Comment on mode of inheritance: As there are now more than 3 individuals reported with both mono- and bi-allelic variants in RHOBTB2 with epilepsy, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Early onset or syndromic epilepsy v8.170 RHOBTB2 Ida Ertmanska Phenotypes for gene: RHOBTB2 were changed from Epileptic encephalopathy, early infantile, 64 618004 to Developmental and epileptic encephalopathy 64, OMIM:618004; developmental and epileptic encephalopathy, 64, MONDO:0033373
Early onset or syndromic epilepsy v8.169 RHOBTB2 Ida Ertmanska Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508
Early onset or syndromic epilepsy v8.168 RHOBTB2 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: RHOBTB2.
Early onset or syndromic epilepsy v8.168 RHOBTB2 Ida Ertmanska reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37165955; Phenotypes: Developmental and epileptic encephalopathy 64, OMIM:618004; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v6.182 PPP2R1A Arina Puzriakova Phenotypes for gene: PPP2R1A were changed from INTELLECTUAL DISABILITY to Houge-Janssens syndrome 2, OMIM:616362
Arthrogryposis v9.32 DDR2 Eleanor Williams Phenotypes for gene: DDR2 were changed from to Warburg-Cinotti syndrome, OMIM:618175
Childhood onset hereditary spastic paraplegia v8.44 PTPN1 Ida Ertmanska Classified gene: PTPN1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.44 PTPN1 Ida Ertmanska Added comment: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Childhood onset hereditary spastic paraplegia v8.44 PTPN1 Ida Ertmanska Gene: ptpn1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.43 PTPN1 Ida Ertmanska gene: PTPN1 was added
gene: PTPN1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q1_26_promote_green, Q1_26_expert_review tags were added to gene: PTPN1.
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 10066179; 39986310
Phenotypes for gene: PTPN1 were set to Encephalopathy, HP:0001298; dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Review for gene: PTPN1 was set to GREEN
Added comment: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.

Brain MRI findings: Cerebral atrophy (9/12 patients), non-specific white matter changes (8/12), intracranial calcification (2/12). In 8 cases, the brain abnormalities resolved.Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

Functional evidence: PMID: 10066179 Elchebly et al., 1999 - Ptpn1 knock-out (KO) mice are both viable and healthy, demonstrating enhanced insulin sensitivity and resistance to metabolic syndrome.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Intellectual disability v9.351 PTPN1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: PTPN1.
White matter disorders and cerebral calcification - narrow panel v7.24 PTPN1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: PTPN1.
Childhood onset dystonia, chorea or related movement disorder v7.20 PTPN1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: PTPN1.
Childhood onset dystonia, chorea or related movement disorder v7.20 PTPN1 Ida Ertmanska Classified gene: PTPN1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v7.20 PTPN1 Ida Ertmanska Added comment: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Childhood onset dystonia, chorea or related movement disorder v7.20 PTPN1 Ida Ertmanska Gene: ptpn1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.19 PTPN1 Ida Ertmanska gene: PTPN1 was added
gene: PTPN1 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Q1_26_promote_green tags were added to gene: PTPN1.
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 10066179; 39986310
Phenotypes for gene: PTPN1 were set to Encephalopathy, HP:0001298; dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Review for gene: PTPN1 was set to GREEN
Added comment: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.

Brain MRI findings: Cerebral atrophy (9/12 patients), non-specific white matter changes (8/12), intracranial calcification (2/12). In 8 cases, the brain abnormalities resolved.Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

Functional evidence: PMID: 10066179 Elchebly et al., 1999 - Ptpn1 knock-out (KO) mice are both viable and healthy, demonstrating enhanced insulin sensitivity and resistance to metabolic syndrome.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v7.24 PTPN1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: PTPN1.
White matter disorders and cerebral calcification - narrow panel v7.24 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Added comment: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.; Changed rating: GREEN
Intellectual disability v9.351 PTPN1 Ida Ertmanska changed review comment from: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.; to: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Intellectual disability v9.351 PTPN1 Ida Ertmanska commented on gene: PTPN1: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Intellectual disability v9.351 PTPN1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: PTPN1.
Intellectual disability v9.351 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed rating: GREEN
Intellectual disability v9.351 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from Encephalopathy, HP:0001298 to Encephalopathy, HP:0001298; dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Intellectual disability v9.350 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed phenotypes to: Encephalopathy, HP:0001298, dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
White matter disorders and cerebral calcification - narrow panel v7.24 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed phenotypes to: Encephalopathy, HP:0001298, dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
White matter disorders and cerebral calcification - narrow panel v7.24 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from Encephalopathy, HP:0001298 to Encephalopathy, HP:0001298; dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Intellectual disability v9.350 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed publications to: 10066179, 39986310; Changed phenotypes to: Encephalopathy, HP:0001298
Intellectual disability v9.350 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from to Encephalopathy, HP:0001298
White matter disorders and cerebral calcification - narrow panel v7.23 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from to Encephalopathy, HP:0001298
White matter disorders and cerebral calcification - narrow panel v7.22 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed publications to: 10066179, 39986310; Changed phenotypes to: Encephalopathy, HP:0001298
White matter disorders and cerebral calcification - narrow panel v7.22 PTPN1 Ida Ertmanska Publications for gene: PTPN1 were set to 39986310
White matter disorders and cerebral calcification - narrow panel v7.21 PTPN1 Ida Ertmanska Classified gene: PTPN1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v7.21 PTPN1 Ida Ertmanska Gene: ptpn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.349 PTPN1 Ida Ertmanska Publications for gene: PTPN1 were set to 39986310
Intellectual disability v9.348 PTPN1 Ida Ertmanska Classified gene: PTPN1 as Amber List (moderate evidence)
Intellectual disability v9.348 PTPN1 Ida Ertmanska Gene: ptpn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.347 PTPN1 Ida Ertmanska changed review comment from: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.
Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature; to: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.

Brain MRI findings: Cerebral atrophy (9/12 patients), non-specific white matter changes (8/12), intracranial calcification (2/12). In 8 cases, the brain abnormalities resolved.Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

Functional evidence: PMID: 10066179 Elchebly et al., 1999 - Ptpn1 knock-out (KO) mice are both viable and healthy, demonstrating enhanced insulin sensitivity and resistance to metabolic syndrome.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v7.20 PTPN1 Ida Ertmanska gene: PTPN1 was added
gene: PTPN1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 39986310
Review for gene: PTPN1 was set to AMBER
Added comment: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.

Brain MRI findings: Cerebral atrophy (9/12 patients), non-specific white matter changes (8/12), intracranial calcification (2/12). In 8 cases, the brain abnormalities resolved.Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

Functional evidence: PMID: 10066179 Elchebly et al., 1999 - Ptpn1 knock-out (KO) mice are both viable and healthy, demonstrating enhanced insulin sensitivity and resistance to metabolic syndrome.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Intellectual disability v9.347 PTPN1 Ida Ertmanska gene: PTPN1 was added
gene: PTPN1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 39986310
Review for gene: PTPN1 was set to AMBER
Added comment: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.
Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Severe microcephaly v8.36 LMNB2 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been kept as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Severe microcephaly v8.36 LMNB2 Eleanor Williams changed review comment from: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Childhood interstitial lung disease v0.8 Arina Puzriakova Panel status changed from public to internal
Sarcoma of possible germline origin v0.6 Arina Puzriakova Panel status changed from public to internal
Embryonal tumour of possible germline origin v0.9 Arina Puzriakova Panel status changed from public to internal
Mitochondrial disorders v9.47 IDH1 Ida Ertmanska edited their review of gene: IDH1: Changed rating: AMBER
Mitochondrial disorders v9.47 IDH1 Ida Ertmanska Classified gene: IDH1 as Amber List (moderate evidence)
Mitochondrial disorders v9.47 IDH1 Ida Ertmanska Added comment: Comment on list classification: The rating of this gene has been updated to Amber following NHS Genomic Medicine Service approval. As all variants reported in this gene are somatic mosaic, they would not be reliably detected by a WGS test. Mosaic skin disorders - deep sequencing panel is more appropriate for IDH1 testing.
Mitochondrial disorders v9.47 IDH1 Ida Ertmanska Gene: idh1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.105 IDH1 Ida Ertmanska Classified gene: IDH1 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.105 IDH1 Ida Ertmanska Added comment: Comment on list classification: The rating of this gene has been updated to Amber following NHS Genomic Medicine Service approval. As all variants reported in this gene are somatic mosaic, they would not be reliably detected by a WGS test. Mosaic skin disorders - deep sequencing panel is more appropriate for IDH1 testing.
Likely inborn error of metabolism v8.105 IDH1 Ida Ertmanska Gene: idh1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v8.39 IDH1 Ida Ertmanska Classified gene: IDH1 as Amber List (moderate evidence)
Skeletal dysplasia v8.39 IDH1 Ida Ertmanska Added comment: Comment on list classification: The rating of this gene has been updated to Amber following NHS Genomic Medicine Service approval. As all variants reported in this gene are somatic mosaic, they would not be reliably detected by a WGS test. Mosaic skin disorders - deep sequencing panel is more appropriate for IDH1 testing.
Skeletal dysplasia v8.39 IDH1 Ida Ertmanska Gene: idh1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Ludmila Volozonoka reviewed gene: POPDC2: Rating: ; Mode of pathogenicity: None; Publications: 41456958, 40409267; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.346 MYCBP2 Ludmila Volozonoka gene: MYCBP2 was added
gene: MYCBP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MYCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYCBP2 were set to 41200582; 36200388; 41543631
Review for gene: MYCBP2 was set to GREEN
Added comment: PMID: 36200388 reports eight de novo MYCBP2 variants (two loss-of-function and six missense) in patients presenting with dysmorphism, global developmental delay, varying degrees of intellectual disability, language delay, and ASD. Less common features include corpus callosum dysgenesis and epilepsy.

PMID: 41200582 describes a loss-of-function MYCBP2 variant identified in a mother and her two sons, all exhibiting similar clinical features as in PMID: 36200388.

PMID: 41543631 demonstrates another loss-of-function variant in a proband with NDD, inherited from a mother with mild features (notably subtle executive dysfunction).
The gene is highly constrained of LOF variants in a general population (pLI = 1).
Sources: Literature
Fetal anomalies v6.181 ITCH Ludmila Volozonoka reviewed gene: ITCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 36338154; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic diabetes v3.14 ZNF808 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ZNF808.
Tag Q1_26_NHS_review tag was added to gene: ZNF808.
Monogenic diabetes v3.14 ZNF808 Ida Ertmanska changed review comment from: PMID: 41500078 Russ-Silsby et al 2026
17 previously unreported individuals with biallelic loss-of-function ZNF808 variants.19 individuals had permanent neonatal diabetes; 12 had other diabetes phenotypes: 5 with infancy-onset diabetes, 4 with transient diabetes and 3 with diabetes diagnosed aged 10, 14 and 23 years.
Variable severity associated with the variants e.g.,:
p.(Thr630Serfs*24) was detected in a homozyogus state in Patient 14 (diabetes diagnosed at 23 yrs), as well as Patient 1 (PNDM diagnosed at 13 weeks), and in patient 11 (transient diabetes diagnosed at 1 day old).
p.(Tyr662*) detected in homozygous state in Patient 15 (diabetes diagnosed at 10yo) and heterozygous, in trans with a deletion, in Patient 13 (diabetes diagnosed at 14 years.; to: PMID: 41500078 Russ-Silsby et al 2026
17 previously unreported individuals with biallelic loss-of-function ZNF808 variants.19 individuals had permanent neonatal diabetes; 12 had other diabetes phenotypes: 5 with infancy-onset diabetes, 4 with transient diabetes and 3 with diabetes diagnosed aged 10, 14 and 23 years.
Variable severity associated with the variants e.g.,:
p.(Thr630Serfs*24) was detected in a homozyogus state in Patient 14 (diabetes diagnosed at 23 yrs), as well as Patient 1 (PNDM diagnosed at 13 weeks), and in patient 11 (transient diabetes diagnosed at 1 day old).
p.(Tyr662*) detected in homozygous state in Patient 15 (diabetes diagnosed at 10yo) and heterozygous, in trans with a deletion, in Patient 13 (diabetes diagnosed at 14 years).
Intellectual disability v9.346 SOD1 Ida Ertmanska Tag treatable tag was added to gene: SOD1.
Intellectual disability v9.346 SOD1 Ida Ertmanska commented on gene: SOD1
Childhood onset hereditary spastic paraplegia v8.42 SOD1 Ida Ertmanska Tag treatable tag was added to gene: SOD1.
Childhood onset hereditary spastic paraplegia v8.42 SOD1 Ida Ertmanska commented on gene: SOD1
Adult onset neurodegenerative disorder v8.21 SOD1 Ida Ertmanska Phenotypes for gene: SOD1 were changed from Amyotrophic lateral sclerosis 1, OMIM:105400 to Amyotrophic lateral sclerosis 1, OMIM:105400; Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598
Adult onset neurodegenerative disorder v8.20 SOD1 Ida Ertmanska commented on gene: SOD1
Adult onset neurodegenerative disorder v8.20 SOD1 Ida Ertmanska Tag treatable tag was added to gene: SOD1.
Hereditary neuropathy or pain disorder v7.45 SOD1 Ida Ertmanska commented on gene: SOD1: Tofersen is a genetic therapy developed for a rare inherited form of motor neurone disease (MND) caused by mutations in the SOD1 gene. The MHRA approved Tofersen in July 2025 for adults with SOD1‑related MND; however, it has not been approved by NICE for routine NHS use, and the NICE appraisal process is ongoing. Hence, 'treatable' tag has been added.
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska Deleted their comment
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska commented on gene: ACVR2B: Tofersen is a genetic therapy developed for a rare inherited form of motor neurone disease (MND) caused by mutations in the SOD1 gene. The MHRA approved Tofersen in July 2025 for adults with SOD1‑related MND; however, it has not been approved by NICE for routine NHS use, and the NICE appraisal process is ongoing. Hence, 'treatable' tag has been added.
Hereditary neuropathy or pain disorder v7.45 SOD1 Ida Ertmanska Tag treatable tag was added to gene: SOD1.
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska changed review comment from: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).
ACVR2B:c.1480G>A p.Val494Ile is rare in gnomAD v4 (14 alleles reported, no homozygotes, MAF = 0.00003378).
ACVR2B:c.119G>A, p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare dominant disorder.

PMID: 21864452 Ma et al., 2011
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: c.1147C>T, p.Arg383Cys missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear. The p.Arg309Cys variant is rare in gnomAD v4, with 30 alleles reported and no homozygotes (MAF = 0.00005490); VUS in ClinVar.

Functional evidence:
PMID: 9242489 Oh & Li 1997 - knockout acvr2b -/- mice die after birth with complicated cardiac defects including randomized heart position, malposition of the great arteries, and ventricular and atrial septal defects; the heart anomalies are associated with right pulmonary isomerism and splenic abnormalities.
PMID: 21864452 Ma et al., 2011 - Activin receptor IIB (Acvr2b) is expressed asymmetrically along left-right axis in mouse and chick

The gene is associated with AD Heterotaxy, visceral, 4, autosomal, MIM:613751 in OMIM. ACVR2B has not been curated in ClinGen and it is limited in Gene2Phenotype.; to: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).
ACVR2B:c.1480G>A p.Val494Ile is rare in gnomAD v4 (14 alleles reported, no homozygotes, MAF = 0.00003378).
ACVR2B:c.119G>A, p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare dominant disorder.

PMID: 21864452 Ma et al., 2011
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: c.1147C>T, p.Arg383Cys missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear. The p.Arg309Cys variant is rare in gnomAD v4, with 30 alleles reported and no homozygotes (MAF = 0.00005490); VUS in ClinVar.

Functional evidence:
PMID: 9242489 Oh & Li 1997 - knockout acvr2b -/- mice die after birth with complicated cardiac defects including randomized heart position, malposition of the great arteries, and ventricular and atrial septal defects; the heart anomalies are associated with right pulmonary isomerism and splenic abnormalities.
PMID: 17849440 Goto et al., 2007 - The acvr2b+/− mice were revealed to be normal and viable; left–right patterning defects seen in some of the (acvr2b+/−smad2+/−) mice - digenic inheritance?
PMID: 21864452 Ma et al., 2011 - Activin receptor IIB (Acvr2b) is expressed asymmetrically along left-right axis in mouse and chick

The gene is associated with AD Heterotaxy, visceral, 4, autosomal, MIM:613751 in OMIM. ACVR2B has not been curated in ClinGen and it is limited in Gene2Phenotype.
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska changed review comment from: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).
ACVR2B:c.1480G>A p.Val494Ile is rare in gnomAD v4 (14 alleles reported, no homozygotes, MAF = 0.00003378).
ACVR2B:c.119G>A, p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare dominant disorder.

PMID: 21864452 Ma et al., 2012
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: c.1147C>T, p.Arg383Cys missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear. The p.Arg309Cys variant is rare in gnomAD v4, with 30 alleles reported and no homozygotes (MAF = 0.00005490); VUS in ClinVar.

The gene is associated with AD Heterotaxy, visceral, 4, autosomal, MIM:613751 in OMIM. ACVR2B has not been curated in ClinGen and it is limited in Gene2Phenotype.; to: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).
ACVR2B:c.1480G>A p.Val494Ile is rare in gnomAD v4 (14 alleles reported, no homozygotes, MAF = 0.00003378).
ACVR2B:c.119G>A, p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare dominant disorder.

PMID: 21864452 Ma et al., 2011
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: c.1147C>T, p.Arg383Cys missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear. The p.Arg309Cys variant is rare in gnomAD v4, with 30 alleles reported and no homozygotes (MAF = 0.00005490); VUS in ClinVar.

Functional evidence:
PMID: 9242489 Oh & Li 1997 - knockout acvr2b -/- mice die after birth with complicated cardiac defects including randomized heart position, malposition of the great arteries, and ventricular and atrial septal defects; the heart anomalies are associated with right pulmonary isomerism and splenic abnormalities.
PMID: 21864452 Ma et al., 2011 - Activin receptor IIB (Acvr2b) is expressed asymmetrically along left-right axis in mouse and chick

The gene is associated with AD Heterotaxy, visceral, 4, autosomal, MIM:613751 in OMIM. ACVR2B has not been curated in ClinGen and it is limited in Gene2Phenotype.
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska changed review comment from: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).

PMID: 21864452 Ma et al., 2012
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease. The p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare disorder.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: p.(R383C) missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear.; to: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).
ACVR2B:c.1480G>A p.Val494Ile is rare in gnomAD v4 (14 alleles reported, no homozygotes, MAF = 0.00003378).
ACVR2B:c.119G>A, p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare dominant disorder.

PMID: 21864452 Ma et al., 2012
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: c.1147C>T, p.Arg383Cys missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear. The p.Arg309Cys variant is rare in gnomAD v4, with 30 alleles reported and no homozygotes (MAF = 0.00005490); VUS in ClinVar.

The gene is associated with AD Heterotaxy, visceral, 4, autosomal, MIM:613751 in OMIM. ACVR2B has not been curated in ClinGen and it is limited in Gene2Phenotype.
Likely inborn error of metabolism v8.104 SLC52A3 Achchuthan Shanmugasundram commented on gene: SLC52A3: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Likely inborn error of metabolism v8.104 SLC52A3 Achchuthan Shanmugasundram Mode of inheritance for gene: SLC52A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.103 SLC52A3 Achchuthan Shanmugasundram Tag Q1_26_MOI was removed from gene: SLC52A3.
Congenital myaesthenic syndrome v5.8 UNC13A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 23 Mar 2026.
Congenital myaesthenic syndrome v5.8 UNC13A Ida Ertmanska Phenotypes for gene: UNC13A were changed from congenital myasthenic syndrome, MONDO:0018940 to congenital myasthenic syndrome, MONDO:0018940; Neurodevelopmental disorder with hypotonia, epilepsy, and absent speech, OMIM:621455
Early onset or syndromic epilepsy v8.168 UNC13A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 23 Mar 2026.
Early onset or syndromic epilepsy v8.168 UNC13A Ida Ertmanska Phenotypes for gene: UNC13A were changed from developmental and epileptic encephalopathy, MONDO:0100620 to Neurodevelopmental disorder with speech delay, movement abnormalities, and seizures, OMIM:621456; Neurodevelopmental disorder with hypotonia, epilepsy, and absent speech, OMIM:621455; ?Intellectual development disorder with seizures and dysmorphic facies , OMIM:621457
Intellectual disability v9.346 UNC13A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 23 Mar 2026.
Intellectual disability v9.346 UNC13A Ida Ertmanska Phenotypes for gene: UNC13A were changed from developmental and epileptic encephalopathy, MONDO:0100620 to Neurodevelopmental disorder with speech delay, movement abnormalities, and seizures, OMIM:621456; Neurodevelopmental disorder with hypotonia, epilepsy, and absent speech, OMIM:621455; ?Intellectual development disorder with seizures and dysmorphic facies , OMIM:621457
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Dmitrijs Rots gene: POPDC2 was added
gene: POPDC2 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POPDC2 were set to PMID: 40409267
Phenotypes for gene: POPDC2 were set to cardiac conduction defects and hypertrophic cardiomyopathy
Penetrance for gene: POPDC2 were set to unknown
Review for gene: POPDC2 was set to GREEN
Added comment: PMID: 40409267 reports 4 families with recessive inheritance with presenting with cardiac conduction defects and hypertrophic cardiomyopathy with some functional evidence. enough for green rating.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v7.19 ALPK1 Dmitrijs Rots gene: ALPK1 was added
gene: ALPK1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to PMID: 35868845
Phenotypes for gene: ALPK1 were set to ROSAH
Penetrance for gene: ALPK1 were set to Complete
Mode of pathogenicity for gene: ALPK1 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: ALPK1 was set to GREEN
Added comment: Associated with ROSAH syndrome, but the phenotype is variable among the individuals. The authors of PMID: 35868845 report:" However, seven of the patients had premature mineralisation/calcification of the globus pallidi, red nuclei and substantia nigra, worsening with age, eventually involving the rest of the basal ganglia (figure 2E). White matter abnormalities have also been reported and patient F10.1 initially received a diagnosis of multiple sclerosis after she presented with loss of colour vision and was reported to have multiple lesions on MRI.".

The gene is currently not in any "brain" panels, while showing obvious brain abnormalities.
Sources: Literature
Pigmentary skin disorders v4.13 XRCC2 Veronica Kinsler reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 41526458, 22232082, 27208205, 30042186; Phenotypes: Fanconi anaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v4.13 SNAI2 Veronica Kinsler reviewed gene: SNAI2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12444107, 12955764, 30936914; Phenotypes: Waardenburg syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v4.13 MLPH Veronica Kinsler reviewed gene: MLPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12897212, 21883982, 22711375, 26337734; Phenotypes: Griscelli syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.103 SLC52A3 Achchuthan Shanmugasundram changed review comment from: There is strong evidence available for the association of biallelic variants in SLC52A3 with human disease. Biallelic variants are associated with relevant phenotypes in OMIM (MIMs #211530 & #211500, last accessed 20 March 2026) and Gene2Phenotype (with definitive ratings on DD and Ear panels). Autosomal recessive variants are associated with Brown-Vialetto-van Laere syndrome 1 phenotype (MONDO:0024537) with 'definitive' rating on ClinGen by the Hearing Loss GCEP (https://search.clinicalgenome.org/CCID:006194).

There is also evidence available for the association of monoallelic SLC52A3 variants with human disease, despite not being associated with phenotypes in OMIM, G2P, ClinGen or PanelApp Australia.

PMID:22718020 (2012) reported three patients with Brown-Vialetto-Van Laere syndrome. Variant in only one allele was identified in SLC52A3 by Sanger sequencing in two of these three patents.

PMID:29053833 (2017) reported five patients with monoallelic variants identified by PCR and Sanger sequencing. They showed phenotypes indistinguishable from biallelic cases in severity, age of onset, and clinical features. The authors used array CGH to exclude large deletions/duplications on the second allele.

PMID:34384672 (2021) reported three patients with adult-onset Brown-Vialetto-van Laere syndrome and with SLC52A3 variants, of which one patient was identified with a heterozygous variant.
​
PMID:38469093 (2024) reported a 16-year-old female with a phenotype consistent with riboflavin transporter deficiency. She was identified with a novel heterozygous variant, identified by WGS. Her asymptomatic brother was also identified with the same heterozygous variant, directly demonstrating reduced penetrance for this monoallelic state. Her condition however improved in response to riboflavin supplementation.

PMID:40539137 (2025) reported a 68-year-old female patient with atypical late-onset Brown-Vialetto-Van Laere syndrome carrying a variant (p.Val413Ala) previously seen only in compound heterozygous patients in heterozygous state.; to: There is strong evidence available for the association of biallelic variants in SLC52A3 with human disease. Biallelic variants are associated with relevant phenotypes in OMIM (MIMs #211530 & #211500, last accessed 20 March 2026) and Gene2Phenotype (with definitive ratings on DD and Ear panels). Autosomal recessive variants are associated with Brown-Vialetto-van Laere syndrome 1 phenotype (MONDO:0024537) with 'definitive' rating on ClinGen by the Hearing Loss GCEP (https://search.clinicalgenome.org/CCID:006194).

There is also evidence available for the association of monoallelic SLC52A3 variants with human disease, despite not being associated with phenotypes in OMIM, G2P, ClinGen or PanelApp Australia.

PMID:22718020 (2012) reported three patients with Brown-Vialetto-Van Laere syndrome. Variant in only one allele was identified in SLC52A3 by Sanger sequencing in two of these three patents.

PMID:29053833 (2017) reported five patients with monoallelic variants identified by PCR and Sanger sequencing. They showed phenotypes indistinguishable from biallelic cases in severity, age of onset, and clinical features. The authors used array CGH to exclude large deletions/duplications on the second allele.

PMID:34384672 (2021) reported three patients with adult-onset Brown-Vialetto-van Laere syndrome and with SLC52A3 variants, of which one patient was identified with a heterozygous variant.
​
PMID:38469093 (2024) reported a 16-year-old female with a phenotype consistent with riboflavin transporter deficiency. She was identified with a novel heterozygous variant, identified by WGS. Her asymptomatic brother was also identified with the same heterozygous variant, directly demonstrating reduced penetrance for this monoallelic state. Her condition however improved in response to riboflavin supplementation.

PMID:40539137 (2025) reported a 68-year-old female patient with atypical late-onset Brown-Vialetto-Van Laere syndrome carrying a variant (p.Val413Ala) previously seen only in compound heterozygous patients in heterozygous state.
Likely inborn error of metabolism v8.103 SLC52A3 Achchuthan Shanmugasundram changed review comment from: There is strong evidence available for the association of biallelic variants in SLC52A3 with human disease. Biallelic variants are associated with relevant phenotypes in OMIM (MIMs #211530 & #211500, last accessed 20 March 2026) and Gene2Phenotype (with definitive ratings on DD and Ear panels). Autosomal recessive variants are associated with Brown-Vialetto-van Laere syndrome 1 phenotype (MONDO:0024537) with 'definitive' rating on ClinGen by the Hearing Loss GCEP (https://search.clinicalgenome.org/CCID:006194).

There is also evidence available for the association of monoallelic SLC52A3 variants with human disease, despite not being associated with phenotypes in OMIM, G2P, ClinGen or PanelApp Australia.

PMID:22718020 (2012) reported three patients with Brown-Vialetto-Van Laere syndrome. Only one variant was identified in SLC52A3 by Sanger sequencing in two of these three patents.

PMID:29053833 (2017) reported five patients with monoallelic variants identified by PCR and Sanger sequencing. They showed phenotypes indistinguishable from biallelic cases in severity, age of onset, and clinical features. The authors used array CGH to exclude large deletions/duplications on the second allele.

PMID:34384672 (2021) reported three patients with adult-onset Brown-Vialetto-van Laere syndrome and with SLC52A3 variants, of which one patient was identified with a heterozygous variant.
​
PMID:38469093 (2024) reported a 16-year-old female with a phenotype consistent with riboflavin transporter deficiency. She was identified with a novel heterozygous variant, identified by WGS. Her asymptomatic brother was also identified with the same heterozygous variant, directly demonstrating reduced penetrance for this monoallelic state. Her condition however improved in response to riboflavin supplementation.

PMID:40539137 (2025) reported a 68-year-old female patient with atypical late-onset Brown-Vialetto-Van Laere syndrome carrying a variant (p.Val413Ala) previously seen only in compound heterozygous patients in heterozygous state.; to: There is strong evidence available for the association of biallelic variants in SLC52A3 with human disease. Biallelic variants are associated with relevant phenotypes in OMIM (MIMs #211530 & #211500, last accessed 20 March 2026) and Gene2Phenotype (with definitive ratings on DD and Ear panels). Autosomal recessive variants are associated with Brown-Vialetto-van Laere syndrome 1 phenotype (MONDO:0024537) with 'definitive' rating on ClinGen by the Hearing Loss GCEP (https://search.clinicalgenome.org/CCID:006194).

There is also evidence available for the association of monoallelic SLC52A3 variants with human disease, despite not being associated with phenotypes in OMIM, G2P, ClinGen or PanelApp Australia.

PMID:22718020 (2012) reported three patients with Brown-Vialetto-Van Laere syndrome. Variant in only one allele was identified in SLC52A3 by Sanger sequencing in two of these three patents.

PMID:29053833 (2017) reported five patients with monoallelic variants identified by PCR and Sanger sequencing. They showed phenotypes indistinguishable from biallelic cases in severity, age of onset, and clinical features. The authors used array CGH to exclude large deletions/duplications on the second allele.

PMID:34384672 (2021) reported three patients with adult-onset Brown-Vialetto-van Laere syndrome and with SLC52A3 variants, of which one patient was identified with a heterozygous variant.
​
PMID:38469093 (2024) reported a 16-year-old female with a phenotype consistent with riboflavin transporter deficiency. She was identified with a novel heterozygous variant, identified by WGS. Her asymptomatic brother was also identified with the same heterozygous variant, directly demonstrating reduced penetrance for this monoallelic state. Her condition however improved in response to riboflavin supplementation.

PMID:40539137 (2025) reported a 68-year-old female patient with atypical late-onset Brown-Vialetto-Van Laere syndrome carrying a variant (p.Val413Ala) previously seen only in compound heterozygous patients in heterozygous state.
Likely inborn error of metabolism v8.103 SLC52A3 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is evidence available for the association of both monoallelic and biallelic variants in this gene to riboflavin transporter deficiency. The MOI of this gene has already been set to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on Mitochondrial disorders panel (https://panelapp.genomicsengland.co.uk/panels/112/gene/SLC52A3/). Hence, the MOI should be updated to BOTH on this panel.
Likely inborn error of metabolism v8.103 SLC52A3 Achchuthan Shanmugasundram Mode of inheritance for gene: SLC52A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v8.102 SLC52A3 Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: SLC52A3.
Likely inborn error of metabolism v8.102 SLC52A3 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A3 were changed from Brown-Vialetto-Van Laere syndrome 1 211530; Fazio-Londe disease 211500 to Brown-Vialetto-Van Laere syndrome 1, OMIM:211530; Brown-Vialetto-van Laere syndrome 1, MONDO:0024537; ?Fazio-Londe disease, OMIM:211500; riboflavin transporter deficiency, MONDO:0008891
Likely inborn error of metabolism v8.101 SLC52A3 Achchuthan Shanmugasundram Publications for gene: SLC52A3 were set to
Likely inborn error of metabolism v8.100 SLC52A3 Achchuthan Shanmugasundram changed review comment from: There is strong evidence available for the association of biallelic variants in SLC52A3 with human disease. Biallelic variants are associated with relevant phenotypes in OMIM (MIMs #211530 & #211500, last accessed 20 March 2026) and Gene2Phenotype (with definitive ratings on DD and Ear panels). Autosomal recessive variants are associated with Brown-Vialetto-van Laere syndrome 1 phenotype (MONDO:0024537) with 'definitive' rating on ClinGen by the Hearing Loss GCEP (https://search.clinicalgenome.org/CCID:006194).

There is also evidence available for the association of monoallelic SLC52A3 variants with human disease, despite not being associated with phenotypes in OMIM, G2P, ClinGen or PanelApp Australia.

PMID:22718020 (2012) reported three patients with Brown-Vialetto-Van Laere syndrome. Only one variant was identified in SLC52A3 by Sanger sequencing in two of these three patents.

PMID:29053833 (2017) reported five patients with monoallelic variants identified by PCR and Sanger sequencing. They showed phenotypes indistinguishable from biallelic cases in severity, age of onset, and clinical features. The authors used array CGH to exclude large deletions/duplications on the second allele.

PMID:34384672 (2021) reported three patients with SLC52A3 variants, of which one patient was identified with a heterozygous variant.
​
PMID:38469093 (2024) reported a 16-year-old female with a phenotype consistent with riboflavin transporter deficiency. She was identified with a novel heterozygous variant, identified by WGS. Her asymptomatic brother was also identified with the same heterozygous variant, directly demonstrating reduced penetrance for this monoallelic state. Her condition however improved in response to riboflavin supplementation.

PMID:40539137 (2025) reported a 68-year-old female patient with atypical late-onset Brown-Vialetto-Van Laere syndrome carrying a variant (p.Val413Ala) previously seen only in compound heterozygous patients in heterozygous state.; to: There is strong evidence available for the association of biallelic variants in SLC52A3 with human disease. Biallelic variants are associated with relevant phenotypes in OMIM (MIMs #211530 & #211500, last accessed 20 March 2026) and Gene2Phenotype (with definitive ratings on DD and Ear panels). Autosomal recessive variants are associated with Brown-Vialetto-van Laere syndrome 1 phenotype (MONDO:0024537) with 'definitive' rating on ClinGen by the Hearing Loss GCEP (https://search.clinicalgenome.org/CCID:006194).

There is also evidence available for the association of monoallelic SLC52A3 variants with human disease, despite not being associated with phenotypes in OMIM, G2P, ClinGen or PanelApp Australia.

PMID:22718020 (2012) reported three patients with Brown-Vialetto-Van Laere syndrome. Only one variant was identified in SLC52A3 by Sanger sequencing in two of these three patents.

PMID:29053833 (2017) reported five patients with monoallelic variants identified by PCR and Sanger sequencing. They showed phenotypes indistinguishable from biallelic cases in severity, age of onset, and clinical features. The authors used array CGH to exclude large deletions/duplications on the second allele.

PMID:34384672 (2021) reported three patients with adult-onset Brown-Vialetto-van Laere syndrome and with SLC52A3 variants, of which one patient was identified with a heterozygous variant.
​
PMID:38469093 (2024) reported a 16-year-old female with a phenotype consistent with riboflavin transporter deficiency. She was identified with a novel heterozygous variant, identified by WGS. Her asymptomatic brother was also identified with the same heterozygous variant, directly demonstrating reduced penetrance for this monoallelic state. Her condition however improved in response to riboflavin supplementation.

PMID:40539137 (2025) reported a 68-year-old female patient with atypical late-onset Brown-Vialetto-Van Laere syndrome carrying a variant (p.Val413Ala) previously seen only in compound heterozygous patients in heterozygous state.
Likely inborn error of metabolism v8.100 SLC52A3 Achchuthan Shanmugasundram edited their review of gene: SLC52A3: Changed publications to: 22718020, 29053833, 34384672, 38469093, 40539137; Changed phenotypes to: Brown-Vialetto-Van Laere syndrome 1, OMIM:211530, Brown-Vialetto-van Laere syndrome 1, MONDO:0024537, ?Fazio-Londe disease, OMIM:211500, riboflavin transporter deficiency, MONDO:0008891
Likely inborn error of metabolism v8.100 SLC52A3 Achchuthan Shanmugasundram reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska edited their review of gene: ACVR2B: Changed publications to: 9916847, 21864452, 30622330, 35547246
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska changed review comment from: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).

PMID: 21864452 Ma et al., 2012
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease. The p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare disorder.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: p.(R383C) missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.; to: PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).

PMID: 21864452 Ma et al., 2012
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease. The p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare disorder.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: p.(R383C) missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear.
Early onset or syndromic epilepsy v8.167 UNC13A Achchuthan Shanmugasundram changed review comment from: 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.; to: 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.
Hereditary neuropathy or pain disorder v7.45 PPOX Achchuthan Shanmugasundram changed review comment from: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; to: The mode of inheritance of this gene has been updated to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v7.45 PPOX Achchuthan Shanmugasundram edited their review of gene: PPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v7.37 ACVR2B Ida Ertmanska reviewed gene: ACVR2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 9916847, 21864452, 30622330; Phenotypes: Heterotaxy, visceral, 4, autosomal, OMIM:613751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.167 UNC13A Arina Puzriakova Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.345 UNC13A Arina Puzriakova Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.166 UNC13A Arina Puzriakova Tag Q1_26_MOI was removed from gene: UNC13A.
Intellectual disability v9.344 UNC13A Arina Puzriakova Tag Q1_26_MOI was removed from gene: UNC13A.
Intellectual disability v9.344 UNC13A Arina Puzriakova changed review comment from: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; to: 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.
Childhood onset hereditary spastic paraplegia v8.42 SPTSSA Arina Puzriakova Mode of inheritance for gene: SPTSSA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v8.41 SPTSSA Arina Puzriakova Tag Q1_26_MOI was removed from gene: SPTSSA.
Childhood onset hereditary spastic paraplegia v8.41 SPTSSA Arina Puzriakova commented on gene: SPTSSA
Hereditary neuropathy v1.508 PPOX Arina Puzriakova Added comment: 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 has been set to 'BIALLELIC, autosomal or pseudoautosomal'.
Hereditary neuropathy v1.508 PPOX Arina Puzriakova Mode of inheritance for gene: PPOX was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.344 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to allow detection of SNVs.
Intellectual disability v9.344 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v7.45 PPOX Arina Puzriakova 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
Hereditary neuropathy or pain disorder v7.44 PPOX Arina Puzriakova Tag Q3_25_MOI was removed from gene: PPOX.
Severe microcephaly v8.36 LMNB2 Arina Puzriakova Mode of inheritance for gene: LMNB2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset neurodegenerative disorder v8.20 ISCA-37478-Loss Arina Puzriakova Classified Region: ISCA-37478-Loss as Green List (high evidence)
Adult onset neurodegenerative disorder v8.20 ISCA-37478-Loss Arina Puzriakova Region: isca-37478-loss has been classified as Green List (High Evidence).
Adult onset neurodegenerative disorder v8.19 ISCA-37478-Loss Arina Puzriakova Tag curated_removed was removed from Region: ISCA-37478-Loss.
Adult onset neurodegenerative disorder v8.19 ISCA-37478-Loss Arina Puzriakova edited their review of Region: ISCA-37478-Loss: Added comment: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. Additional information: regions can be added to the panel as this clinical indication has now moved to WGS testing.; Changed rating: GREEN
Adult onset neurodegenerative disorder v8.19 ISCA-37446-Loss Arina Puzriakova changed review comment from: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. Additional information: regions can be added to the panel as this clinical indication has now moved to WGS testing. Other regions that were previously removed should also be reviewed. ; to: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval. Additional information: regions can be added to the panel as this clinical indication has now moved to WGS testing.
Acute rhabdomyolysis v2.8 AMPD1 Arina Puzriakova Classified gene: AMPD1 as Red List (low evidence)
Acute rhabdomyolysis v2.8 AMPD1 Arina Puzriakova Gene: ampd1 has been classified as Red List (Low Evidence).
Acute rhabdomyolysis v2.7 AMPD1 Arina Puzriakova Tag Q3_25_expert_review was removed from gene: AMPD1.
Tag Q3_25_demote_red was removed from gene: AMPD1.
Acute rhabdomyolysis v2.7 AMPD1 Arina Puzriakova edited their review of gene: AMPD1: Added comment: The rating of this gene has been updated to red following NHS Genomic Medicine Service approval.; Changed rating: RED
Fetal anomalies v6.181 C1orf127 Ida Ertmanska Tag gene-checked was removed from gene: C1orf127.
Laterality disorders and isomerism v4.10 C1orf127 Ida Ertmanska Tag gene-checked was removed from gene: C1orf127.
Fetal anomalies v6.181 C16orf62 Ida Ertmanska Tag gene-checked was removed from gene: C16orf62.
Intellectual disability v9.343 CXorf56 Ida Ertmanska Tag gene-checked was removed from gene: CXorf56.
Fetal anomalies v6.181 EFCAB1 Ida Ertmanska Tag gene-checked was removed from gene: EFCAB1.
Respiratory ciliopathies including non-CF bronchiectasis v4.55 EFCAB1 Ida Ertmanska Tag gene-checked was removed from gene: EFCAB1.
Monogenic hearing loss v5.57 KIAA1024L Ida Ertmanska Tag gene-checked was removed from gene: KIAA1024L.
DDG2P v6.447 C11orf70 Ida Ertmanska Tag gene-checked was removed from gene: C11orf70.
Fetal anomalies v6.181 C11orf70 Ida Ertmanska Tag gene-checked was removed from gene: C11orf70.
Respiratory ciliopathies including non-CF bronchiectasis v4.55 C11orf70 Ida Ertmanska Tag gene-checked was removed from gene: C11orf70.
Laterality disorders and isomerism v4.10 C11orf70 Ida Ertmanska Tag new-gene-name tag was added to gene: C11orf70.
Laterality disorders and isomerism v4.10 C11orf70 Ida Ertmanska Tag new-gene-name was removed from gene: C11orf70.
Tag gene-checked was removed from gene: C11orf70.
Fetal anomalies v6.181 AL117258.1 Ida Ertmanska Tag gene-checked was removed from gene: AL117258.1.
Laterality disorders and isomerism v4.10 AL117258.1 Ida Ertmanska Tag gene-checked was removed from gene: AL117258.1.
Childhood onset dystonia, chorea or related movement disorder v7.18 PDE1B Ida Ertmanska Tag gene-checked tag was added to gene: PDE1B.
Intellectual disability v9.343 PDE1B Ida Ertmanska Tag gene-checked tag was added to gene: PDE1B.
Ataxia and cerebellar anomalies - narrow panel v8.72 PDE1B Ida Ertmanska Tag gene-checked tag was added to gene: PDE1B.
Mitochondrial disorders v9.46 PDE12 Ida Ertmanska Tag gene-checked tag was added to gene: PDE12.
Fetal anomalies v6.181 PDE12 Ida Ertmanska Tag gene-checked tag was added to gene: PDE12.
Possible mitochondrial disorder - nuclear genes v4.23 PDE12 Ida Ertmanska Tag gene-checked tag was added to gene: PDE12.
Likely inborn error of metabolism v8.100 PDE12 Ida Ertmanska Tag gene-checked tag was added to gene: PDE12.
Fetal anomalies v6.181 PDCD2 Ida Ertmanska Tag gene-checked tag was added to gene: PDCD2.
Monogenic short stature v1.31 PAPPA2 Ida Ertmanska Tag gene-checked was removed from gene: PAPPA2.
Paediatric disorders - additional genes v7.37 PAPPA2 Ida Ertmanska Tag gene-checked was removed from gene: PAPPA2.
DDG2P v6.447 NTNG2 Ida Ertmanska Tag gene-checked was removed from gene: NTNG2.
Intellectual disability v9.343 NTNG2 Ida Ertmanska Tag gene-checked was removed from gene: NTNG2.
Intellectual disability v9.343 NHLRC2 Ida Ertmanska Tag gene-checked was removed from gene: NHLRC2.
DDG2P v6.447 NHLRC2 Ida Ertmanska Tag gene-checked was removed from gene: NHLRC2.
DDG2P v6.447 NHLRC2 Ida Ertmanska Phenotypes for gene: NHLRC2 were changed from NHLRC2-related fibrosis, neurodegeneration, and cerebral angiomatosis, OMIM:618278 to FINCA syndrome OMIM:618278; NHLRC2-related fibrosis, neurodegeneration, and cerebral angiomatosis, OMIM:618278
Paediatric disorders - additional genes v7.37 NHLRC2 Ida Ertmanska Tag gene-checked was removed from gene: NHLRC2.
Rare anaemia v3.19 NHLRC2 Ida Ertmanska Tag gene-checked was removed from gene: NHLRC2.
Monogenic short stature v1.31 NHLRC2 Ida Ertmanska Tag gene-checked was removed from gene: NHLRC2.
Respiratory ciliopathies including non-CF bronchiectasis v4.55 NEK10 Ida Ertmanska Tag gene-checked was removed from gene: NEK10.
Paediatric or syndromic cardiomyopathy v7.99 NDUFAF8 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Paediatric or syndromic cardiomyopathy v7.99 NDUFAF8 Ida Ertmanska Phenotypes for gene: NDUFAF8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776
DDG2P v6.446 NDUFAF8 Ida Ertmanska Tag gene-checked was removed from gene: NDUFAF8.
Mitochondrial disorders v9.46 NDUFAF8 Ida Ertmanska Tag gene-checked was removed from gene: NDUFAF8.
Fetal anomalies v6.181 NDUFAF8 Ida Ertmanska Tag gene-checked was removed from gene: NDUFAF8.
Likely inborn error of metabolism v8.100 NDUFAF8 Ida Ertmanska Tag gene-checked was removed from gene: NDUFAF8.
Mitochondrial disorder with complex I deficiency v3.19 NDUFAF8 Ida Ertmanska Tag gene-checked was removed from gene: NDUFAF8.
Possible mitochondrial disorder - nuclear genes v4.23 NDUFAF8 Ida Ertmanska Tag gene-checked was removed from gene: NDUFAF8.
Hereditary neuropathy v1.507 NDC1 Ida Ertmanska Phenotypes for gene: NDC1 were changed from demyelinating neuropathy; alacrima; achalasia to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, OMIM:621328; neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MONDO:0979875
Hereditary neuropathy or pain disorder v7.44 NDC1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Hereditary neuropathy or pain disorder v7.44 NDC1 Ida Ertmanska Phenotypes for gene: NDC1 were changed from demyelinating neuropathy; alacrima; achalasia to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, OMIM:621328; neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MONDO:0979875
Hereditary neuropathy or pain disorder v7.43 NDC1 Ida Ertmanska Tag gene-checked was removed from gene: NDC1.
Haematological malignancies for rare disease v1.19 NAF1 Ida Ertmanska Tag gene-checked was removed from gene: NAF1.
Childhood interstitial lung disease v0.7 NAF1 Ida Ertmanska Tag gene-checked was removed from gene: NAF1.
Haematological malignancies cancer susceptibility v4.40 NAF1 Ida Ertmanska Tag gene-checked was removed from gene: NAF1.
Pulmonary fibrosis familial v1.9 NAF1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Pulmonary fibrosis familial v1.9 NAF1 Ida Ertmanska Phenotypes for gene: NAF1 were changed from Pulmonary fibrosis-emphysema to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, OMIM:620365; pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MONDO:0957261
Pulmonary fibrosis familial v1.8 NAF1 Ida Ertmanska Tag gene-checked was removed from gene: NAF1.
Congenital myopathy v6.45 MYMX Ida Ertmanska Tag gene-checked was removed from gene: MYMX.
Early onset or syndromic epilepsy v8.166 MT-TK Ida Ertmanska Tag gene-checked tag was added to gene: MT-TK.
Intellectual disability v9.343 METTL5 Ida Ertmanska Tag gene-checked was removed from gene: METTL5.
DDG2P v6.446 METTL5 Ida Ertmanska Tag gene-checked was removed from gene: METTL5.
Severe microcephaly v8.35 METTL5 Ida Ertmanska Tag gene-checked was removed from gene: METTL5.
Intellectual disability v9.343 MARK2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 20 Mar 2026.
Intellectual disability v9.343 MARK2 Ida Ertmanska Phenotypes for gene: MARK2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 76, OMIM:621285; intellectual developmental disorder, autosomal dominant 76, MONDO:0979575
Intellectual disability v9.342 MARK2 Ida Ertmanska Tag gene-checked was removed from gene: MARK2.
Early onset or syndromic epilepsy v8.166 MARK2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 20 Mar 2026.
Early onset or syndromic epilepsy v8.166 MARK2 Ida Ertmanska Phenotypes for gene: MARK2 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 76, OMIM:621285; intellectual developmental disorder, autosomal dominant 76, MONDO:0979575
Early onset or syndromic epilepsy v8.165 MARK2 Ida Ertmanska Tag gene-checked was removed from gene: MARK2.
Intellectual disability v9.342 LRRC7 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.342 LRRC7 Ida Ertmanska Phenotypes for gene: LRRC7 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 77, OMIM:621415; intellectual developmental disorder, autosomal dominant 77, MONDO:0980748
Intellectual disability v9.341 LRRC7 Ida Ertmanska Tag gene-checked was removed from gene: LRRC7.
DDG2P v6.446 LRRC56 Ida Ertmanska Tag gene-checked was removed from gene: LRRC56.
Fetal anomalies v6.181 LRRC56 Ida Ertmanska Tag gene-checked was removed from gene: LRRC56.
Laterality disorders and isomerism v4.10 LRRC56 Ida Ertmanska Tag gene-checked was removed from gene: LRRC56.
Respiratory ciliopathies including non-CF bronchiectasis v4.55 LRRC56 Ida Ertmanska Tag gene-checked was removed from gene: LRRC56.
Early onset or syndromic epilepsy v8.165 LMBRD2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Early onset or syndromic epilepsy v8.165 LMBRD2 Ida Ertmanska Phenotypes for gene: LMBRD2 were changed from Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye to Developmental delay with variable neurologic and brain abnormalities, OMIM:619694
Early onset or syndromic epilepsy v8.164 LMBRD2 Ida Ertmanska Tag gene-checked was removed from gene: LMBRD2.
Intellectual disability v9.341 LMBRD2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.341 LMBRD2 Ida Ertmanska Phenotypes for gene: LMBRD2 were changed from Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye to Developmental delay with variable neurologic and brain abnormalities, OMIM:619694
Intellectual disability v9.340 LMBRD2 Ida Ertmanska Tag gene-checked was removed from gene: LMBRD2.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.8 LINC01082 Ida Ertmanska Tag gene-checked tag was added to gene: LINC01082.
Fetal anomalies v6.181 LINC01082 Ida Ertmanska Tag gene-checked tag was added to gene: LINC01082.
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.8 LINC01081 Ida Ertmanska Tag gene-checked tag was added to gene: LINC01081.
DDG2P v6.446 ZNRF3 Arina Puzriakova Tag gene-checked tag was added to gene: ZNRF3.
Fetal anomalies v6.181 LINC01081 Ida Ertmanska Tag gene-checked tag was added to gene: LINC01081.
Intellectual disability v9.340 ZNFX1 Arina Puzriakova Tag gene-checked was removed from gene: ZNFX1.
Early onset or syndromic epilepsy v8.164 ZNFX1 Arina Puzriakova Tag gene-checked was removed from gene: ZNFX1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.88 ZNFX1 Arina Puzriakova Tag gene-checked was removed from gene: ZNFX1.
DDG2P v6.446 ZNF808 Arina Puzriakova Tag gene-checked was removed from gene: ZNF808.
Neonatal diabetes v5.20 ZNF808 Arina Puzriakova Phenotypes for gene: ZNF808 were changed from neonatal diabetes mellitus, MONDO:0016391; pancreatic agenesis, MONDO:0009832 to Pancreatic agenesis 3, OMIM:620991; neonatal diabetes mellitus, MONDO:0016391
DDG2P v6.446 KLHL20 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
DDG2P v6.446 KLHL20 Ida Ertmanska Phenotypes for gene: KLHL20 were changed from KLHL20-related developmental disorder with seizures to KLHL20-related developmental disorder with seizures; Neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, OMIM:621390
Neonatal diabetes v5.19 ZNF808 Arina Puzriakova Tag gene-checked was removed from gene: ZNF808.
DDG2P v6.445 KLHL20 Ida Ertmanska Tag gene-checked was removed from gene: KLHL20.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.88 ZNF341 Arina Puzriakova Tag gene-checked was removed from gene: ZNF341.
Early onset or syndromic epilepsy v8.164 KLHL20 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Early onset or syndromic epilepsy v8.164 KLHL20 Ida Ertmanska Phenotypes for gene: KLHL20 were changed from developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder to Neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, OMIM:621390
DDG2P v6.445 ZFYVE19 Arina Puzriakova Tag gene-checked was removed from gene: ZFYVE19.
Cholestasis v3.19 ZFYVE19 Arina Puzriakova Tag gene-checked was removed from gene: ZFYVE19.
Early onset or syndromic epilepsy v8.163 KLHL20 Ida Ertmanska Tag gene-checked was removed from gene: KLHL20.
Intellectual disability v9.340 ZFHX4 Arina Puzriakova Tag gene-checked tag was added to gene: ZFHX4.
Intellectual disability v9.340 KLHL20 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.340 KLHL20 Ida Ertmanska Phenotypes for gene: KLHL20 were changed from developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder to Neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, OMIM:621390
DDG2P v6.445 ZFHX4 Arina Puzriakova Tag gene-checked tag was added to gene: ZFHX4.
Intellectual disability v9.339 KLHL20 Ida Ertmanska Tag gene-checked was removed from gene: KLHL20.
DDG2P v6.445 ZBTB11 Arina Puzriakova Tag gene-checked was removed from gene: ZBTB11.
Intellectual disability v9.339 ZBTB11 Arina Puzriakova Tag gene-checked was removed from gene: ZBTB11.
Severe microcephaly v8.35 YIF1B Arina Puzriakova Tag gene-checked was removed from gene: YIF1B.
Fetal anomalies v6.181 YIF1B Arina Puzriakova Tag gene-checked was removed from gene: YIF1B.
Early onset or syndromic epilepsy v8.163 YIF1B Arina Puzriakova Tag gene-checked was removed from gene: YIF1B.
Intellectual disability v9.339 YIF1B Arina Puzriakova Tag gene-checked was removed from gene: YIF1B.
Childhood onset dystonia, chorea or related movement disorder v7.18 YIF1B Arina Puzriakova Tag gene-checked was removed from gene: YIF1B.
DDG2P v6.445 KDM2B Ida Ertmanska Tag gene-checked was removed from gene: KDM2B.
DDG2P v6.445 XPO1 Arina Puzriakova Tag gene-checked tag was added to gene: XPO1.
DDG2P v6.445 KDM2B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
DDG2P v6.445 KDM2B Ida Ertmanska Phenotypes for gene: KDM2B were changed from KDM2B-related neurodevelopmental disorder to KDM2B-related neurodevelopmental disorder; Neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities, OMIM:621474
Intellectual disability v9.339 WSB2 Arina Puzriakova Tag gene-checked tag was added to gene: WSB2.
Early onset or syndromic epilepsy v8.163 WSB2 Arina Puzriakova Tag gene-checked tag was added to gene: WSB2.
Ataxia and cerebellar anomalies - narrow panel v8.72 WSB2 Arina Puzriakova Tag gene-checked tag was added to gene: WSB2.
Fetal anomalies v6.181 WSB2 Arina Puzriakova Tag gene-checked tag was added to gene: WSB2.
Intellectual disability v9.339 KDM2B Ida Ertmanska Publications for gene: KDM2B were set to 36322151
Intellectual disability v9.338 KDM2B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Intellectual disability v9.338 KDM2B Ida Ertmanska Phenotypes for gene: KDM2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities, OMIM:621474
Intellectual disability v9.337 KDM2B Ida Ertmanska Tag gene-checked was removed from gene: KDM2B.
Fetal anomalies v6.181 KDM2B Ida Ertmanska Tag gene-checked was removed from gene: KDM2B.
Fetal anomalies v6.181 KDM2B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Fetal anomalies v6.181 KDM2B Ida Ertmanska Phenotypes for gene: KDM2B were changed from Neurodevelopmental disorder MONDO:0700092, KDM2B-related to Neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities, OMIM:621474
Fetal anomalies v6.180 KCNJ8 Ida Ertmanska Tag gene-checked tag was added to gene: KCNJ8.
DDG2P v6.444 KCNB2 Ida Ertmanska Tag gene-checked tag was added to gene: KCNB2.
Paediatric disorders - additional genes v7.37 ISL1 Ida Ertmanska Tag gene-checked tag was added to gene: ISL1.
Intellectual disability v9.337 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Fetal anomalies v6.180 WDR91 Arina Puzriakova Tag gene-checked tag was added to gene: WDR91.
Fetal anomalies v6.180 WDR91 Arina Puzriakova Publications for gene: WDR91 were set to 32732226; 34028500; 28860274
DDG2P v6.444 HPDL Ida Ertmanska Phenotypes for gene: HPDL were changed from HPDL Neurodegenerative Disease to HPDL Neurodegenerative Disease; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities OMIM:619026 Spastic paraplegia 83, autosomal recessive OMIM:619027
DDG2P v6.443 WDR83OS Arina Puzriakova Phenotypes for gene: WDR83OS were changed from MONDO:0975877; WDR83OS-related neurodevelopmental disorder with hypercholanemia to neurodevelopmental disorder with variable familial hypercholanemia, MONDO:0975877; WDR83OS-related neurodevelopmental disorder with hypercholanemia
DDG2P v6.442 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Early onset or syndromic epilepsy v8.163 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Possible mitochondrial disorder - nuclear genes v4.23 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Intellectual disability v9.337 WDR83OS Arina Puzriakova Tag gene-checked was removed from gene: WDR83OS.
DDG2P v6.442 WDR83OS Arina Puzriakova Tag gene-checked was removed from gene: WDR83OS.
Mitochondrial disorders v9.46 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Likely inborn error of metabolism v8.100 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Hereditary neuropathy or pain disorder v7.43 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
DDG2P v6.442 WDR83OS Arina Puzriakova Tag gene-checked tag was added to gene: WDR83OS.
Childhood onset hereditary spastic paraplegia v8.41 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
Severe microcephaly v8.35 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
DDG2P v6.442 WDR44 Arina Puzriakova Tag gene-checked tag was added to gene: WDR44.
White matter disorders and cerebral calcification - narrow panel v7.19 HPDL Ida Ertmanska Tag gene-checked was removed from gene: HPDL.
DDG2P v6.442 IKZF2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 20 Mar 2026.
DDG2P v6.442 IKZF2 Ida Ertmanska Phenotypes for gene: IKZF2 were changed from IKZF2-related ICHAD syndrome to Immunodysregulation with variable immunodeficiency and autoimmunity, OMIM:621233; Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, OMIM:621234
Early onset or syndromic epilepsy v8.163 WDR37 Arina Puzriakova Phenotypes for gene: WDR37 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system; Neurooculocardiogenitourinary syndrome, OMIM:618652 to Neurooculocardiogenitourinary syndrome, OMIM:618652
Intellectual disability v9.337 WDR37 Arina Puzriakova Phenotypes for gene: WDR37 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system; Neurooculocardiogenitourinary syndrome, OMIM:618652 to Neurooculocardiogenitourinary syndrome, OMIM:618652
Fetal anomalies v6.179 IKZF2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 20 Mar 2026.
Fetal anomalies v6.179 IKZF2 Ida Ertmanska Phenotypes for gene: IKZF2 were changed from Immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay, OMIM:621234 to Immunodysregulation with variable immunodeficiency and autoimmunity, OMIM:621233; Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, OMIM:621234
Structural eye disease v4.40 WDR37 Arina Puzriakova Tag gene-checked was removed from gene: WDR37.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.88 IKZF2 Ida Ertmanska Tag gene-checked was removed from gene: IKZF2.
Intellectual disability v9.336 WDR37 Arina Puzriakova Tag gene-checked was removed from gene: WDR37.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.88 IKZF2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 20 Mar 2026.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.88 IKZF2 Ida Ertmanska Phenotypes for gene: IKZF2 were changed from combined immunodeficiency; thrush; mucosal ulcers; chronic lymphoadenopathy; reduced MAIT cells to Immunodysregulation with variable immunodeficiency and autoimmunity, OMIM:621233; Immunodysregulation, craniofacial anomalies, hearing impairment, athelia, and developmental delay, OMIM:621234
Early onset or syndromic epilepsy v8.162 WDR37 Arina Puzriakova Tag gene-checked was removed from gene: WDR37.
DDG2P v6.441 WDR37 Arina Puzriakova Tag gene-checked was removed from gene: WDR37.
Fetal anomalies v6.178 WDR37 Arina Puzriakova Tag gene-checked was removed from gene: WDR37.
Severe microcephaly v8.35 WDR37 Arina Puzriakova Tag gene-checked was removed from gene: WDR37.
Paediatric disorders - additional genes v7.37 WBP11 Arina Puzriakova Tag gene-checked was removed from gene: WBP11.
Fetal anomalies v6.178 WBP11 Arina Puzriakova Tag gene-checked was removed from gene: WBP11.
Skeletal dysplasia v8.38 WBP11 Arina Puzriakova Tag gene-checked was removed from gene: WBP11.
Retinal disorders v8.100 USP45 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Retinal disorders v8.100 USP45 Arina Puzriakova Phenotypes for gene: USP45 were changed from Lebers congenital amaurosis; retinal dystrophy; ?Leber congenital amaurosis 19, OMIMM:618513 to ?Leber congenital amaurosis 19, OMIM:618513
Retinal disorders v8.99 USP45 Arina Puzriakova Tag gene-checked was removed from gene: USP45.
Intellectual disability v9.336 UPF1 Arina Puzriakova Tag gene-checked tag was added to gene: UPF1.
Fetal anomalies v6.178 HMGB1 Ida Ertmanska Publications for gene: HMGB1 were set to 34164801
Fetal anomalies v6.177 HMGB1 Ida Ertmanska Tag gene-checked tag was added to gene: HMGB1.
Renal ciliopathies v4.11 TXNDC15 Arina Puzriakova Tag gene-checked was removed from gene: TXNDC15.
Neurological ciliopathies v6.15 TXNDC15 Arina Puzriakova Tag gene-checked was removed from gene: TXNDC15.
Rare multisystem ciliopathy disorders v1.180 TXNDC15 Arina Puzriakova Tag gene-checked was removed from gene: TXNDC15.
Fetal anomalies v6.177 TXNDC15 Arina Puzriakova Tag gene-checked was removed from gene: TXNDC15.
Limb disorders v7.22 TXNDC15 Arina Puzriakova Tag gene-checked was removed from gene: TXNDC15.
Intellectual disability v9.336 HECTD4 Ida Ertmanska Tag gene-checked was removed from gene: HECTD4.
Early onset or syndromic epilepsy v8.162 HECTD4 Ida Ertmanska Tag gene-checked was removed from gene: HECTD4.
Intellectual disability v9.336 TUBGCP2 Arina Puzriakova Tag gene-checked was removed from gene: TUBGCP2.
Early onset or syndromic epilepsy v8.162 TUBGCP2 Arina Puzriakova Tag gene-checked was removed from gene: TUBGCP2.
DDG2P v6.441 HECTD4 Ida Ertmanska Tag gene-checked was removed from gene: HECTD4.
DDG2P v6.441 TUBGCP2 Arina Puzriakova Tag gene-checked was removed from gene: TUBGCP2.
Fetal anomalies v6.177 TUBGCP2 Arina Puzriakova Tag gene-checked was removed from gene: TUBGCP2.
Severe microcephaly v8.35 TUBGCP2 Arina Puzriakova Tag gene-checked was removed from gene: TUBGCP2.
Malformations of cortical development v7.39 TUBGCP2 Arina Puzriakova Tag gene-checked was removed from gene: TUBGCP2.
Fetal anomalies v6.177 HECTD4 Ida Ertmanska Tag gene-checked was removed from gene: HECTD4.
Childhood onset hereditary spastic paraplegia v8.41 HECTD4 Ida Ertmanska Tag gene-checked was removed from gene: HECTD4.
Malformations of cortical development v7.39 HECTD4 Ida Ertmanska Tag gene-checked was removed from gene: HECTD4.
Severe microcephaly v8.35 TTC5 Arina Puzriakova Tag gene-checked was removed from gene: TTC5.
DDG2P v6.441 TTC5 Arina Puzriakova Tag gene-checked was removed from gene: TTC5.
Intellectual disability v9.336 TTC5 Arina Puzriakova Tag gene-checked was removed from gene: TTC5.
DDG2P v6.441 HEATR5B Ida Ertmanska Tag gene-checked tag was added to gene: HEATR5B.
Intellectual disability v9.336 HEATR5B Ida Ertmanska Tag gene-checked tag was added to gene: HEATR5B.
Early onset or syndromic epilepsy v8.162 HEATR5B Ida Ertmanska Tag gene-checked tag was added to gene: HEATR5B.
Mitochondrial disorders v9.46 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
Intellectual disability v9.336 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
Early onset or syndromic epilepsy v8.162 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
DDG2P v6.441 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
Fetal anomalies v6.177 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
Possible mitochondrial disorder - nuclear genes v4.23 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
Likely inborn error of metabolism v8.100 TRIT1 Arina Puzriakova Tag gene-checked was removed from gene: TRIT1.
Ataxia and cerebellar anomalies - narrow panel v8.72 HEATR5B Ida Ertmanska Tag gene-checked tag was added to gene: HEATR5B.
DDG2P v6.441 TRIM71 Arina Puzriakova Phenotypes for gene: TRIM71 were changed from TRIM71-related neurodevelopmental disorder with ventriculomegaly and hydrocephalus; MONDO:0032862; OMIM:618667.0 to TRIM71-related neurodevelopmental disorder with ventriculomegaly and hydrocephalus; hydrocephalus, congenital communicating, 1, MONDO:0032862; Hydrocephalus, congenital communicating, 1, OMIM:618667
DDG2P v6.440 GTF3C5 Ida Ertmanska Tag gene-checked tag was added to gene: GTF3C5.
Fetal anomalies v6.177 TRIM71 Arina Puzriakova Tag gene-checked was removed from gene: TRIM71.
Hydrocephalus v5.12 TRIM71 Arina Puzriakova Tag gene-checked was removed from gene: TRIM71.
Paediatric disorders - additional genes v7.37 GREB1L Ida Ertmanska Phenotypes for gene: GREB1L were changed from Deafness, autosomal dominant 80 OMIM:619274; deafness, autosomal dominant 80, MONDO:0030998; Renal hypodysplasia/aplasia 3, OMIM:617805 Renal agenesis, MONDO:0018470 to Deafness, autosomal dominant 80 OMIM:619274; deafness, autosomal dominant 80, MONDO:0030998; Renal hypodysplasia/aplasia 3, OMIM:617805; Renal agenesis, MONDO:0018470
Monogenic hearing loss v5.57 FOXI1 Barbara Vona reviewed gene: FOXI1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 41833579; Phenotypes: Hearing loss with Mondini malformation and and enlarged vestibular aqueduct; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v7.36 GREB1L Ida Ertmanska Phenotypes for gene: GREB1L were changed from CAKUT; Renal hypodysplasia/aplasia 3, 617805; inner ear malformations to Deafness, autosomal dominant 80 OMIM:619274; deafness, autosomal dominant 80, MONDO:0030998; Renal hypodysplasia/aplasia 3, OMIM:617805 Renal agenesis, MONDO:0018470
Childhood solid tumours v5.10 TRIM28 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Childhood solid tumours v5.10 TRIM28 Arina Puzriakova Phenotypes for gene: TRIM28 were changed from Familial Wilms tumor; Wilms tumour to Wilms tumor 7, OMIM:621332
Childhood solid tumours v5.9 TRIM28 Arina Puzriakova Tag gene-checked was removed from gene: TRIM28.
Intellectual disability v9.336 TRA2B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.336 TRA2B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability v9.336 TRA2B Achchuthan Shanmugasundram Deleted their comment
Monogenic hearing loss v5.57 GREB1L Ida Ertmanska Tag gene-checked was removed from gene: GREB1L.
DDG2P v6.440 GREB1L Ida Ertmanska Tag gene-checked was removed from gene: GREB1L.
Fetal anomalies v6.177 GREB1L Ida Ertmanska Tag gene-checked was removed from gene: GREB1L.
Intellectual disability v9.336 TRA2B Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.336 TRA2B Arina Puzriakova Phenotypes for gene: TRA2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Ramond-Elliott neurodevelopmental syndrome, OMIM:621421
Early onset or syndromic epilepsy v8.162 TRA2B Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Early onset or syndromic epilepsy v8.162 TRA2B Arina Puzriakova Phenotypes for gene: TRA2B were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to Ramond-Elliott neurodevelopmental syndrome, OMIM:621421
CAKUT v1.182 GREB1L Ida Ertmanska Tag gene-checked was removed from gene: GREB1L.
CAKUT v1.182 GREB1L Ida Ertmanska Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, 617805 to Renal hypodysplasia/aplasia 3, OMIM:617805 Renal agenesis, MONDO:0018470
Severe microcephaly v8.35 TRA2B Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Severe microcephaly v8.35 TRA2B Arina Puzriakova Phenotypes for gene: TRA2B were changed from neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149 to Ramond-Elliott neurodevelopmental syndrome, OMIM:621421
Paediatric disorders - additional genes v7.35 GREB1L Ida Ertmanska Tag gene-checked was removed from gene: GREB1L.
Intellectual disability v9.335 TRA2B Arina Puzriakova Tag gene-checked was removed from gene: TRA2B.
Early onset or syndromic epilepsy v8.161 TRA2B Arina Puzriakova Tag gene-checked was removed from gene: TRA2B.
Fetal anomalies v6.177 GPKOW Ida Ertmanska Tag gene-checked tag was added to gene: GPKOW.
DDG2P v6.440 TRA2B Arina Puzriakova Tag gene-checked was removed from gene: TRA2B.
Severe microcephaly v8.34 GPKOW Ida Ertmanska Tag gene-checked tag was added to gene: GPKOW.
Paediatric disorders - additional genes v7.35 GPKOW Ida Ertmanska Tag gene-checked tag was added to gene: GPKOW.
Intellectual disability v9.335 TMEM94 Arina Puzriakova Tag gene-checked was removed from gene: TMEM94.
DDG2P v6.440 TMEM94 Arina Puzriakova Tag gene-checked was removed from gene: TMEM94.
Fetal anomalies v6.177 TMEM94 Arina Puzriakova Tag gene-checked was removed from gene: TMEM94.
Retinal disorders v8.99 GPATCH11 Ida Ertmanska Tag gene-checked tag was added to gene: GPATCH11.
Intellectual disability v9.335 GPATCH11 Ida Ertmanska Tag gene-checked tag was added to gene: GPATCH11.
Intellectual disability v9.335 TMEM63C Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.335 TMEM63C Arina Puzriakova Phenotypes for gene: TMEM63C were changed from hereditary spastic paraplegia, MONDO:0019064 to Spastic paraplegia 87, autosomal recessive, OMIM:619966
Childhood onset hereditary spastic paraplegia v8.41 TMEM63C Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Childhood onset hereditary spastic paraplegia v8.41 TMEM63C Arina Puzriakova Phenotypes for gene: TMEM63C were changed from hereditary spastic paraplegia, MONDO:0019064 to Spastic paraplegia 87, autosomal recessive, OMIM:619966
Fetal anomalies v6.177 GINS3 Ida Ertmanska Tag gene-checked tag was added to gene: GINS3.
DDG2P v6.440 TMEM63C Arina Puzriakova Tag gene-checked was removed from gene: TMEM63C.
Intellectual disability v9.334 TMEM63C Arina Puzriakova Tag gene-checked was removed from gene: TMEM63C.
Hereditary ataxia with onset in adulthood v8.30 GDAP2 Ida Ertmanska Tag gene-checked was removed from gene: GDAP2.
Childhood onset hereditary spastic paraplegia v8.40 TMEM63C Arina Puzriakova Tag gene-checked was removed from gene: TMEM63C.
Intellectual disability v9.334 TMEM63B Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.334 TMEM63B Arina Puzriakova Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062 to Developmental and epileptic encephalopathy 118, OMIM:621250
Early onset or syndromic epilepsy v8.161 TMEM63B Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Early onset or syndromic epilepsy v8.161 TMEM63B Arina Puzriakova Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062 to Developmental and epileptic encephalopathy 118, OMIM:621250
Hereditary ataxia with onset in adulthood v8.30 GDAP2 Ida Ertmanska Tag gene-checked tag was added to gene: GDAP2.
Intellectual disability v9.333 TMEM63B Arina Puzriakova Tag gene-checked was removed from gene: TMEM63B.
Early onset or syndromic epilepsy v8.160 TMEM63B Arina Puzriakova Tag gene-checked was removed from gene: TMEM63B.
DDG2P v6.440 TMEM63B Arina Puzriakova Tag gene-checked was removed from gene: TMEM63B.
DDG2P v6.440 GABRA4 Ida Ertmanska Tag gene-checked tag was added to gene: GABRA4.
DDG2P v6.440 TMEM63A Arina Puzriakova Tag gene-checked was removed from gene: TMEM63A.
White matter disorders and cerebral calcification - narrow panel v7.19 TMEM63A Arina Puzriakova Tag gene-checked was removed from gene: TMEM63A.
Skeletal dysplasia v8.38 TMEM251 Arina Puzriakova Tag gene-checked was removed from gene: TMEM251.
DDG2P v6.440 TMEM251 Arina Puzriakova Tag gene-checked was removed from gene: TMEM251.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.4 TMEM251 Arina Puzriakova Tag gene-checked was removed from gene: TMEM251.
Intellectual disability v9.333 FRYL Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 20 Mar 2026.
Intellectual disability v9.333 FRYL Ida Ertmanska Phenotypes for gene: FRYL were changed from Neurodevelopmental disorder, MONDO:0700092 to Pan-Chung-Bellen syndrome, OMIM:621049; Pan-Chung-Bellen syndrome, MONDO:0975953
Intellectual disability v9.332 FRYL Ida Ertmanska Tag gene-checked was removed from gene: FRYL.
DDG2P v6.440 FRYL Ida Ertmanska Tag gene-checked was removed from gene: FRYL.
Fetal anomalies v6.177 FRYL Ida Ertmanska Tag gene-checked was removed from gene: FRYL.
Fetal anomalies v6.177 FRYL Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 20 Mar 2026.
Fetal anomalies v6.177 FRYL Ida Ertmanska Phenotypes for gene: FRYL were changed from Neurodevelopmental disorder, MONDO:0700092, FRYL-related to Pan-Chung-Bellen syndrome, OMIM:621049; Pan-Chung-Bellen syndrome, MONDO:0975953
DDG2P v6.440 FRYL Ida Ertmanska Phenotypes for gene: FRYL were changed from Pan-Chung-Bellen syndrome, OMIM:621049; MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities to Pan-Chung-Bellen syndrome, OMIM:621049; Pan-Chung-Bellen syndrome, MONDO:0975953
DDG2P v6.439 FRYL Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 20 Mar 2026.
DDG2P v6.439 FRYL Ida Ertmanska Phenotypes for gene: FRYL were changed from MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities to Pan-Chung-Bellen syndrome, OMIM:621049; MONDO:0975953; FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities
Intellectual disability v9.332 TMEM222 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.332 TMEM222 Arina Puzriakova Phenotypes for gene: TMEM222 were changed from Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality to Neurodevelopmental disorder with motor and speech delay and behavioral abnormalities, OMIM:619470
Early onset or syndromic epilepsy v8.160 TMEM222 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Early onset or syndromic epilepsy v8.160 TMEM222 Arina Puzriakova Phenotypes for gene: TMEM222 were changed from Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality to Neurodevelopmental disorder with motor and speech delay and behavioral abnormalities, OMIM:619470
DDG2P v6.438 TMEM222 Arina Puzriakova Tag gene-checked was removed from gene: TMEM222.
Intellectual disability v9.331 TMEM222 Arina Puzriakova Tag gene-checked was removed from gene: TMEM222.
Early onset or syndromic epilepsy v8.159 TMEM222 Arina Puzriakova Tag gene-checked was removed from gene: TMEM222.
Fetal anomalies v6.176 TMEM17 Arina Puzriakova Tag gene-checked was removed from gene: TMEM17.
Neurological ciliopathies v6.15 TMEM218 Arina Puzriakova Tag gene-checked was removed from gene: TMEM218.
Ophthalmological ciliopathies v5.15 TMEM218 Arina Puzriakova Tag gene-checked was removed from gene: TMEM218.
Rare multisystem ciliopathy disorders v1.180 TMEM218 Arina Puzriakova Tag gene-checked was removed from gene: TMEM218.
Retinal disorders v8.99 TMEM218 Arina Puzriakova Tag gene-checked was removed from gene: TMEM218.
DDG2P v6.438 TMEM218 Arina Puzriakova Tag gene-checked was removed from gene: TMEM218.
Fetal anomalies v6.176 TMEM218 Arina Puzriakova Tag gene-checked was removed from gene: TMEM218.
Fetal anomalies v6.176 TMEM17 Arina Puzriakova Publications for gene: TMEM17 were set to
Fetal anomalies v6.175 TMEM17 Arina Puzriakova Phenotypes for gene: TMEM17 were changed from Ciliopathy to ciliopathy, MONDO:0005308
Fetal anomalies v6.174 TMEM17 Arina Puzriakova Tag gene-checked tag was added to gene: TMEM17.
Early onset or syndromic epilepsy v8.159 TMEM167A Arina Puzriakova Tag gene-checked tag was added to gene: TMEM167A.
Fetal anomalies v6.174 TMEM167A Arina Puzriakova Tag gene-checked tag was added to gene: TMEM167A.
Severe microcephaly v8.34 TMEM167A Arina Puzriakova Tag gene-checked tag was added to gene: TMEM167A.
Neonatal diabetes v5.19 TMEM167A Arina Puzriakova Tag gene-checked tag was added to gene: TMEM167A.
Fetal anomalies v6.174 TMEM167A Arina Puzriakova Publications for gene: TMEM167A were set to
Fetal anomalies v6.173 TMEM167A Arina Puzriakova Phenotypes for gene: TMEM167A were changed from Microcephaly, epilepsy and diabetes syndrome to Microcephaly, epilepsy, and diabetes syndrome, MONDO:0100328
Childhood onset dystonia, chorea or related movement disorder v7.18 TMEM151A Arina Puzriakova Tag gene-checked was removed from gene: TMEM151A.
Ataxia and cerebellar anomalies - narrow panel v8.72 THG1L Arina Puzriakova Tag gene-checked was removed from gene: THG1L.
Intellectual disability v9.331 TBC1D8B Arina Puzriakova Tag gene-checked was removed from gene: TBC1D8B.
Proteinuric renal disease v5.9 TBC1D8B Arina Puzriakova Tag gene-checked was removed from gene: TBC1D8B.
DDG2P v6.438 TBC1D2B Arina Puzriakova Tag gene-checked was removed from gene: TBC1D2B.
Early onset or syndromic epilepsy v8.159 TBC1D2B Arina Puzriakova Tag gene-checked was removed from gene: TBC1D2B.
Intellectual disability v9.331 TBC1D2B Arina Puzriakova Tag gene-checked was removed from gene: TBC1D2B.
Intellectual disability v9.331 SVBP Arina Puzriakova Tag gene-checked was removed from gene: SVBP.
Severe microcephaly v8.34 SVBP Arina Puzriakova Tag gene-checked was removed from gene: SVBP.
Ataxia and cerebellar anomalies - narrow panel v8.72 SVBP Arina Puzriakova Tag gene-checked was removed from gene: SVBP.
Childhood onset dystonia, chorea or related movement disorder v7.18 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
Intellectual disability v9.331 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
Early onset or syndromic epilepsy v8.159 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
Monogenic hearing loss v5.57 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
DDG2P v6.438 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
Childhood onset hereditary spastic paraplegia v8.40 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
Severe microcephaly v8.34 SPATA5L1 Arina Puzriakova Tag gene-checked was removed from gene: SPATA5L1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.87 SNORA31 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Primary immunodeficiency or monogenic inflammatory bowel disease v8.87 SNORA31 Arina Puzriakova Phenotypes for gene: SNORA31 were changed from Herpes simplex encephalitis to {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 10}, OMIM:619396
Primary immunodeficiency or monogenic inflammatory bowel disease v8.86 SNORA31 Arina Puzriakova Tag gene-checked was removed from gene: SNORA31.
DDG2P v6.438 SEPHS1 Arina Puzriakova Tag gene-checked was removed from gene: SEPHS1.
Intellectual disability v9.331 SEPHS1 Arina Puzriakova Tag gene-checked was removed from gene: SEPHS1.
Retinal disorders v8.99 SAMD7 Arina Puzriakova Tag gene-checked was removed from gene: SAMD7.
Fetal anomalies v6.172 RREB1 Arina Puzriakova Publications for gene: RREB1 were set to
Fetal anomalies v6.171 RREB1 Arina Puzriakova Phenotypes for gene: RREB1 were changed from Rasopathy, mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay to RASopathy, MONDO:0021060; Rasopathy, mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay
Fetal anomalies v6.170 RREB1 Arina Puzriakova Tag gene-checked tag was added to gene: RREB1.
Intellectual disability v9.331 RNU7-1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Intellectual disability v9.331 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like; Type I interferonopathy to Aicardi-Goutieres syndrome 9, OMIM:619487; Type I interferonopathy
Fetal anomalies v6.170 RNU7-1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Fetal anomalies v6.170 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi-Goutieres syndrome 9 OMIM:619487 to Aicardi-Goutieres syndrome 9, OMIM:619487; Type I interferonopathy
Childhood onset dystonia, chorea or related movement disorder v7.18 RNU7-1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Childhood onset dystonia, chorea or related movement disorder v7.18 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like; Type I interferonopathy to Aicardi-Goutieres syndrome 9, OMIM:619487; Type I interferonopathy
Childhood onset hereditary spastic paraplegia v8.40 RNU7-1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Childhood onset hereditary spastic paraplegia v8.40 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Type I interferonopathy; Aicardi-Goutières syndrome to Aicardi-Goutieres syndrome 9, OMIM:619487; Type I interferonopathy
White matter disorders and cerebral calcification - narrow panel v7.19 RNU7-1 Arina Puzriakova commented on gene: RNU7-1: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Childhood onset dystonia, chorea or related movement disorder v7.17 RNU7-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU7-1.
Intellectual disability v9.330 RNU7-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU7-1.
Fetal anomalies v6.169 RNU7-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU7-1.
Childhood onset hereditary spastic paraplegia v8.39 RNU7-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU7-1.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.86 RNU7-1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Primary immunodeficiency or monogenic inflammatory bowel disease v8.86 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi-Goutières syndrome-like; Type 1 interferonopathy to Aicardi-Goutieres syndrome 9, OMIM:619487; Type I interferonopathy
Primary immunodeficiency or monogenic inflammatory bowel disease v8.85 RNU7-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU7-1.
White matter disorders and cerebral calcification - narrow panel v7.19 RNU7-1 Arina Puzriakova Phenotypes for gene: RNU7-1 were changed from Aicardi–Goutières syndrome-like; Type I interferonopathy to Aicardi-Goutieres syndrome 9, OMIM:619487; Type I interferonopathy
White matter disorders and cerebral calcification - narrow panel v7.18 RNU7-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU7-1.
Intellectual disability v9.330 RNU5B-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU5B-1.
Early onset or syndromic epilepsy v8.159 RNU5B-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU5B-1.
DDG2P v6.438 RNU5B-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU5B-1.
Fetal anomalies v6.169 RNU5B-1 Arina Puzriakova Tag gene-checked was removed from gene: RNU5B-1.
Intellectual disability v9.330 RNU4-2 Arina Puzriakova Tag gene-checked was removed from gene: RNU4-2.
Severe microcephaly v8.34 RNU4-2 Arina Puzriakova Tag gene-checked was removed from gene: RNU4-2.
Fetal anomalies v6.169 RNU4-2 Arina Puzriakova Tag gene-checked was removed from gene: RNU4-2.
DDG2P v6.438 RNU4-2 Arina Puzriakova Tag gene-checked was removed from gene: RNU4-2.
Early onset or syndromic epilepsy v8.159 RNU4-2 Arina Puzriakova Tag gene-checked was removed from gene: RNU4-2.
DDG2P v6.438 RNU12 Arina Puzriakova Tag gene-checked was removed from gene: RNU12.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.4 RNU12 Arina Puzriakova Tag gene-checked was removed from gene: RNU12.
Fetal anomalies v6.169 RNU12 Arina Puzriakova Tag gene-checked was removed from gene: RNU12.
Rare genetic inflammatory skin disorders v4.18 RNU12 Arina Puzriakova Tag gene-checked was removed from gene: RNU12.
Monogenic short stature v1.31 RNPC3 Arina Puzriakova Tag gene-checked was removed from gene: RNPC3.
Intellectual disability v9.330 RNPC3 Arina Puzriakova Tag gene-checked was removed from gene: RNPC3.
DDG2P v6.438 RNPC3 Arina Puzriakova Tag gene-checked was removed from gene: RNPC3.
Pituitary hormone deficiency v4.4 RNPC3 Arina Puzriakova Tag gene-checked was removed from gene: RNPC3.
Mitochondrial disorders v9.46 PITRM1 Arina Puzriakova Tag gene-checked was removed from gene: PITRM1.
Intellectual disability v9.330 PITRM1 Arina Puzriakova Tag gene-checked was removed from gene: PITRM1.
Likely inborn error of metabolism v8.100 PITRM1 Arina Puzriakova Tag gene-checked was removed from gene: PITRM1.
Ataxia and cerebellar anomalies - narrow panel v8.72 PITRM1 Arina Puzriakova Tag gene-checked was removed from gene: PITRM1.
Fetal anomalies v6.169 FRYL Ida Ertmanska Tag gene-checked tag was added to gene: FRYL.
Intellectual disability v9.330 FRYL Ida Ertmanska Tag gene-checked tag was added to gene: FRYL.
DDG2P v6.438 FRYL Ida Ertmanska Tag gene-checked tag was added to gene: FRYL.
Intellectual disability v9.330 FICD Ida Ertmanska Tag gene-checked was removed from gene: FICD.
Childhood onset hereditary spastic paraplegia v8.39 FICD Ida Ertmanska Tag gene-checked was removed from gene: FICD.
Neonatal diabetes v5.19 FICD Ida Ertmanska Tag gene-checked was removed from gene: FICD.
Hereditary neuropathy or pain disorder v7.43 FICD Ida Ertmanska Tag gene-checked was removed from gene: FICD.
Neonatal diabetes v5.19 FICD Ida Ertmanska Tag gene-checked tag was added to gene: FICD.
Intellectual disability v9.330 FICD Ida Ertmanska Tag gene-checked tag was added to gene: FICD.
DDG2P v6.438 FEZF2 Ida Ertmanska Tag gene-checked tag was added to gene: FEZF2.
Intellectual disability v9.330 FEM1B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 19 Mar 2026.
Intellectual disability v9.330 FEM1B Ida Ertmanska Phenotypes for gene: FEM1B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, OMIM:621263; neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability v9.329 FEM1B Ida Ertmanska Tag gene-checked was removed from gene: FEM1B.
DDG2P v6.438 FEM1B Ida Ertmanska Tag gene-checked was removed from gene: FEM1B.
DDG2P v6.438 FEM1B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 19 Mar 2026.
DDG2P v6.438 FEM1B Ida Ertmanska Phenotypes for gene: FEM1B were changed from FEM1B-related neurodevelopmental disorder with or without brain abnormalities to Neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, OMIM:613539; FEM1B-related neurodevelopmental disorder with or without brain abnormalities
Fetal anomalies v6.169 FAM177A1 Ida Ertmanska Tag gene-checked tag was added to gene: FAM177A1.
DDG2P v6.437 FAM177A1 Ida Ertmanska Tag gene-checked tag was added to gene: FAM177A1.
Rare multisystem ciliopathy disorders v1.180 FAM149B1 Ida Ertmanska Tag gene-checked tag was added to gene: FAM149B1.
Intellectual disability v9.329 EPB41L3 Ida Ertmanska Tag gene-checked tag was added to gene: EPB41L3.
White matter disorders and cerebral calcification - narrow panel v7.18 EPB41L3 Ida Ertmanska Tag gene-checked tag was added to gene: EPB41L3.
Early onset or syndromic epilepsy v8.159 EPB41L3 Ida Ertmanska Tag gene-checked tag was added to gene: EPB41L3.
DDG2P v6.437 EIF3B Ida Ertmanska Tag gene-checked tag was added to gene: EIF3B.
Paediatric disorders - additional genes v7.35 EIF3B Ida Ertmanska Tag gene-checked tag was added to gene: EIF3B.
Fetal anomalies v6.169 EIF3B Ida Ertmanska Tag gene-checked tag was added to gene: EIF3B.
Paediatric disorders - additional genes v7.35 EIF3A Ida Ertmanska Tag gene-checked tag was added to gene: EIF3A.
DDG2P v6.437 EIF3A Ida Ertmanska Tag gene-checked tag was added to gene: EIF3A.
DDG2P v6.437 DOT1L Ida Ertmanska Phenotypes for gene: DOT1L were changed from DOT1L-related neurodevelopmental disorder with intracranial anomalies to Nil-Deshwar neurodevelopmental syndrome, OMIM:621265
DDG2P v6.436 DOT1L Ida Ertmanska Tag gene-checked was removed from gene: DOT1L.
Intellectual disability v9.329 DDX39B Ida Ertmanska Tag gene-checked tag was added to gene: DDX39B.
Fetal anomalies v6.169 DDX17 Ida Ertmanska Tag gene-checked tag was added to gene: DDX17.
DDG2P v6.436 DDX17 Ida Ertmanska Tag gene-checked tag was added to gene: DDX17.
Embryonal tumour of possible germline origin v0.8 CTR9 Ida Ertmanska Tag gene-checked tag was added to gene: CTR9.
DDG2P v6.436 CSDE1 Ida Ertmanska Tag gene-checked tag was added to gene: CSDE1.
Fetal anomalies v6.169 CSDE1 Ida Ertmanska Tag gene-checked tag was added to gene: CSDE1.
Intellectual disability v9.329 CFAP47 Ida Ertmanska Tag gene-checked tag was added to gene: CFAP47.
Cystic kidney disease v8.8 CFAP47 Ida Ertmanska Tag gene-checked tag was added to gene: CFAP47.
Fetal anomalies v6.169 CEP76 Ida Ertmanska Tag gene-checked tag was added to gene: CEP76.
Intellectual disability v9.329 CELF4 Ida Ertmanska Tag gene-checked tag was added to gene: CELF4.
Early onset or syndromic epilepsy v8.159 CELF4 Ida Ertmanska Tag gene-checked tag was added to gene: CELF4.
DDG2P v6.436 CELF4 Ida Ertmanska Tag gene-checked tag was added to gene: CELF4.
Fetal anomalies v6.169 CCDC32 Ida Ertmanska Tag gene-checked tag was added to gene: CCDC32.
Fetal anomalies v6.169 CACHD1 Ida Ertmanska Tag gene-checked tag was added to gene: CACHD1.
Paediatric disorders - additional genes v7.35 CACHD1 Ida Ertmanska Tag gene-checked tag was added to gene: CACHD1.
Fetal anomalies v6.169 C14orf80 Ida Ertmanska Tag gene-checked tag was added to gene: C14orf80.
DDG2P v6.436 C14orf80 Ida Ertmanska Tag gene-checked tag was added to gene: C14orf80.
Intellectual disability v9.329 TAOK2 Arina Puzriakova Publications for gene: TAOK2 were set to 39737487
Intellectual disability v9.328 TAOK2 Arina Puzriakova Tag gene-checked tag was added to gene: TAOK2.
Mitochondrial disorders v9.46 SUPV3L1 Arina Puzriakova Tag gene-checked tag was added to gene: SUPV3L1.
Intellectual disability v9.328 SUPV3L1 Arina Puzriakova Tag gene-checked tag was added to gene: SUPV3L1.
Likely inborn error of metabolism v8.100 SUPV3L1 Arina Puzriakova Tag gene-checked tag was added to gene: SUPV3L1.
DDG2P v6.436 SREBF2 Arina Puzriakova Tag gene-checked tag was added to gene: SREBF2.
DDG2P v6.436 SP9 Arina Puzriakova Phenotypes for gene: SP9 were changed from MONDO:0100038; SP9-related neurodevelopmental disorder with or without epileptic encephalopathy to complex neurodevelopmental disorder, MONDO:0100038; SP9-related neurodevelopmental disorder with or without epileptic encephalopathy
DDG2P v6.435 SP9 Arina Puzriakova Tag gene-checked tag was added to gene: SP9.
Intellectual disability v9.328 SMARCA1 Arina Puzriakova Tag gene-checked tag was added to gene: SMARCA1.
DDG2P v6.435 SLC13A1 Arina Puzriakova Tag gene-checked tag was added to gene: SLC13A1.
Intellectual disability v9.328 BRSK1 Ida Ertmanska Tag gene-checked tag was added to gene: BRSK1.
Fetal anomalies v6.169 SIX2 Arina Puzriakova Publications for gene: SIX2 were set to
Fetal anomalies v6.168 SIX2 Arina Puzriakova Phenotypes for gene: SIX2 were changed from frontonasal dysplasia to six2-related frontonasal dysplasia, MONDO:0044628
Fetal anomalies v6.167 SIX2 Arina Puzriakova Tag gene-checked tag was added to gene: SIX2.
Early onset or syndromic epilepsy v8.159 BRSK1 Ida Ertmanska Tag gene-checked tag was added to gene: BRSK1.
Fetal anomalies v6.167 SHROOM4 Arina Puzriakova Tag gene-checked tag was added to gene: SHROOM4.
Fetal anomalies v6.167 BRF2 Ida Ertmanska Tag gene-checked tag was added to gene: BRF2.
DDG2P v6.435 ATXN7L3 Ida Ertmanska Tag gene-checked tag was added to gene: ATXN7L3.
Fetal anomalies v6.167 SHROOM4 Arina Puzriakova Phenotypes for gene: SHROOM4 were changed from Abnormal corpus callosum; congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems; Stocco dos Santos X-linked mental retardation syndrome, 300434 to Abnormal corpus callosum; congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems
Fetal anomalies v6.166 SHROOM4 Arina Puzriakova Publications for gene: SHROOM4 were set to 36379543; 32565546
DDG2P v6.435 SF1 Arina Puzriakova Tag gene-checked tag was added to gene: SF1.
Intellectual disability v9.328 SF1 Arina Puzriakova Tag gene-checked tag was added to gene: SF1.
DDG2P v6.435 SF1 Arina Puzriakova Phenotypes for gene: SF1 were changed from MONDO:0700092; SF1-related neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092; SF1-related neurodevelopmental disorder
DDG2P v6.434 SEPHS1 Arina Puzriakova Phenotypes for gene: SEPHS1 were changed from MONDO:0700092; SEPHS1-related neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092; SEPHS1-related neurodevelopmental disorder
Fetal anomalies v6.165 TMEM251 Ida Ertmanska commented on gene: TMEM251
DDG2P v6.433 SEPHS1 Arina Puzriakova Tag gene-checked tag was added to gene: SEPHS1.
Intellectual disability v9.328 SEPHS1 Arina Puzriakova Phenotypes for gene: SEPHS1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Ververi-Brady syndrome 2, OMIM:621325; Neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.165 RSG1 Ida Ertmanska commented on gene: RSG1
Arthrogryposis v9.31 MYLPF Ida Ertmanska commented on gene: MYLPF
Fetal anomalies v6.165 SART3 Arina Puzriakova Tag gene-checked tag was added to gene: SART3.
Fetal anomalies v6.165 MYLPF Ida Ertmanska commented on gene: MYLPF
Fetal anomalies v6.165 TTC26 Ida Ertmanska commented on gene: TTC26
DDG2P v6.433 RYBP Arina Puzriakova Tag gene-checked tag was added to gene: RYBP.
DDG2P v6.433 RYBP Arina Puzriakova Phenotypes for gene: RYBP were changed from RYBP-related neurodevelopmental disorder with congenital anomalies; MONDO:0100038 to RYBP-related neurodevelopmental disorder with congenital anomalies; complex neurodevelopmental disorder, MONDO:0100038
Fetal anomalies v6.165 RSG1 Arina Puzriakova Tag gene-checked tag was added to gene: RSG1.
Fetal anomalies v6.165 H3F3B Ida Ertmanska commented on gene: H3F3B
Fetal anomalies v6.165 RSG1 Arina Puzriakova Phenotypes for gene: RSG1 were changed from ciliopathy to ciliopathy, MONDO:0005308
Fetal anomalies v6.164 RSG1 Arina Puzriakova Publications for gene: RSG1 were set to
Intellectual disability v9.327 WARS Ida Ertmanska commented on gene: WARS
Severe microcephaly v8.34 WARS Ida Ertmanska commented on gene: WARS
Retinal disorders v8.99 AP5M1 Ida Ertmanska Tag gene-checked tag was added to gene: AP5M1.
Fetal anomalies v6.163 ARF3 Ida Ertmanska Tag gene-checked tag was added to gene: ARF3.
Intellectual disability v9.327 ABI2 Ida Ertmanska Tag gene-checked tag was added to gene: ABI2.
Intellectual disability v9.327 RREB1 Arina Puzriakova Tag gene-checked tag was added to gene: RREB1.
Early onset or syndromic epilepsy v8.159 ABI2 Ida Ertmanska Tag gene-checked tag was added to gene: ABI2.
Fetal anomalies v6.163 ABI2 Ida Ertmanska Tag gene-checked tag was added to gene: ABI2.
White matter disorders and cerebral calcification - narrow panel v7.18 ABI2 Ida Ertmanska Tag gene-checked tag was added to gene: ABI2.
Fetal anomalies v6.163 RNU7-1 Arina Puzriakova Tag gene-checked tag was added to gene: RNU7-1.
Retinal disorders v8.99 RNU6-9 Arina Puzriakova Tag gene-checked tag was added to gene: RNU6-9.
Retinal disorders v8.99 RNU6-8 Arina Puzriakova Tag gene-checked tag was added to gene: RNU6-8.
Retinal disorders v8.99 RNU6-2 Arina Puzriakova Tag gene-checked tag was added to gene: RNU6-2.
Retinal disorders v8.99 RNU6-1 Arina Puzriakova Tag gene-checked tag was added to gene: RNU6-1.
DDG2P v6.432 RNU5B-1 Arina Puzriakova Tag locus-type-rna-small-nuclear tag was added to gene: RNU5B-1.
DDG2P v6.432 RNU5B-1 Arina Puzriakova Tag gene-checked tag was added to gene: RNU5B-1.
Fetal anomalies v6.163 RNU5B-1 Arina Puzriakova Tag locus-type-rna-small-nuclear tag was added to gene: RNU5B-1.
DDG2P v6.432 RNU2-2P Arina Puzriakova Phenotypes for gene: RNU2-2P were changed from RNU2-2-related neurodevelopmental disorder with seizures and hyperventilation; MONDO:0100038 to RNU2-2-related neurodevelopmental disorder with seizures and hyperventilation; complex neurodevelopmental disorder, MONDO:0100038; Developmental and epileptic encephalopathy 119, OMIM:621304
Early onset or syndromic epilepsy v8.159 RNU2-2P Arina Puzriakova Phenotypes for gene: RNU2-2P were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to Developmental and epileptic encephalopathy 119, OMIM:621304
Intellectual disability v9.327 RNU2-2P Arina Puzriakova Phenotypes for gene: RNU2-2P were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Developmental and epileptic encephalopathy 119, OMIM:621304
Fetal anomalies v6.163 RNU2-2P Arina Puzriakova Phenotypes for gene: RNU2-2P were changed from neurodevelopmental disorder to Developmental and epileptic encephalopathy 119, OMIM:621304
DDG2P v6.431 RFX4 Arina Puzriakova Tag gene-checked tag was added to gene: RFX4.
DDG2P v6.431 RFX4 Arina Puzriakova Phenotypes for gene: RFX4 were changed from MONDO:0100038; RFX4-related neurodevelopmental disorder with autism and other behavioural abnormalities to complex neurodevelopmental disorder, MONDO:0100038; RFX4-related neurodevelopmental disorder with autism and other behavioural abnormalities
DDG2P v6.430 RFX3 Arina Puzriakova Tag gene-checked tag was added to gene: RFX3.
DDG2P v6.430 RFX3 Arina Puzriakova Phenotypes for gene: RFX3 were changed from RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalities; MONDO:0100038 to RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalities; complex neurodevelopmental disorder, MONDO:0100038
Paediatric disorders - additional genes v7.35 RBFOX2 Arina Puzriakova Tag gene-checked tag was added to gene: RBFOX2.
Fetal anomalies v6.162 RBBP5 Arina Puzriakova Publications for gene: RBBP5 were set to
Fetal anomalies v6.161 RBBP5 Arina Puzriakova Phenotypes for gene: RBBP5 were changed from neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.160 RBBP5 Arina Puzriakova Tag gene-checked tag was added to gene: RBBP5.
DDG2P v6.429 RAB5C Arina Puzriakova Tag gene-checked tag was added to gene: RAB5C.
Hereditary ataxia with onset in adulthood v8.30 RAB3A Arina Puzriakova Tag gene-checked tag was added to gene: RAB3A.
Ataxia and cerebellar anomalies - narrow panel v8.72 RAB3A Arina Puzriakova Tag gene-checked tag was added to gene: RAB3A.
Clefting v6.23 PRKCI Arina Puzriakova Tag gene-checked tag was added to gene: PRKCI.
Fetal anomalies v6.160 PRKCI Arina Puzriakova Tag gene-checked tag was added to gene: PRKCI.
Fetal anomalies v6.160 PRKCI Arina Puzriakova Phenotypes for gene: PRKCI were changed from Van der Woude syndrome to Van der Woude syndrome, MONDO:0019508
Intellectual disability v9.326 PPP1R21 Arina Puzriakova Tag gene-checked was removed from gene: PPP1R21.
DDG2P v6.429 PPP1R21 Arina Puzriakova Tag gene-checked was removed from gene: PPP1R21.
Fetal anomalies v6.159 TMEM251 Ida Ertmanska Tag new-gene-name tag was added to gene: TMEM251.
Fetal anomalies v6.159 PPP1R21 Arina Puzriakova Tag gene-checked was removed from gene: PPP1R21.
Fetal anomalies v6.159 PPP1R21 Arina Puzriakova Tag gene-checked tag was added to gene: PPP1R21.
Fetal anomalies v6.159 RSG1 Ida Ertmanska Tag new-gene-name tag was added to gene: RSG1.
Arthrogryposis v9.31 MYLPF Ida Ertmanska Tag new-gene-name tag was added to gene: MYLPF.
Fetal anomalies v6.159 MYLPF Ida Ertmanska Tag new-gene-name tag was added to gene: MYLPF.
Acute rhabdomyolysis v2.7 POC5 Arina Puzriakova Tag dd_review was removed from gene: POC5.
Tag gene-checked tag was added to gene: POC5.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.4 H3F3B Ida Ertmanska Tag new-gene-name tag was added to gene: H3F3B.
Monogenic diabetes v3.14 POC5 Arina Puzriakova Tag gene-checked tag was added to gene: POC5.
Severe insulin resistance and lipodystrophy syndromes v4.67 POC5 Arina Puzriakova Tag gene-checked tag was added to gene: POC5.
Fetal anomalies v6.159 H3F3B Ida Ertmanska Tag new-gene-name tag was added to gene: H3F3B.
Ophthalmological ciliopathies v5.15 POC5 Arina Puzriakova Tag gene-checked tag was added to gene: POC5.
Retinal disorders v8.99 POC5 Arina Puzriakova Tag gene-checked tag was added to gene: POC5.
Rhabdomyolysis and metabolic muscle disorders v5.17 POC5 Arina Puzriakova Tag dd_review was removed from gene: POC5.
Tag gene-checked tag was added to gene: POC5.
Fetal anomalies v6.159 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Severe microcephaly v8.34 WARS Ida Ertmanska Tag new-gene-name tag was added to gene: WARS.
DDG2P v6.429 PLXNB2 Arina Puzriakova Tag gene-checked tag was added to gene: PLXNB2.
Intellectual disability v9.326 WARS Ida Ertmanska Tag new-gene-name tag was added to gene: WARS.
DDG2P v6.429 PHF5A Arina Puzriakova Phenotypes for gene: PHF5A were changed from PHF5A-related neurodevelopmental disorder with congenital malformations to PHF5A-related neurodevelopmental disorder with congenital malformations; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.326 PHF5A Arina Puzriakova Phenotypes for gene: PHF5A were changed from PHF5A-related neurodevelopmental disorder with congenital malformations to PHF5A-related neurodevelopmental disorder with congenital malformations; neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.159 PHF5A Arina Puzriakova Phenotypes for gene: PHF5A were changed from PHF5A-related neurodevelopmental disorder with congenital malformations to PHF5A-related neurodevelopmental disorder with congenital malformations; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.325 PHF5A Arina Puzriakova Tag gene-checked tag was added to gene: PHF5A.
DDG2P v6.428 PHF12 Arina Puzriakova Tag gene-checked tag was added to gene: PHF12.
Intellectual disability v9.325 PHF12 Arina Puzriakova Tag gene-checked tag was added to gene: PHF12.
DDG2P v6.428 PHF12 Arina Puzriakova Phenotypes for gene: PHF12 were changed from MONDO:0700092; PHF12-related developmental disorder to neurodevelopmental disorder, MONDO:0700092; PHF12-related developmental disorder
Fetal anomalies v6.158 PDIA6 Arina Puzriakova Tag gene-checked tag was added to gene: PDIA6.
Thrombocythaemia v1.12 SH2B3 Ida Ertmanska commented on gene: SH2B3
Embryonal tumour of possible germline origin v0.8 Arina Puzriakova Panel status changed from internal to public
Sarcoma of possible germline origin v0.5 Arina Puzriakova Panel status changed from internal to public
Childhood interstitial lung disease v0.7 Arina Puzriakova Panel status changed from internal to public
Intellectual disability v9.325 TANC2 Eleanor Williams Phenotypes for gene: TANC2 were changed from Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906 to Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906; intellectual developmental disorder with autistic features and language delay, with or without seizures, MONDO:0030051
Early onset or syndromic epilepsy v8.158 TANC2 Eleanor Williams Phenotypes for gene: TANC2 were changed from Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906 to Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906; intellectual developmental disorder with autistic features and language delay, with or without seizures, MONDO:0030051
Fetal anomalies v6.158 ZNF865 Eleanor Williams Tag Q1_26_promote_green tag was added to gene: ZNF865.
Fetal anomalies v6.158 ZNF865 Eleanor Williams Classified gene: ZNF865 as Amber List (moderate evidence)
Fetal anomalies v6.158 ZNF865 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation of a green rating with a monoallelic MOI following GMS review.
Fetal anomalies v6.158 ZNF865 Eleanor Williams Gene: znf865 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.72 JAM2 Eleanor Williams Phenotypes for gene: JAM2 were changed from Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824 to Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824; basal ganglia calcification, idiopathic, 8, autosomal recessive, MONDO:0032938
White matter disorders and cerebral calcification - narrow panel v7.18 JAM2 Eleanor Williams Phenotypes for gene: JAM2 were changed from Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824 to Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824; basal ganglia calcification, idiopathic, 8, autosomal recessive, MONDO:0032938
Hereditary ataxia with onset in adulthood v8.30 JAM2 Eleanor Williams Phenotypes for gene: JAM2 were changed from Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824 to Basal ganglia calcification, idiopathic, 8, autosomal recessive, OMIM:618824; basal ganglia calcification, idiopathic, 8, autosomal recessive, MONDO:0032938
Intellectual disability v9.324 TYW1 Eleanor Williams Phenotypes for gene: TYW1 were changed from cerebral palsy, MONDO:0006497 to cerebral palsy, MONDO:0006497; intellectual disability, MONDO:0001071
DDG2P v6.427 SHOX Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Although this gene is associated with X-linked MOI (allelic requirement) in Gene2Phenotype, it is on the pseudoautosomal region. Hence, the MOI should remain as 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
DDG2P v6.427 SHOX Achchuthan Shanmugasundram Mode of inheritance for gene: SHOX was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
DDG2P v6.426 SHOX Achchuthan Shanmugasundram Deleted their comment
DDG2P v6.426 SHOX Achchuthan Shanmugasundram edited their review of gene: SHOX: Added comment: Although this gene is associated with X-linked MOI in Gene2Phenotype, this gene is on the pseudoautosomal region. Hence, the MOI should be set as 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic diabetes v3.14 ZNF808 Ida Ertmanska Phenotypes for gene: ZNF808 were changed from Diabetes to Pancreatic agenesis 3, OMIM:620991; diabetes mellitus, MONDO:0005015
Monogenic diabetes v3.13 ZNF808 Ida Ertmanska Publications for gene: ZNF808 were set to PMID: 41500078
Monogenic diabetes v3.12 ZNF808 Ida Ertmanska Classified gene: ZNF808 as Amber List (moderate evidence)
Monogenic diabetes v3.12 ZNF808 Ida Ertmanska Gene: znf808 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.11 ZNF808 Ida Ertmanska reviewed gene: ZNF808: Rating: GREEN; Mode of pathogenicity: None; Publications: 37973953, 41500078; Phenotypes: Pancreatic agenesis 3, OMIM:620991, diabetes mellitus, MONDO:0005015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.323 GABRA3 Arina Puzriakova Publications for gene: GABRA3 were set to 41289009
Early onset or syndromic epilepsy v8.157 GABRA3 Arina Puzriakova Publications for gene: GABRA3 were set to 41289009
Monogenic diabetes v3.11 ZNF808 Ida Ertmanska Mode of inheritance for gene: ZNF808 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.322 CDC42BPB Arina Puzriakova Mode of inheritance for gene: CDC42BPB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.156 CDC42BPB Arina Puzriakova Mode of inheritance for gene: CDC42BPB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.321 CDC42BPB Arina Puzriakova Publications for gene: CDC42BPB were set to 32031333
Early onset or syndromic epilepsy v8.155 CDC42BPB Arina Puzriakova Phenotypes for gene: CDC42BPB were changed from Chilton-Okur-Chung neurodevelopmental syndrome, OMIM:619841 Chilton-Okur-Chung neurodevelopmental syndrome, MONDO:0859239 to Chilton-Okur-Chung neurodevelopmental syndrome, OMIM:619841; Chilton-Okur-Chung neurodevelopmental syndrome, MONDO:0859239
Intellectual disability v9.320 CDC42BPB Arina Puzriakova Tag Q1_26_promote_green tag was added to gene: CDC42BPB.
Early onset or syndromic epilepsy v8.154 CDC42BPB Arina Puzriakova Mode of inheritance for gene: CDC42BPB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v9.320 KCNT2 Arina Puzriakova Publications for gene: KCNT2 were set to 29069600; 29740868
Intellectual disability v9.319 KCNT2 Arina Puzriakova Phenotypes for gene: KCNT2 were changed from Developmental and epileptic encephalopathy 57, OMIM:617771 developmental and epileptic encephalopathy, 57, MONDO:0033366 to Developmental and epileptic encephalopathy 57, OMIM:617771; developmental and epileptic encephalopathy, 57, MONDO:0033366
Ataxia and cerebellar anomalies - narrow panel v8.71 TRMT5 Ida Ertmanska gene: TRMT5 was added
gene: TRMT5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: TRMT5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMT5 were set to 35342985
Phenotypes for gene: TRMT5 were set to Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay, OMIM:616539
Review for gene: TRMT5 was set to RED
Added comment: PMID: 35342985 Argente-Escrig et al., 2022
3 cases from apparently unrelated Southern European families with infantile onset demyelinating neuropathy. All compound het for the same TRMT5 variants: [c.312_315del; p.Ile105Serfs*4] and [c.665 T > C; p.Ile222Thr].
The cerebellar ataxia was described as mild (gait disturbance). Neuropathy is the main presentation.
Sources: Literature
Adult onset hereditary spastic paraplegia v6.9 TRMT5 Ida Ertmanska Classified gene: TRMT5 as Amber List (moderate evidence)
Adult onset hereditary spastic paraplegia v6.9 TRMT5 Ida Ertmanska Added comment: Comment on list classification: There are at least 2 unrelated families with affected individuals harbouring biallelic TRMT5 variants, presenting with spastic paraparesis / spastic gait. However, spasticity is not the main presenting feature of this progressive syndrome. Based on available evidence, this gene can only be rated Amber for Adult onset hereditary spastic paraplegia.
Adult onset hereditary spastic paraplegia v6.9 TRMT5 Ida Ertmanska Gene: trmt5 has been classified as Amber List (Moderate Evidence).
Adult onset hereditary spastic paraplegia v6.8 TRMT5 Ida Ertmanska gene: TRMT5 was added
gene: TRMT5 was added to Adult onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: TRMT5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMT5 were set to 26189817; 29021354
Phenotypes for gene: TRMT5 were set to Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay, OMIM:616539
Review for gene: TRMT5 was set to AMBER
Added comment: PMID: 26189817 Powell et al., 2015
Subject 73901- lifelong exercise intolerance, presented at the age of 25 years with prolonged dyspnea associated with lactic acidosis, diagnosed with a mitochondrial myopathy associated with a marked histochemical and biochemical deficiency of COX and a defect in complex III activity. At 35 yrs showed hyperreflexia and extensor plantar reflexes with some clinical spasticity. Compound het for c.312_315del (p.Ile105Serfs∗4) frameshift and a c.872G>A (p.Arg291His).

PMID: 29021354 Tarnopolsky et al., 2017
P1 - 46yo female, presented at age 27 years with a lifelong history of exercise intolerance, muscle weakness, and shortness of breath on exertion. EMG normal at 27yo, progressive axonal sensory neuropathy seen at 43 years. 46yo - progression of proximal weakness with a waddling and spastic gait.
P2 (sister of P1) - presented at age 33 yrs with worsening gait and an increased frequency of falls; diagnosed with cerebral palsy in childhood; lower extremities: mild proximal and severe distal weakness/atrophy, severe spasticity, and upgoing toes; she showed gross motor, cognitive, and speech delays.
Both sisters compound het for TRMT5: c.872G>A (p.Arg291His) and c.312_315del (p.Ile105Serfs4X), confirmed in trans.

TRMT5 is associated with Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay, OMIM:616539 in OMIM (accessed 18 Mar 2026).
Sources: Literature
Intellectual disability v9.318 ISCA-37448-Loss Ida Ertmanska Variant type for ISCA-37448-Loss was changed from small to cnv_loss.
Early onset or syndromic epilepsy v8.153 ISCA-37448-Loss Ida Ertmanska Variant type for ISCA-37448-Loss was changed from small to cnv_loss.
Early onset or syndromic epilepsy v8.152 AMACR Ida Ertmanska changed review comment from: Comment on list classification: More than 50% of patients with biallelic AMACR variants present with seizures or have an epilepsy diagnosis. Based on available evidence, AMACR is tagged for promotion to Green on Early onset or syndromic epilepsy at the next update. As the seizures may be caused by pathological brain lesions, the gene is also tagged for expert review, to ascertain whether this gene is in scope of testing.; to: Comment on list classification: More than 50% of patients with biallelic AMACR variants present with seizures / have an epilepsy diagnosis. Based on available evidence, AMACR is tagged for promotion to Green on Early onset or syndromic epilepsy at the next update. As the seizures may be caused by pathological brain lesions, the gene is also tagged for expert review, to ascertain whether this gene is in scope of testing.
Early onset or syndromic epilepsy v8.152 AMACR Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: AMACR.
Early onset or syndromic epilepsy v8.152 AMACR Ida Ertmanska edited their review of gene: AMACR: Added comment: Comment on list classification: More than 50% of patients with biallelic AMACR variants present with seizures or have an epilepsy diagnosis. Based on available evidence, AMACR is tagged for promotion to Green on Early onset or syndromic epilepsy at the next update. As the seizures may be caused by pathological brain lesions, the gene is also tagged for expert review, to ascertain whether this gene is in scope of testing.; Changed rating: GREEN
Early onset or syndromic epilepsy v8.152 AMACR Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: AMACR.
Early onset or syndromic epilepsy v8.152 AMACR Ida Ertmanska Classified gene: AMACR as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.152 AMACR Ida Ertmanska Gene: amacr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.151 AMACR Ida Ertmanska gene: AMACR was added
gene: AMACR was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: AMACR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMACR were set to 37452652
Phenotypes for gene: AMACR were set to Alpha-methylacyl-CoA racemase deficiency, OMIM:614307
Review for gene: AMACR was set to AMBER
Added comment: PMID: 37452652 Palacio-Montoya et al., 2023
3 sibs with recurrent episodes of encephalopathy, seizures, and behavioural disturbances. In all 3, brain MRI showed lesions in the thalami, cerebral peduncles, and mesencephalic tegmentum, as well as brain volume loss. Homozygous AMACR c826 G>C p.Ala276Pro variant detected in affected individuals.

In a literature review in the same paper, 9/16 previously reported patients with AMACR deficency had seizures / epilepsy, which correlated with abnormal brain MRI findings. The most common variant was c.154T>C, p.Ser52Pro (7/16 patients).
Sources: Literature