Activity

Filter

Cancel
Date Panel Item Activity
3000 actions
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
Early onset or syndromic epilepsy v8.150 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as No list
Early onset or syndromic epilepsy v8.150 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been removed from the panel.
Early onset or syndromic epilepsy v8.149 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red was removed from Region: ISCA-37433-Loss.
Tag curated_removed tag was added to Region: ISCA-37433-Loss.
Early onset or syndromic epilepsy v8.149 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss: The rating of this gene has been updated to Grey (removed) following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.149 ISCA-37404-Loss Arina Puzriakova Tag curated_removed tag was added to Region: ISCA-37404-Loss.
Early onset or syndromic epilepsy v8.149 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Early onset or syndromic epilepsy v8.149 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Early onset or syndromic epilepsy v8.148 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red was removed from Region: ISCA-37404-Loss.
Early onset or syndromic epilepsy v8.148 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss: The rating of this gene has been updated to Grey (removed) following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.148 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Green List (high evidence)
Early onset or syndromic epilepsy v8.148 ISCA-37448-Loss Arina Puzriakova Region: isca-37448-loss has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.147 ISCA-37448-Loss Arina Puzriakova Tag Q3_25_promote_green was removed from Region: ISCA-37448-Loss.
Early onset or syndromic epilepsy v8.147 ISCA-37448-Loss Arina Puzriakova commented on Region: ISCA-37448-Loss: The rating of this region has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.147 IKBKG Achchuthan Shanmugasundram Tag currently-ngs-unreportable tag was added to gene: IKBKG.
Early onset or syndromic epilepsy v8.147 PPP2R1A Ida Ertmanska changed review comment from: PMID: 33106617 Lenaerts et al., 2021
Report of 30 individuals with 16 different de novo variants in PPP2R1A. Shared phenotype: developmental delay (97%), hypotonia (93%), hypermobile joints (58%), CC hypoplasia/agenesis (56%), epilepsy (38%), macrocephaly (38%). Macrocephaly and epilepsy were mutually exclusive. Intellectual disability ranged from mild to severe, based on functional effects of each variant.

Functional evidence: HEK293T cells transfected with PPP2R1A mutants - variants from patients with less severe ID, no seizures, and sometimes macrocephaly typically showed normal B55α and STRN3 binding, while more severe ID, seizures, and sometimes microcephaly correlated with lost B55α binding and increased STRN3 binding.

PPP2R1A is now associated with AD Houge-Janssens syndrome 2, OMIM:616362 (OMIM accessed 13th Mar 2026). PPP2R1A is Definitve in ClinGen for an AD complex neurodevelopmental disorder (Nov 2022).
Sources: Literature; to: PMID: 33106617 Lenaerts et al., 2021
Report of 30 individuals with 16 different de novo variants in PPP2R1A. Shared phenotype: developmental delay (97%), hypotonia (93%), hypermobile joints (58%), CC hypoplasia/agenesis (56%), epilepsy (38%), macrocephaly (38%). Macrocephaly and epilepsy were mutually exclusive. Intellectual disability ranged from mild to severe, based on functional effects of each variant.

Functional evidence: HEK293T cells transfected with PPP2R1A mutants - variants from patients with less severe ID, no seizures, and sometimes macrocephaly typically showed normal B55α and STRN3 binding, while more severe ID, seizures, and sometimes microcephaly correlated with lost B55α binding and increased STRN3 binding.

17/35 (49%) of patients with PPP2R1A-Related Neurodevelopmental Disorder presented with epilepsy according to GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK580243/)

PPP2R1A is now associated with AD Houge-Janssens syndrome 2, OMIM:616362 (OMIM accessed 13th Mar 2026). PPP2R1A is Definitve in ClinGen for an AD complex neurodevelopmental disorder (Nov 2022).
Sources: Literature
Early onset or syndromic epilepsy v8.147 PPP2R1A Ida Ertmanska Classified gene: PPP2R1A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.147 PPP2R1A Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported in literature with heterozygous PPP2R1A variants and a neurodevelopmental syndrome, which includes epilepsy in 40-50% of patients. Hence, this gene should be promoted to Green for Early onset or syndromic epilepsy at the next update.
Early onset or syndromic epilepsy v8.147 PPP2R1A Ida Ertmanska Gene: ppp2r1a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.146 PPP2R1A Ida Ertmanska gene: PPP2R1A was added
gene: PPP2R1A was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_26_promote_green tags were added to gene: PPP2R1A.
Mode of inheritance for gene: PPP2R1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2R1A were set to 33106617
Phenotypes for gene: PPP2R1A were set to Houge-Janssens syndrome 2, OMIM:616362; Houge-Janssens syndrome 2, MONDO:0014605
Review for gene: PPP2R1A was set to GREEN
Added comment: PMID: 33106617 Lenaerts et al., 2021
Report of 30 individuals with 16 different de novo variants in PPP2R1A. Shared phenotype: developmental delay (97%), hypotonia (93%), hypermobile joints (58%), CC hypoplasia/agenesis (56%), epilepsy (38%), macrocephaly (38%). Macrocephaly and epilepsy were mutually exclusive. Intellectual disability ranged from mild to severe, based on functional effects of each variant.

Functional evidence: HEK293T cells transfected with PPP2R1A mutants - variants from patients with less severe ID, no seizures, and sometimes macrocephaly typically showed normal B55α and STRN3 binding, while more severe ID, seizures, and sometimes microcephaly correlated with lost B55α binding and increased STRN3 binding.

PPP2R1A is now associated with AD Houge-Janssens syndrome 2, OMIM:616362 (OMIM accessed 13th Mar 2026). PPP2R1A is Definitve in ClinGen for an AD complex neurodevelopmental disorder (Nov 2022).
Sources: Literature
Early onset or syndromic epilepsy v8.145 HCN2 Ida Ertmanska Phenotypes for gene: HCN2 were changed from Genetic epilepsy with febrile seizures plus; Other seizure disorders to Generalized epilepsy with febrile seizures plus, type 11, OMIM:602477; neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.144 HCN2 Ida Ertmanska Publications for gene: HCN2 were set to 29064616; 20437590; 12514127; 17931874; 22131395
Early onset or syndromic epilepsy v8.143 HCN2 Ida Ertmanska edited their review of gene: HCN2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.143 HCN2 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: HCN2.
Early onset or syndromic epilepsy v8.143 HCN2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: HCN2.
Early onset or syndromic epilepsy v8.143 HCN2 Ida Ertmanska reviewed gene: HCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40468825; Phenotypes: Generalized epilepsy with febrile seizures plus, type 11, OMIM:602477, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.143 TANC2 Ida Ertmanska Classified gene: TANC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.143 TANC2 Ida Ertmanska Added comment: Comment on list classification: There are numerous patients reported in literature with heterozygous TANC2 variants and epilepsy. Epilepsy was the sole presenting feature in some cases. Hence, TANC2 should be promoted to Green at the next GMS update.
Early onset or syndromic epilepsy v8.143 TANC2 Ida Ertmanska Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.142 TANC2 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: TANC2.
Early onset or syndromic epilepsy v8.142 TANC2 Ida Ertmanska Publications for gene: TANC2 were set to 31616000
Early onset or syndromic epilepsy v8.141 TANC2 Ida Ertmanska 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
Early onset or syndromic epilepsy v8.140 TANC2 Ida Ertmanska Mode of inheritance for gene: TANC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.139 TANC2 Ida Ertmanska edited their review of gene: TANC2: Changed publications to: 34861844, 40110879
Early onset or syndromic epilepsy v8.139 TANC2 Ida Ertmanska changed review comment from: PMID: 34861844 - boy with Lennox-Gastaut syndrome (LGS), a severe epileptic encephalopathy.

TANC2 is linked to AD Intellectual developmental disorder with autistic features and language delay, with or without seizures, MIM:618906 (OMIM accessed 12th Mar 2026).; to: PMID: 40110879 Luo et al., 2025
Trio exome, Chinese cohort of epilepsy patients. De novo TANC2 variants were identified in six unrelated childhood-onset cases (4 null and 2 missense). Patients with null variants exhibited severe phenotypes: 3 with epilepsy and neurodevelopmental disorders, 1 individual with developmental and epileptic encephalopathy (DEE). In contrast, the patients with missense variants presented with only epilepsy.

PMID: 34861844 Tian et al., 2021
Case report of a Chinese boy (1yr 11 mo) with Lennox-Gastaut syndrome (LGS), a severe epileptic encephalopathy. WES + Sanger detected a de novo c.4321C > T(p.Gln1441Ter) mutation in TANC2.

TANC2 is linked to AD Intellectual developmental disorder with autistic features and language delay, with or without seizures, MIM:618906 (OMIM accessed 12th Mar 2026).
Early onset or syndromic epilepsy v8.139 TANC2 Ida Ertmanska edited their review of gene: TANC2: Changed publications to: 34861844; Changed phenotypes to: Intellectual developmental disorder with autistic features and language delay, with or without seizures, OMIM:618906
Early onset or syndromic epilepsy v8.139 TANC2 Ida Ertmanska changed review comment from: PMID: 34861844 - boy with Lennox-Gastaut syndrome (LGS), a severe epileptic encephalopathy.; to: PMID: 34861844 - boy with Lennox-Gastaut syndrome (LGS), a severe epileptic encephalopathy.

TANC2 is linked to AD Intellectual developmental disorder with autistic features and language delay, with or without seizures, MIM:618906 (OMIM accessed 12th Mar 2026).
Early onset or syndromic epilepsy v8.139 TANC2 Ida Ertmanska Deleted their comment
Early onset or syndromic epilepsy v8.139 TANC2 Ida Ertmanska commented on gene: TANC2: PMID: 34861844 - boy with Lennox-Gastaut syndrome (LGS), a severe epileptic encephalopathy.
Early onset or syndromic epilepsy v8.139 TANC2 Ida Ertmanska reviewed gene: TANC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.139 WDR47 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: WDR47.
Early onset or syndromic epilepsy v8.139 UNC13A Arina Puzriakova Tag Q3_25_promote_green was removed from gene: UNC13A.
Early onset or syndromic epilepsy v8.139 UGGT1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: UGGT1.
Early onset or syndromic epilepsy v8.139 UBR5 Arina Puzriakova Tag dd_review was removed from gene: UBR5.
Tag Q3_25_promote_green was removed from gene: UBR5.
Early onset or syndromic epilepsy v8.139 TRPM7 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: TRPM7.
Early onset or syndromic epilepsy v8.139 TMEM167A Arina Puzriakova Tag Q3_25_promote_green was removed from gene: TMEM167A.
Early onset or syndromic epilepsy v8.139 TARS2 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: TARS2.
Early onset or syndromic epilepsy v8.139 SPOUT1 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: SPOUT1.
Early onset or syndromic epilepsy v8.139 RYR3 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: RYR3.
Early onset or syndromic epilepsy v8.139 RNU5B-1 Arina Puzriakova Tag dd_review was removed from gene: RNU5B-1.
Tag Q3_25_promote_green was removed from gene: RNU5B-1.
Early onset or syndromic epilepsy v8.139 RNU2-2P Arina Puzriakova Tag dd_review was removed from gene: RNU2-2P.
Tag Q2_25_ promote_green was removed from gene: RNU2-2P.
Early onset or syndromic epilepsy v8.139 PPP2R5C Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: PPP2R5C.
Early onset or syndromic epilepsy v8.139 PPP2R2B Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: PPP2R2B.
Early onset or syndromic epilepsy v8.139 PPOX Arina Puzriakova Tag Q3_25_promote_green was removed from gene: PPOX.
Early onset or syndromic epilepsy v8.139 PNPLA8 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: PNPLA8.
Early onset or syndromic epilepsy v8.139 PABPC1 Arina Puzriakova Tag Q4_24_MOI was removed from gene: PABPC1.
Early onset or syndromic epilepsy v8.139 NOTCH3 Arina Puzriakova Tag dd_review was removed from gene: NOTCH3.
Tag Q3_25_promote_green was removed from gene: NOTCH3.
Early onset or syndromic epilepsy v8.139 MT-TK Arina Puzriakova Tag Q3_25_promote_green was removed from gene: MT-TK.
Tag Q3_25_NHS_review was removed from gene: MT-TK.
Early onset or syndromic epilepsy v8.139 MARK2 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: MARK2.
Early onset or syndromic epilepsy v8.139 LSS Arina Puzriakova Tag Q3_25_promote_green was removed from gene: LSS.
Early onset or syndromic epilepsy v8.139 LGI1 Arina Puzriakova Tag Q3_25_MOI was removed from gene: LGI1.
Early onset or syndromic epilepsy v8.139 LAMC3 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: LAMC3.
Early onset or syndromic epilepsy v8.139 KCND3 Arina Puzriakova Tag dd_review was removed from gene: KCND3.
Tag Q3_25_promote_green was removed from gene: KCND3.
Early onset or syndromic epilepsy v8.139 INPP4A Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: INPP4A.
Early onset or syndromic epilepsy v8.139 GTF3C3 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 11-03-2026
Early onset or syndromic epilepsy v8.139 GTF3C3 Arina Puzriakova Phenotypes for gene: GTF3C3 were changed from Global developmental delay; Intellectual disability; Seizures to Neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, OMIM:621201
Early onset or syndromic epilepsy v8.138 GTF3C3 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: GTF3C3.
Early onset or syndromic epilepsy v8.138 GLS Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: GLS.
Early onset or syndromic epilepsy v8.138 FLVCR1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: FLVCR1.
Early onset or syndromic epilepsy v8.138 EPB41L3 Arina Puzriakova Tag Q2_25_ promote_green was removed from gene: EPB41L3.
Tag Q2_25_ NHS_review was removed from gene: EPB41L3.
Early onset or syndromic epilepsy v8.138 ELFN1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: ELFN1.
Early onset or syndromic epilepsy v8.138 EEFSEC Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: EEFSEC.
Early onset or syndromic epilepsy v8.138 CTSF Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: CTSF.
Early onset or syndromic epilepsy v8.138 CRNKL1 Arina Puzriakova Mode of pathogenicity for gene: CRNKL1 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v8.137 CRNKL1 Arina Puzriakova Tag dd_review was removed from gene: CRNKL1.
Tag Q3_25_promote_green was removed from gene: CRNKL1.
Early onset or syndromic epilepsy v8.137 CRELD1 Arina Puzriakova Tag Q4_24_NHS_review was removed from gene: CRELD1.
Tag Q4_24_MOI was removed from gene: CRELD1.
Early onset or syndromic epilepsy v8.137 CELF4 Arina Puzriakova Tag dd_review was removed from gene: CELF4.
Tag Q2_25_ promote_green was removed from gene: CELF4.
Early onset or syndromic epilepsy v8.137 RYR3 Achchuthan Shanmugasundram edited their review of gene: RYR3: Added comment: Additional comments from reviewing GLHs: Insufficient evidence to prove a monogenic cause of epilepsy. Larger cohort size analysis required to conclusively prove this gene / variants in this gene could act as a susceptibility gene for idiopathic partial epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v8.137 CELF4 Achchuthan Shanmugasundram edited their review of gene: CELF4: Added comment: Additional comments from reviewing GLHs: gnomad data would make this difficult to classify variants (gnomADv4.1.0 pLI score). All ClinVar variants are VUS.; Changed rating: AMBER
Early onset or syndromic epilepsy v8.136 CDK5 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: CDK5.
Early onset or syndromic epilepsy v8.136 C12orf66 Arina Puzriakova Tag Q1_25_ promote_green was removed from gene: C12orf66.
Early onset or syndromic epilepsy v8.136 BRSK1 Arina Puzriakova Tag Q3_25_promote_green was removed from gene: BRSK1.
Early onset or syndromic epilepsy v8.136 BRSK1 Arina Puzriakova Classified gene: BRSK1 as Green List (high evidence)
Early onset or syndromic epilepsy v8.136 BRSK1 Arina Puzriakova Gene: brsk1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.135 BRSK1 Arina Puzriakova Classified gene: BRSK1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.135 BRSK1 Arina Puzriakova Gene: brsk1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.134 WDR47 Achchuthan Shanmugasundram commented on gene: WDR47: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 UNC13A Achchuthan Shanmugasundram commented on gene: UNC13A: 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.
Early onset or syndromic epilepsy v8.134 UGGT1 Achchuthan Shanmugasundram commented on gene: UGGT1: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 UBR5 Achchuthan Shanmugasundram commented on gene: UBR5: 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.
Early onset or syndromic epilepsy v8.134 TRPM7 Achchuthan Shanmugasundram reviewed gene: TRPM7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 TMEM167A Achchuthan Shanmugasundram reviewed gene: TMEM167A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 TARS2 Achchuthan Shanmugasundram reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 SPOUT1 Achchuthan Shanmugasundram reviewed gene: SPOUT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 RYR3 Achchuthan Shanmugasundram commented on gene: RYR3
Early onset or syndromic epilepsy v8.134 RNU5B-1 Achchuthan Shanmugasundram edited their review of gene: RNU5B-1: Added comment: The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v8.134 RNU2-2P Achchuthan Shanmugasundram commented on gene: RNU2-2P: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 PPP2R5C Achchuthan Shanmugasundram reviewed gene: PPP2R5C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 PPP2R2B Achchuthan Shanmugasundram reviewed gene: PPP2R2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 PPOX Achchuthan Shanmugasundram reviewed gene: PPOX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 PNPLA8 Achchuthan Shanmugasundram reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 PABPC1 Achchuthan Shanmugasundram commented on gene: PABPC1: The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 NOTCH3 Achchuthan Shanmugasundram commented on gene: NOTCH3: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 MT-TK Achchuthan Shanmugasundram reviewed gene: MT-TK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 MARK2 Achchuthan Shanmugasundram commented on gene: MARK2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 LSS Achchuthan Shanmugasundram commented on gene: LSS: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 LGI1 Achchuthan Shanmugasundram commented on gene: LGI1
Early onset or syndromic epilepsy v8.134 LAMC3 Achchuthan Shanmugasundram commented on gene: LAMC3: The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 KCND3 Achchuthan Shanmugasundram reviewed gene: KCND3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 INPP4A Achchuthan Shanmugasundram commented on gene: INPP4A: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 GTF3C3 Achchuthan Shanmugasundram reviewed gene: GTF3C3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 GLS Achchuthan Shanmugasundram commented on gene: GLS: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 FLVCR1 Achchuthan Shanmugasundram reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 EPB41L3 Achchuthan Shanmugasundram reviewed gene: EPB41L3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 ELFN1 Achchuthan Shanmugasundram reviewed gene: ELFN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 EEFSEC Achchuthan Shanmugasundram commented on gene: EEFSEC: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v8.134 CTSF Achchuthan Shanmugasundram reviewed gene: CTSF: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 CRNKL1 Achchuthan Shanmugasundram commented on gene: CRNKL1: 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.
Early onset or syndromic epilepsy v8.134 CRELD1 Achchuthan Shanmugasundram commented on gene: CRELD1
Early onset or syndromic epilepsy v8.134 CELF4 Achchuthan Shanmugasundram commented on gene: CELF4: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber.
Early onset or syndromic epilepsy v8.134 CDK5 Achchuthan Shanmugasundram reviewed gene: CDK5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 C12orf66 Achchuthan Shanmugasundram reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 BRSK1 Achchuthan Shanmugasundram reviewed gene: BRSK1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 WDR47 Arina Puzriakova Source NHS GMS was added to WDR47.
Source Expert Review Green was added to WDR47.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 UNC13A Arina Puzriakova Source NHS GMS was added to UNC13A.
Source Expert Review Green was added to UNC13A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 UGGT1 Arina Puzriakova Source NHS GMS was added to UGGT1.
Source Expert Review Green was added to UGGT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 UBR5 Arina Puzriakova Source NHS GMS was added to UBR5.
Source Expert Review Green was added to UBR5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 TRPM7 Arina Puzriakova Source NHS GMS was added to TRPM7.
Source Expert Review Green was added to TRPM7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 TMEM167A Arina Puzriakova Source NHS GMS was added to TMEM167A.
Source Expert Review Green was added to TMEM167A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 TARS2 Arina Puzriakova Source NHS GMS was added to TARS2.
Source Expert Review Green was added to TARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 SPOUT1 Arina Puzriakova Source NHS GMS was added to SPOUT1.
Source Expert Review Green was added to SPOUT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 RNU5B-1 Arina Puzriakova Source NHS GMS was added to RNU5B-1.
Source Expert Review Green was added to RNU5B-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 RNU2-2P Arina Puzriakova Source NHS GMS was added to RNU2-2P.
Source Expert Review Green was added to RNU2-2P.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 PPP2R5C Arina Puzriakova Source NHS GMS was added to PPP2R5C.
Source Expert Review Green was added to PPP2R5C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 PPP2R2B Arina Puzriakova Source NHS GMS was added to PPP2R2B.
Source Expert Review Green was added to PPP2R2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 PPOX Arina Puzriakova Source NHS GMS was added to PPOX.
Source Expert Review Green was added to PPOX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 PNPLA8 Arina Puzriakova Source NHS GMS was added to PNPLA8.
Source Expert Review Green was added to PNPLA8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 PABPC1 Arina Puzriakova Mode of inheritance for gene PABPC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.134 NOTCH3 Arina Puzriakova Source NHS GMS was added to NOTCH3.
Source Expert Review Green was added to NOTCH3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 MT-TK Arina Puzriakova Source NHS GMS was added to MT-TK.
Source Expert Review Green was added to MT-TK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 MARK2 Arina Puzriakova Source Expert Review Green was added to MARK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 LSS Arina Puzriakova Source Expert Review Green was added to LSS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 LGI1 Arina Puzriakova Mode of inheritance for gene LGI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.134 LAMC3 Arina Puzriakova Source NHS GMS was added to LAMC3.
Source Expert Review Green was added to LAMC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 KCND3 Arina Puzriakova Source NHS GMS was added to KCND3.
Source Expert Review Green was added to KCND3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 INPP4A Arina Puzriakova Source NHS GMS was added to INPP4A.
Source Expert Review Green was added to INPP4A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 GTF3C3 Arina Puzriakova Source NHS GMS was added to GTF3C3.
Source Expert Review Green was added to GTF3C3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 GLS Arina Puzriakova Source NHS GMS was added to GLS.
Source Expert Review Green was added to GLS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 FLVCR1 Arina Puzriakova Source NHS GMS was added to FLVCR1.
Source Expert Review Green was added to FLVCR1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 EPB41L3 Arina Puzriakova Source NHS GMS was added to EPB41L3.
Source Expert Review Green was added to EPB41L3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 ELFN1 Arina Puzriakova Source NHS GMS was added to ELFN1.
Source Expert Review Green was added to ELFN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 EEFSEC Arina Puzriakova Source NHS GMS was added to EEFSEC.
Source Expert Review Green was added to EEFSEC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 CTSF Arina Puzriakova Source Expert Review Green was added to CTSF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 CRNKL1 Arina Puzriakova Source NHS GMS was added to CRNKL1.
Source Expert Review Green was added to CRNKL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 CRELD1 Arina Puzriakova Mode of inheritance for gene CRELD1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.134 CDK5 Arina Puzriakova Source NHS GMS was added to CDK5.
Source Expert Review Green was added to CDK5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 C12orf66 Arina Puzriakova Source NHS GMS was added to C12orf66.
Source Expert Review Green was added to C12orf66.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.134 BRSK1 Arina Puzriakova Source NHS GMS was added to BRSK1.
Source Expert Review Green was added to BRSK1.
Mode of inheritance for gene BRSK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.133 GABRA3 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with variants in GABRA3 and epilepsy. GOF variants cause a more severe, X-linked dominant phenotype (early-onset, treatment resistant epilepsy), while LOF variants usually result in a milder phenotype (epilepsy is rare) and an X-linked recessive inheritance pattern. Based on available evidence, GABRA3 should be promoted to Green with MOI X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).; to: Comment on list classification: There are numerous patients reported in literature with variants in GABRA3 and epilepsy. GOF variants cause a more severe, X-linked dominant phenotype (early-onset, treatment resistant epilepsy), while LOF variants usually result in a milder phenotype (epilepsy is rare) and an X-linked recessive inheritance pattern. Functional evidence in mouse models supports these mechanistic findings. Based on available evidence, GABRA3 should be promoted to Green with MOI X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Early onset or syndromic epilepsy v8.133 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.

Functional evidence from PMID: 41289009 - Gabra3 KO mice do not exhibit early mortality or seizures; in contrast, an engineered mouse model carrying the GOF p.(Gln242Leu) variant recapitulated key human findings: male pups were not viable, while female mice had increased mortality in the first 2 months of life, and developed seizures in adulthood.

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
Early onset or syndromic epilepsy v8.133 GABRA3 Ida Ertmanska Classified gene: GABRA3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.133 GABRA3 Ida Ertmanska Added comment: Comment on list classification: There are numerous patients reported in literature with variants in GABRA3 and epilepsy. GOF variants cause a more severe, X-linked dominant phenotype (early-onset, treatment resistant epilepsy), while LOF variants usually result in a milder phenotype (epilepsy is rare) and an X-linked recessive inheritance pattern. Based on available evidence, GABRA3 should be promoted to Green with MOI X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).
Early onset or syndromic epilepsy v8.133 GABRA3 Ida Ertmanska Gene: gabra3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.132 GABRA3 Ida Ertmanska gene: GABRA3 was added
gene: GABRA3 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_26_promote_green tags were added to gene: GABRA3.
Mode of inheritance for gene: GABRA3 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: GABRA3 were set to 41289009
Phenotypes for gene: GABRA3 were set to Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features, OMIM:301091
Review for gene: GABRA3 was set to GREEN
Added comment: 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
Early onset or syndromic epilepsy v8.131 NRDC Ida Ertmanska changed review comment from: PMID: 41734767 Pehlivan et al., 2026
Report of 14 individuals from nine unrelated families carrying homozygous NRDC pathogenic variants. 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; to: 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
Early onset or syndromic epilepsy v8.131 NRDC Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are more than 3 individuals reported with biallelic NRDC variants and syndromic epilepsy. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 individuals reported with biallelic NRDC variants and syndromic epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v8.131 NRDC Ida Ertmanska Classified gene: NRDC as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.131 NRDC Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are more than 3 individuals reported with biallelic NRDC variants and syndromic epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v8.131 NRDC Ida Ertmanska Gene: nrdc has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.130 NRDC Ida Ertmanska Phenotypes for gene: NRDC were changed from to neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.129 NRDC Ida Ertmanska gene: NRDC was added
gene: NRDC was added to Early onset or syndromic epilepsy. 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
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. 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
Early onset or syndromic epilepsy v8.128 FSD1L Ida Ertmanska Classified gene: FSD1L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.128 FSD1L Ida Ertmanska Added comment: Comment on list classification: There are more than 3 families reported in literature with affected individuals presenting with a severe neurodevelopmental disorder, including epilepsy. There is enough evidence to promote FSD1L to Green at the next update.
Early onset or syndromic epilepsy v8.128 FSD1L Ida Ertmanska Gene: fsd1l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.127 FSD1L Ida Ertmanska gene: FSD1L was added
gene: FSD1L was added to Early onset or syndromic epilepsy. 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
Early onset or syndromic epilepsy v8.126 ALPL Arina Puzriakova Phenotypes for gene: ALPL were changed from Hypophosphatasia, adult 146300 AD, AR; Hypophosphatasia, childhood 241510 AR; Hypophosphatasia, infantile 241500 AR; Odontohypophosphatasia 146300 AD, AR to Hypophosphatasia, childhood, OMIM:241510; Hypophosphatasia, infantile, OMIM:241500
Early onset or syndromic epilepsy v8.125 ABI2 Ida Ertmanska Classified gene: ABI2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.125 ABI2 Ida Ertmanska Gene: abi2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.124 ABI2 Ida Ertmanska edited their review of gene: ABI2: Added comment: Comment on list classification: This gene will be recommended for a promotion to Green once the pre-print article is published.; Changed rating: GREEN
Early onset or syndromic epilepsy v8.124 ABI2 Ida Ertmanska gene: ABI2 was added
gene: ABI2 was added to Early onset or syndromic epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: ABI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABI2 were set to 40475134
Phenotypes for gene: ABI2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: ABI2 was set to AMBER
Added comment: PMID: 40475134 Argilli et al., 2025 - PRE-PRINT
Report of 8 unrelated individuals with severe neurodevelopmental delays linked to heterozygous ABI2 missense variants, including a recurrent c.1472A>G, p.Tyr491Cys (6/8 individuals, confirmed de novo in 4). ABI2 c.1388T>C, p.Val463Ala was observed de novo in individual 7, and ABI2 c.1348C>T, p.Pro450Ser was detected in individual 8 (origin unknown). Seq method: Trio/singleton exome. Shared syndromic presentation with intellectual disability (7/7), epilepsy (6/7, 4 patients with onset under 2yo), hypoplasia of the corpus callosum (7/8), white matter abnormalities, hypotonia (5/6), developmental delay (7/7, moderate to severe, 2 with regression of skills) + other less common features.

ABI2 is not yet associated with a phenotype in OMIM (checked 27th Feb 2026).
Sources: Expert list, Literature
Early onset or syndromic epilepsy v8.123 KCNT2 Ida Ertmanska Phenotypes for gene: KCNT2 were changed from Developmental and epileptic encephalopathy 57, OMIM:617771 to Developmental and epileptic encephalopathy 57, OMIM:617771; developmental and epileptic encephalopathy, 57, MONDO:0033366
Early onset or syndromic epilepsy v8.122 KCNT2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 27th Feb 2026.
Early onset or syndromic epilepsy v8.122 KCNT2 Ida Ertmanska Phenotypes for gene: KCNT2 were changed from epilepsy; ?Epileptic encephalopathy, early infantile, 57 to Developmental and epileptic encephalopathy 57, OMIM:617771
Early onset or syndromic epilepsy v8.121 KCNT2 Ida Ertmanska Publications for gene: KCNT2 were set to 29069600; 29740868
Early onset or syndromic epilepsy v8.120 CDC42BPB Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype accessed on 24th Feb 2026.
Early onset or syndromic epilepsy v8.120 CDC42BPB Ida Ertmanska Phenotypes for gene: CDC42BPB were changed from CDC42BPB-related Neurodevelopmental Disorder; Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to Chilton-Okur-Chung neurodevelopmental syndrome, OMIM:619841 Chilton-Okur-Chung neurodevelopmental syndrome, MONDO:0859239
Early onset or syndromic epilepsy v8.119 BORCS5 Ida Ertmanska Classified gene: BORCS5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.119 BORCS5 Ida Ertmanska Added comment: Comment on list classification: Gene will not be tagged for promotion to Green until PMID: 40385417 pre-print is published.
Early onset or syndromic epilepsy v8.119 BORCS5 Ida Ertmanska Gene: borcs5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.118 BORCS5 Ida Ertmanska gene: BORCS5 was added
gene: BORCS5 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Phenotypes for gene: BORCS5 were set to arthrogryposis multiplex congenita, MONDO:0015168; neurodevelopmental disorder, MONDO:0700092
Review for gene: BORCS5 was set to GREEN
Added comment: PMID: 40621786 Fisher et al., 2025
Report of 2 fetal cases in a consanguineous Pakistani family. Exome seq revealed a homozygous nonsense variant c.283C>T, p.(Arg95Ter) in BORCS5 (NM_058169.4). Individuals showed neuroaxonal dystrophy with osteopetrosis.

PMID: 40385417 Mencacci et al., 2025 - pre-print
Report of 12 individuals from 7 unrelated families with biallelic BORCS5 variants (NM_058169.4): two missense variants (c.284G>A, p.R95Q; c.296A>C, p.H99P) and four LoF alleles (c.203–1G>T, p.?; c.316delG, p.A106Pfs*20; c.382_383delAG, p.L128Vfs*86; c.417C>G, p.Y139*).
Table 1 = phenotypic spectrum of 6 individuals from families 1-4: profound ID (6/6), severe spasticity (6/6), seizures (6/6), hyperreflexia (6/6), Parkinsonism/dystonia (3/6), limb contractures (5/6), optic atrophy (5/6), abnormal brain MRI including cerebral atrophy and/or corpus callosum agenesis (5/6), microcephaly (6/6 - severity not stated), muscle atrophy (5/6). Infantile onset.
Neuroimaging in 5 cases showed cerebral atrophy, white matter loss, hypomyelination, small T2-hypointense thalami, thin brainstem, and optic nerve atrophy.

PMID: 27435318 Charng et al., 2016
Patient BAB6775 homozygous for NM_058169.4 BORCS5: c.203-1G>T, with DD, microcephaly, seizures, cortical malformations, polymicrogyria, agenesis of corpus callosum. Also reported with more details in PMID:40385417 (do not count).

Additional functional evidence: Zebrafish borcs5 knockout leads to neurodevelopmental defects:microcephaly, ventriculomegaly, movement disorders and epilepsy.

BORCS5 is not yet associated with a disease in OMIM (accessed 20th Feb 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.117 CCT8 Ida Ertmanska Classified gene: CCT8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.117 CCT8 Ida Ertmanska Gene: cct8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.116 CCT8 Ida Ertmanska gene: CCT8 was added
gene: CCT8 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CCT8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT8 were set to 39480921
Phenotypes for gene: CCT8 were set to CCT8-related neurodevelopmental disorder with brain abnormalities
Review for gene: CCT8 was set to AMBER
Added comment: PMID: 39480921 Kraft et al., 2024
Report of 2 individuals (20yo male and 79yo male) with heterozygous CCT7 variants: c.925_929del p.(Asn309Hisfs*16) - de novo & c.1166_1169delAAAG, p.(Glu389Glyfs*3) - inheritance not known. Patients presented with DD/ID (2/2), cerebral/pyramidal signs (1), seizures (2/2) and MRI abnormalities: Polymicrogyria (2/2).

CCT8 is not yet associated with a disease entity in OMIM (accessed 20th Feb 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.115 TCP1 Ida Ertmanska Phenotypes for gene: TCP1 were changed from Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021 to Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021; intellectual developmental disorder with polymicrogyria and seizures, MONDO:0976124
Early onset or syndromic epilepsy v8.114 TCP1 Ida Ertmanska Classified gene: TCP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.114 TCP1 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported with syndromic epilepsy and heterozygous TCP1 variants - tagged for promotion to Green at the next update.
Early onset or syndromic epilepsy v8.114 TCP1 Ida Ertmanska Gene: tcp1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.113 TCP1 Ida Ertmanska gene: TCP1 was added
gene: TCP1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_26_promote_green tags were added to gene: TCP1.
Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCP1 were set to 39480921
Phenotypes for gene: TCP1 were set to Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021
Review for gene: TCP1 was set to GREEN
Added comment: PMID: 39480921 Kraft et al., 2024
8 individuals reported with heterozygous TCP1 (CCT1) variants (frameshift, missense, stop gain - 5 confirmed de novo). Patients presented with ID, seizures, and brain malformations. Phenotype spectrum: DD/ID of variable severity (6/6 assessed), seizures (6/7), visual impairment (2/7), pyramidal signs (4 individuals), brain MRI abnormalities (7/8). MRI findings included polymicrogyria, heterotopia, ventriculomegaly and white matter hyperintensities, hypoplasia of corpus callosum.

TCP1 is associated with Intellectual developmental disorder with polymicrogyria and seizures, OMIM:621021 (OMIM accessed 20th Feb 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.112 SPTAN1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotypes accessed on 16-02-2026
Early onset or syndromic epilepsy v8.112 SPTAN1 Arina Puzriakova Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277 to Developmental and epileptic encephalopathy 5, OMIM:613477; Developmental delay with or without epilepsy, OMIM:620540; Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, OMIM:620538
Early onset or syndromic epilepsy v8.111 ASTN1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. 11 patients were reported to have seizures and/or epileptiform activity on EEG. Based on available evidence, this gene should be promoted to Green for Early onset or syndromic epilepsy.; to: Comment on list classification: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. 11 patients were reported to have seizures and/or epileptiform activity on EEG (PMIDs: 29706646; 41544630). Based on available evidence, this gene should be promoted to Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.111 ASTN1 Ida Ertmanska Phenotypes for gene: ASTN1 were changed from Intellectual disability; epilepsy; cortical malformations to neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.110 ASTN1 Ida Ertmanska Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Early onset or syndromic epilepsy v8.109 ASTN1 Ida Ertmanska Classified gene: ASTN1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.109 ASTN1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic ASTN1 variants and a neurodevelopmental disorder. 11 patients were reported to have seizures and/or epileptiform activity on EEG. Based on available evidence, this gene should be promoted to Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.109 ASTN1 Ida Ertmanska Gene: astn1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.108 ASTN1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ASTN1.
Early onset or syndromic epilepsy v8.108 ASTN1 Ida Ertmanska edited their review of gene: ASTN1: Changed rating: GREEN; Changed publications to: 41544630; Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.108 ASTN1 Ida Ertmanska commented on gene: ASTN1
Early onset or syndromic epilepsy v8.108 JKAMP Ida Ertmanska Classified gene: JKAMP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.108 JKAMP Ida Ertmanska Added comment: Comment on list classification: There are 14 affected individuals from 10 unrelated families reported in literature with biallelic JKAMP variants and a neurodevelopmental disorder. All individuals presented with early-onset, syndromic epilepsy. Based on available evidence, JKAMP should be promoted to Green at the next update.
Early onset or syndromic epilepsy v8.108 JKAMP Ida Ertmanska Gene: jkamp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.107 JKAMP Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: JKAMP.
Early onset or syndromic epilepsy v8.107 JKAMP Ida Ertmanska gene: JKAMP was added
gene: JKAMP was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: JKAMP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JKAMP were set to 41643666
Phenotypes for gene: JKAMP were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: JKAMP was set to GREEN
Added comment: PMID: 41643666 Chacon-Millan et al., 2026
Report of 14 affected individuals from 10 unrelated families with biallelic JKAMP variants and a neurodevelopmental disorder. Individuals came from European and Arab backgrounds; age range 18mo - 25yrs. Several frameshift, missense and splice variants reported (homozygous and compound heterozygous states). Phenotype spectrum: moderate-profound neurodevelopmental delay and ID (14/14), neurodevelopmental regression (5/14), early onset epilepsy (14/14, median age of onset 6.5 months), hypotonia (13/14), microcephaly (5/14, severity not stated), various ocular manifestations (5/14), genitourinary malformations (3/14), and other (less common).
MRI findings: cortical and or cerebral atrophy (11/14), delayed myelination (6/14).
Additional functional evidence: Knockout jkamp-/- zebrafish were generated using CRISPR. Roughly half of the knockout fish had a mild phenotype, and half a 'severe' phenotype - similar to variable severity seen in patient cohort. Morphant phenotype consisted of smaller eyes and heads, and reduced expression of a myelin marker mbpa, partially recapitulating the human phenotype.

JKAMP is not yet linked to a disease entity in OMIM, Gene2Phenotype, or ClinGen (resources accessed 10th Feb 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.106 KCNT2 Nicholas Head reviewed gene: KCNT2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.106 ATP2B1 Arina Puzriakova Phenotypes for gene: ATP2B1 were changed from Intellectual developmental disorder, autosomal dominant 66, 619910 to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910
Early onset or syndromic epilepsy v8.105 BRSK1 Arina Puzriakova edited their review of gene: BRSK1: Changed rating: GREEN
Early onset or syndromic epilepsy v8.105 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436; complex neurodevelopmental disorder, MONDO:0100038
Early onset or syndromic epilepsy v8.104 CRNKL1 Ida Ertmanska Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Early onset or syndromic epilepsy v8.103 CRNKL1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 30th Jan 2026.
Early onset or syndromic epilepsy v8.103 CRNKL1 Ida Ertmanska Phenotypes for gene: CRNKL1 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, OMIM:621436
Early onset or syndromic epilepsy v8.102 BRSK1 Ida Ertmanska Mode of inheritance for gene: BRSK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Tag Q1_26_NHS_review tag was added to gene: ATP2B1.
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Tag watchlist was removed from gene: ATP2B1.
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: ATP2B1.
Early onset or syndromic epilepsy v8.101 ATP2B1 Ida Ertmanska Publications for gene: ATP2B1 were set to 35358416; 33057194
Early onset or syndromic epilepsy v8.100 ATP2B1 Ida Ertmanska Mode of inheritance for gene: ATP2B1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: Comment on list classification: As previously reviewed, there are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.; to: Comment on list classification: As previously reviewed, there are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). Heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy. Hence, this gene should be promoted to Green on this panel.
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.; to: Comment on list classification: As previously reviewed, there are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: PMID: 40834682 Zhu et al., 2025
Report of patient with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 family members with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn). Method: trio WES.
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Patient heterozygous for p.Ile974Val developed seizures at age 11 years, successfully medicated with lamotrigine. The individuals in family 2 had seizure onset at 3 months - 1 year, but the seizures resolved without medication before age 2 years.
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).; to: PMID: 40834682 Zhu et al., 2025
Report of patient with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 family members with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn). Method: trio WES.
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Patient heterozygous for p.Ile974Val developed seizures at age 11 years, successfully medicated with lamotrigine. The individuals in family 2 had seizure onset at 3 months - 1 year, but the seizures resolved without medication before age 2 years.
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska commented on gene: ATP2B1: Comment on list classification: There are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). As heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy, this gene should be promoted to Green on this panel.
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska changed review comment from: PMID: 40834682 Zhu et al., 2025
5 patients - 1 with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 individuals with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn).
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Since epilepsy may be the presenting and only features, ATP2B1 should be promoted to Green for Early onset or syndromic epilepsy.

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).; to: PMID: 40834682 Zhu et al., 2025
Report of patient with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 family members with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn). Method: trio WES.
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Patient heterozygous for p.Ile974Val developed seizures at age 11 years, successfully medicated with lamotrigine. The individuals in family 2 had seizure onset at 3 months - 1 year, but the seizures resolved without medication before age 2 years.
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).
Early onset or syndromic epilepsy v8.99 ATP2B1 Ida Ertmanska reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33057194, 35358416, 40834682; Phenotypes: Intellectual developmental disorder, autosomal dominant 66, OMIM:619910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.99 PAK2 Arina Puzriakova Publications for gene: PAK2 were set to 33693784; 38894571; 39876536; 39994693; 40262506; 40247748
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Tag watchlist tag was added to gene: PAK2.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals reported in literature with retinal detachment associated with PAK2‐related Knobloch syndrome.; to: Comment on list classification: Rating Amber as only 2 cases have been reported with epilepsy to date. PAK2 has mostly been linked to Knobloch syndrome which is primarily characterised by ocular manifestations and prenatal/neonatal pulmonary features. Neurodevelopmental abnormalities are variable but not a defining feature in most cases. However, given there is a case without cardinal features of Knobloch syndrome, where epilepsy was the primary phenotype, this gene has been included on the panel as Amber in case additional evidence emerges that supports promotion to Green in the future.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Deleted their comment
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova changed review comment from: Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.


Other PAK2 cases not reporting ocular abnormalities:

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.; to: Antonarakis et al., 2021 (PMID: 33693784) reported two affected siblings from a non-consanguineous New Zealand family. Both had retinal detachment and interstitial parenchymal pulmonary changes on chest X-rays, but only one child had additional significant features such as cataract, posterior encephalocele, severe DD/ID with ASD, and epilepsy. WES revealed a heterozygous PAK2 variant (c.1303 G>A, p.Glu435Lys) in both individuals that apparently occurred de novo indicating parental germ-line mosaicism; however, mosaicism could not be detected by deep sequencing of blood parental DNA. Functional studies showed that the variant, located in the kinase domain, results in a partial loss of the kinase activity.

Shen et al. 2025 (PMID: 40247748) reported a Chinese family with a proband who primarily presented with epilepsy and developmental delay without the characteristic ocular and structural malformations that define Knobloch syndrome. WES and Sanger validation identified a de novo heterozygous PAK2 variant c.1049G>A, p.(Arg350Lys) located in the kinase domain. In vitro studies demonstrated the variant may lead to reduced protein levels and decreased PAK2 phosphorylation.


Other PAK2 cases not reporting epilepsy:

Schnur et al. 2024 (PMID: 38894571) report a de novo heterozygous PAK2 variant c.1217C>T, p.(Thr406Met) in a newborn with clinical manifestations of Knobloch syndrome including congenital heart defects, atretic parietal meningocele, and rapidly progressive retinopathy. In vitro experiments indicated that this and another reported variant, p.(Asp425Asn), result in substantially impaired protein kinase activity.

Werren et al. 2025 (PMID: 39876536) report a male infant with a de novo heterozygous PAK2 variant c.1273G>A, p.(Asp425Asn) identified by WGS. Clinical features include GDD, congenital retinal detachment, mild cerebral ventriculomegaly, hypotonia, failure to thrive, pyloric stenosis, feeding intolerance, patent ductus arteriosus, and mild facial dysmorphism. The p.(Asp425Asn) variant resides within the protein kinase domain and was predicted functionally damaging by in silico tools. Further functional studies were not performed.

Lodha et al. 2025 (PMID: 40262506) revealed a PAK2 c.1115A>T, p.(Asp372Val) variant in a neonate with bilateral pleural effusion, suggestive of chylothorax on prenatal imaging, and respiratory distress, purpura fulminans and retinal detachment after birth.

Domenach et al. 2025 (PMID: 39994693) identified a novel de novo PAK2 missense variant in the kinase domain, c.836A>C, p.(Gln279Pro), by prenatal trio exome sequencing in a 24 weeks of gestation fetus whose only identifiable sign was severe bilateral pleural effusion.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Tag Q1_26_promote_green was removed from gene: PAK2.
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova Entity copied from Retinal disorders v8.82
Early onset or syndromic epilepsy v8.98 PAK2 Arina Puzriakova gene: PAK2 was added
gene: PAK2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q1_26_promote_green tags were added to gene: PAK2.
Mode of inheritance for gene: PAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAK2 were set to 33693784; 38894571; 39876536; 39994693; 40262506; 40247748
Phenotypes for gene: PAK2 were set to Knobloch 2 syndrome, OMIM:618458
Early onset or syndromic epilepsy v8.97 AIMP2 Eleanor Williams Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, OMIM:618006 to Leukodystrophy, hypomyelinating, 17, OMIM:618006; eukodystrophy, hypomyelinating, 17, MONDO:0054817
Early onset or syndromic epilepsy v8.95 AIMP2 Ida Ertmanska Tag watchlist was removed from gene: AIMP2.
Tag Q1_26_promote_green tag was added to gene: AIMP2.
Early onset or syndromic epilepsy v8.95 AIMP2 Ida Ertmanska Phenotypes for gene: AIMP2 were changed from Epileptic Encephalopathy; Infantile Spasms; Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Leukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.94 AIMP2 Ida Ertmanska Publications for gene: AIMP2 were set to 29215095; 26795593
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Changed phenotypes to: Leukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska edited their review of gene: AIMP2: Added comment: Comment on list classification: There are at least 6 unrelated individuals reported with biallelic variants in AIMP2, of which 5 presented with seizures / epilepsy. Based on available evidence, this gene should be promoted to Green at the next GMS update.; Changed publications to: 35140751, 35568357, 38374194; Changed phenotypes to: eukodystrophy, hypomyelinating, 17, OMIM:618006
Early onset or syndromic epilepsy v8.93 AIMP2 Ida Ertmanska reviewed gene: AIMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.93 DHDDS Ida Ertmanska reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: None; Publications: 38451541; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v8.93 CRNKL1 John Taylor reviewed gene: CRNKL1: 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: 40857589; Phenotypes: microcephaly, pontocerebellar hypoplasia, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.93 C12orf66 John Taylor reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: None; Publications: 39824192; Phenotypes: Seizure, Intellectual disability, delayed speech.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.93 BRSK1 John Taylor reviewed gene: BRSK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 41035394; Phenotypes: Epilepsy, global developmental delay; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Classified gene: CELSR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants in CELSR3 gene with epilepsy/ seizures (five families with each MOI). Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.93 CELSR3 Achchuthan Shanmugasundram Gene: celsr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.92 CELSR3 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: CELSR3.
Early onset or syndromic epilepsy v8.92 CELSR3 Achchuthan Shanmugasundram gene: CELSR3 was added
gene: CELSR3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to 34951123; 38429302
Phenotypes for gene: CELSR3 were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: CELSR3 was set to GREEN
Added comment: PMID:34951123 (2022) reported trio-based whole-exome sequencing in a cohort of 462 cases with febrile seizures (FS)/ epilepsy with antecedent FS (EFS+), where five heterozygous missense variants in CELSR3 gene were identified in eight individuals from five unrelated families. All affected individuals were diagnosed with FS/EFS+, including six patients with FS and two patients with EFS+. All cases presented favorable outcomes without neurodevelopmental disorders.

PMID:38429302 (2024) reported the identification of biallelic variants in CELSR3 gene in 12 individuals from 11 unrelated families. Six of 12 patients presented with homozygous missense and five with compound heterozygous missense CELSR3 variants, while one individual carried a heterozygous missense variant and an in-frame-deletion in trans. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Seizures were reported in six patients from five unrelated families.

There is also functional evidence available from zebrafish, where transient suppression of CELSR3 ortholog Celsr3 leads to anomalies in the developing CNS and urinary system.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 13 January 2026) or ClinGen, but biallelic CELSR3 variants have been associated with 'limited' rating on the DD panel of Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

The other reported phenotypes include microcephaly (six individuals including the foetus - none of them had OFC beyond -3 SD), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (17 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (5 unrelated patients) for the association of KDM2A gene with syndromic intellectual disability. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram changed review comment from: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve).

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41468891 (2025) reported a cohort of 18 unrelated individuals including one foetus with heterozygous de novo variants in KDM2A gene and with a neurodevelopmental disorder.

All individuals, excluding the foetus, exhibited developmental delay and/or intellectual disability, with the severity of developmental delay or intellectual disability ranging from learning disabilities to severe intellectual disability. The majority of individuals were affected by mild developmental delay/intellectual disability (11/17) or learning disabilities (2/17), while four individuals presented with severe developmental delay/intellectual disability.

Thew other reported phenotypes include microcephaly (six individuals including the foetus), seizures (five), hypotonia (four), IUGR (eight), short stature (nine), feeding difficulties (six) and dysmorphic facial features (twelve). Seizure types included focal and generalized seizures as well as epileptic spasms. At the last assessment, two individuals continued to experience seizures, while three achieved seizure freedom. In the latter three, the anti-seizure medication was subsequently weaned off without relapse.

The study proposed dual mechanism of pathogenicity: loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.231
Early onset or syndromic epilepsy v8.91 KDM2A Achchuthan Shanmugasundram gene: KDM2A was added
gene: KDM2A was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q1_26_promote_green tags were added to gene: KDM2A.
Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2A were set to 41468891
Phenotypes for gene: KDM2A were set to neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Classified gene: PRMT9 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>10 unrelated families) for the association of biallelic PRMT9 variants with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.90 PRMT9 Achchuthan Shanmugasundram Gene: prmt9 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.89 PRMT9 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: PRMT9.
Early onset or syndromic epilepsy v8.89 PRMT9 Achchuthan Shanmugasundram gene: PRMT9 was added
gene: PRMT9 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRMT9 were set to 41260215
Phenotypes for gene: PRMT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PRMT9 was set to GREEN
Added comment: PMID:41260215 (2025) reported the identification of biallelic loss-of-function variants in PRMT9 gene in 35 individuals from 26 unrelated families primarily presenting with a neurodevelopmental disorder characterised by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia.

There were 26 different variants identified in total which included frameshifting indels, nonsense variants, missense variants, and two copy-number variants.

Clinical examinations revealed that 14 individuals developed epilepsy, which was suspected in one other individual.

Functional evidence available from skin fibroblasts derived from affected individuals showed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), but has been associated with 'Limited' rating on the DD panel in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. In addition, there is also functional evidence available in support of the association of this gene with the neurodevelopmental disorder. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram edited their review of gene: WSB2: Changed rating: GREEN
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram edited their review of gene: WSB2: Changed rating: RED
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram changed review comment from: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family. One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family (child without seizures is aged 9 years old, while the onset of seizure on the other child was at 10 years of age). One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.88 WSB2 Achchuthan Shanmugasundram Tag watchlist was removed from gene: WSB2.
Tag Q1_26_promote_green tag was added to gene: WSB2.
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram changed review comment from: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).; to: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >10 unrelated individuals reported with developmental and epileptic encephalopathy and monoallelic GLUL variants. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.88 GLUL Achchuthan Shanmugasundram Mode of inheritance for gene: GLUL was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.87 GLUL Achchuthan Shanmugasundram Phenotypes for gene: GLUL were changed from Glutamine deficiency, congenital, 610015; seizures to Glutamine deficiency, congenital, OMIM:610015; Developmental and epileptic encephalopathy 116, OMIM:620806; congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393; developmental and epileptic encephalopathy 116, MONDO:0970945
Early onset or syndromic epilepsy v8.86 GLUL Achchuthan Shanmugasundram Publications for gene: GLUL were set to 21353613; 16267323; 30158707
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: GLUL.
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram commented on gene: GLUL: PMID:38579670 (2024) reported nine unrelated individuals with severe global developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry. The epilepsy was characterized as generalized (4 individuals), combined general and focal (3), focal (1), or unknown (1). Most individuals had a developmental and epileptic encephalopathy, with one individual meeting diagnostic criteria for infantile epileptic spasms syndrome. They were identified with heterozygous de novo variants in GLUL gene via whole-exome sequencing. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon.

PMID:39985170 (2025) reported a male proband with a phenotype of refractory focal and generalized seizures and developmental delays and identified with a heterozygous de novo start-codon-disrupting variant in GLUL (c.-13-2A>G).

PMID:41083803 (2025) reported three additional unrelated patients with heterozygous de novo GLUL variants identified via trio whole-exome sequencing and with developmental and epileptic encephalopathy.

Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #610015 & #620806, last accessed 07 January 2026) and ClinGen (both AR and AD diseases with 'moderate' rating). Only biallelic variants are currently associated with phenotype in Gene2Phenotype ('definitive' rating on DD panel).
Early onset or syndromic epilepsy v8.85 GLUL Achchuthan Shanmugasundram reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: 38579670, 39985170, 41083803; Phenotypes: Glutamine deficiency, congenital, OMIM:610015, Developmental and epileptic encephalopathy 116, OMIM:620806, congenital brain dysgenesis due to glutamine synthetase deficiency, MONDO:0012393, developmental and epileptic encephalopathy 116, MONDO:0970945; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Classified gene: RPS6KC1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.85 RPS6KC1 Achchuthan Shanmugasundram Gene: rps6kc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.84 RPS6KC1 Achchuthan Shanmugasundram Tag Q1_26_promote_green tag was added to gene: RPS6KC1.
Early onset or syndromic epilepsy v8.84 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic UNC13A variants with seizures, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.83 UNC13A Achchuthan Shanmugasundram Mode of inheritance for gene: UNC13A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.82 UNC13A Achchuthan Shanmugasundram Publications for gene: UNC13A were set to 28192369; 39634123
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram Tag Q1_26_MOI tag was added to gene: UNC13A.
Early onset or syndromic epilepsy v8.81 UNC13A Achchuthan Shanmugasundram edited their review of gene: UNC13A: Added comment: PMID:41125872 (2025) identified a neurodevelopmental syndrome caused by variants in the UNC13A gene. Systematic patient and variant characterisation enabled classification of three disease subtypes.

A first group of six patients (18 months to ~15 years old) presented with severe-to-profound global developmental delay (GDD) or intellectual disability (ID), hypotonia and seizures of different types (largely controllable with medication) or death in early childhood caused by respiratory failure after pneumonia in one case. UNC13A variants in these patients were homozygous or compound heterozygous missense, insertion–deletion or splice-site variants with gene-disrupting splicing effects proven by minigene assays.

A second group of 13 patients (21 months to 32 years old) harboured pathogenic, heterozygous de novo missense variants with multiple substitutions at amino acids 808, 811 and 814. They presented with variable degrees of GDD, hypotonia, seizures of different types (mainly refractory to treatment) and typically exhibited ataxia, tremor or dyskinetic movements rarely observed in other patients.

The third group of patients consisted of a family with at least four affected members across two generations (4 years to 35 years old) harbouring a pathogenic heterozygous missense variant (p.Cys587Phe) that caused learning difficulties to mild–moderate intellectual disability as well as controlled seizures.

Both monoallelic and biallelic UNC13A variants have been associated with relevant phenotypes in Gene2Phenotype (both with 'moderate' rating on the DD panel), but not yet in OMIM (last accessed 02 January 2026).; Changed publications to: 28192369, 39634123, 41125872; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: WSB2.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Classified gene: WSB2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with seizures and with biallelic WSB2 variants. However, only one of two patients from the same family was reported with seizures. Hence, this gene should be rated amber with the current evidence.
Early onset or syndromic epilepsy v8.81 WSB2 Achchuthan Shanmugasundram Gene: wsb2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.80 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to AMBER
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Seizures were reported in three of five patients including one of two patients from the Ashkenazi Jew family. One of the patients is now free of seizures and not on medication, while the other two patients responded to treatments.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.79 WDR47 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WDR47.
Early onset or syndromic epilepsy v8.79 OGDHL Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: OGDHL.
Early onset or syndromic epilepsy v8.79 RNU12 Ida Ertmanska commented on gene: RNU12: Comment on list classification: There is one large consanguineous pedigree reported in literature, with a biallelic RNU12 mutation segregating with early-onset ataxia. RNU12 should be rated Red for Early onset or syndromic epilepsy, until more evidence emerges.
Early onset or syndromic epilepsy v8.79 RNU12 Ida Ertmanska gene: RNU12 was added
gene: RNU12 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 27863452; 33577674
Phenotypes for gene: RNU12 were set to ?Spinocerebellar ataxia, autosomal recessive 33, OMIM:620208
Review for gene: RNU12 was set to RED
Added comment: PMID: 27863452 Elsaid et al., 2017
Report of a large consanguineous pedigree with 6 individuals presenting with early-onset ataxia (onset <2 yrs old). Affected individuals were homozygous for RNU12 84C>U mutation. Method: WGS confirmed by Sanger. 2 other mutations segregates with disease in a recessive manner, affecting non-coding regions of genes POLDIP3 and PACSIN2 (uncertain significance).
Affected individuals showed a significant increase in RNU12 snRNA levels; expression of POLDIP3 and PACSIN2 did not differ between affected and unaffected members.
Phenotype spectrum: truncal ataxia 6/6, abnormal cerebellum 5/5 (5 assessed), hypotonia in infancy 5/6, mild learning difficulties 4/6, seizures (febrile / complex partial) 4/6, dysarthric speech 5/6, abnormal gait & falls 5/6.

Functional evidence: PMID: 33577674 Norppa and Frilander, 2021: Show that the 84C>U mutation leads to accelerated decay of the RNU12 snRNA, resulting in significantly reduced steady-state U12 snRNA levels (cell line model).

This gene is putatively linked to Spinocerebellar ataxia, autosomal recessive 33, MIM:620208 and linked to CDAGS syndrome, MIM:603116 (OMIM accessed 19th Dec 2025).
Sources: Literature
Early onset or syndromic epilepsy v8.78 RNU5B-1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621302) and the OMIM record was last accessed on 18 December 2025.
Early onset or syndromic epilepsy v8.78 RNU5B-1 Achchuthan Shanmugasundram Phenotypes for gene: RNU5B-1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with seizures and joint laxity, OMIM:621302; RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, MONDO:1060179
Early onset or syndromic epilepsy v8.77 RNU5B-1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RNU5B-1.
Early onset or syndromic epilepsy v8.77 ATP2B1 Simon Thomas reviewed gene: ATP2B1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 40834682; Phenotypes: generalized epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.77 PPP2R5C Arina Puzriakova Phenotypes for gene: PPP2R5C were changed from neurodevelopmental disorder to Houge-Janssens syndrome 4, OMIM:621185
Early onset or syndromic epilepsy v8.76 RANBP2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.; to: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy with seizures, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.
Early onset or syndromic epilepsy v8.76 RANBP2 Ida Ertmanska Phenotypes for gene: RANBP2 were changed from {Encephalopathy, acute, infection-induced, 3, susceptibility to} 608033 to {Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033
Early onset or syndromic epilepsy v8.75 RANBP2 Ida Ertmanska Publications for gene: RANBP2 were set to
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska edited their review of gene: RANBP2: Changed publications to: 34377735, 36621064, 38050538, 40538544
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion on this panel.; to: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion of RANBP2 on this panel.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska commented on gene: RANBP2: Comment on list classification: There are numerous cases described in literature where patients with heterozygous missense variants in RANBP2 develop acute necrotizing encephalopathy, triggered by an infection. Variant c.1754C>T, p.Thr585Met is the most commonly recurring variant, but other missense variants have been reported - both inherited and de novo. However, the disease penetrance is estimated to be around 40% - expert review will be sought regarding inclusion on this panel.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska changed review comment from: RANBP2 is predicted to be dosage sensitive (pLI score = 1.00) - https://www.deciphergenomics.org/gene/RANBP2/overview/clinical-info. This gene is putatively linked to AD Encephalopathy, acute, infection-induced, 3, susceptibility to - MIM:608033 (OMIM accessed 21st Nov 2025).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID: 34377735 Hartley et al., 2021
Case 1 - 9 month old female presented with a seizure, following 4 days of fever; developed weakness and spasticity in her left side, and developmental regression; positive for Human herpesvirus 6. Seizures recurred 2 years later. Gene panel test detected a heterozygous mutation in RANBP2 (c.1754C>T; p.Thr585Met) - parents not genotyped.
Case 2 - 6-year-old female with no significant past medical history; presented in cardiac arrest likely secondary to hypoxia from refractory status epilepticus; frequent seizures, EEG abnormal, brain MRI was positive for symmetric T2 lesions. Patient recovered after 42 days. Gene panel showed patient was heterozygous for a c.1350A>T; p.Leu450Phe variant in RANBP2 - maternally inherited, 6 heterozygotes reported in gnomAD v4.1.0., Revel score = 0.06 Benign Moderate.
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska edited their review of gene: RANBP2: Changed rating: AMBER; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v8.74 RANBP2 Ida Ertmanska reviewed gene: RANBP2: Rating: ; Mode of pathogenicity: None; Publications: 38050538, 40538544; Phenotypes: {Encephalopathy, acute, infection-induced, 3, susceptibility to}, OMIM:608033; Mode of inheritance: None
Early onset or syndromic epilepsy v8.74 BSN Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BSN.
Tag Q4_25_NHS_review tag was added to gene: BSN.
Early onset or syndromic epilepsy v8.74 BSN Ida Ertmanska Phenotypes for gene: BSN were changed from Seizures - different types to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v8.73 BSN Ida Ertmanska Publications for gene: BSN were set to PMID: 36600631; 39616287; 40393460
Early onset or syndromic epilepsy v8.72 BSN Ida Ertmanska Mode of inheritance for gene: BSN was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.71 BSN Ida Ertmanska Classified gene: BSN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.71 BSN Ida Ertmanska Gene: bsn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.70 BSN Ida Ertmanska reviewed gene: BSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 36600631, 39616287, 40393460; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska edited their review of gene: BAIAP2: Changed publications to: 30696821, 38149472, 41133935
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska Tag Q4_25_promote_green tag was added to gene: BAIAP2.
Tag Q4_25_NHS_review tag was added to gene: BAIAP2.
Early onset or syndromic epilepsy v8.70 BAIAP2 Ida Ertmanska Publications for gene: BAIAP2 were set to PMID: 41133935
Early onset or syndromic epilepsy v8.69 BAIAP2 Ida Ertmanska Phenotypes for gene: BAIAP2 were changed from DEE to developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146
Early onset or syndromic epilepsy v8.68 BAIAP2 Ida Ertmanska Mode of inheritance for gene: BAIAP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v8.67 BAIAP2 Ida Ertmanska Classified gene: BAIAP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.67 BAIAP2 Ida Ertmanska Gene: baiap2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472).; to: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). All individuals presented with early onset epilepsy. Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). Additional functional evidence from coimmunoprecipitation studies shows that missense variants around aa 340-366 in BAIAP2 are likely to disrupt binding of 14-3-3, necessary for BAIAP2 inhibition (PMID: 30696821). Based on the available evidence, BAIAP2 should be promoted to Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska changed review comment from: PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

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

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

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

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

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

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

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

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

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

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

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

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska edited their review of gene: BAIAP2: Added comment: Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472).; Changed phenotypes to: developmental and epileptic encephalopathy, MONDO:0100620, classic lissencephaly, MONDO:0015146
Early onset or syndromic epilepsy v8.66 BAIAP2 Ida Ertmanska reviewed gene: BAIAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38149472, 41133935; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Classified Region: ISCA-37433-Loss as Green List (high evidence)
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

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

Checked and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.66 ISCA-37433-Loss Arina Puzriakova Region: isca-37433-loss has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.65 ISCA-37433-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37433-Loss.
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as Green List (high evidence)
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been deprecated by ClinGen and therefore should be removed from the panel.

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

Checked and approved by the Genomics England Clinical team.
Early onset or syndromic epilepsy v8.65 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.64 ISCA-37404-Loss Arina Puzriakova Tag Q3_25_demote_red tag was added to Region: ISCA-37404-Loss.
Early onset or syndromic epilepsy v8.64 ISCA-37448-Loss Arina Puzriakova Phenotypes for Region: ISCA-37448-Loss were changed from to Developmental delay/intellectual disability, epilepsy, autism spectrum disorder, schizophrenia, congenital heart disease, and variable dysmorphic features
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Classified Region: ISCA-37448-Loss as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.63 ISCA-37448-Loss Arina Puzriakova Added comment: Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

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

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

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

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


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

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

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

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


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

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

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

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


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf). Therefore, agree with the recommendations.
Sources: ClinGen
Early onset or syndromic epilepsy v8.61 BAIAP2 Alexander Symon-Allen gene: BAIAP2 was added
gene: BAIAP2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: BAIAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAIAP2 were set to PMID: 41133935
Phenotypes for gene: BAIAP2 were set to DEE
Penetrance for gene: BAIAP2 were set to unknown
Mode of pathogenicity for gene: BAIAP2 was set to Other
Review for gene: BAIAP2 was set to AMBER
Added comment: De novo missense variants detected in 6 unrelated individuals with DEE. One of which has also been seen on DECIPHER and deposited as a research variant (also de novo).
Seizure type is highly variable.
ID ranges from mild to profound.
Animal models (zebrafish) provide some evidence of pathogenicity through abnormal neurite growth (lack or absence of filopodia) and increased neuronal excitability (reduced rheobase & increased AP firing patterns in whole cell recordings). Ion channels within membrane remain unaffected - no significant difference between WT and mutants in specific AP characteristics such as amplitude, voltage threshold, afterhyperpolarisation, and half-width values.
The above evidence led the authors hypothesis that GoF is the mechanism of disease for the variants in this study, however, they propose that LoF variants may also be pathogenic (no evidence to confirm this).
Further studies needed to verify findings and confirm this proposed biphasic disease mechanism model (LoF & GoF variants cause disease).
Currently only evidence for GoF in for a very specific repertoire of residues that are clustered within the phosphorylation site region that is critical to 14-3-3 binding for autoinhibited conformation: T340, Pro342, Arg363 and one variant within the I-BAR domain which is crucial for maintaining the overall positive charge of the dimer: Glu189Val.
Sources: Literature
Early onset or syndromic epilepsy v8.61 BSN Helen Lord gene: BSN was added
gene: BSN was added to Early onset or syndromic epilepsy. Sources: Other
Mode of inheritance for gene: BSN was set to Unknown
Publications for gene: BSN were set to PMID: 36600631; 39616287; 40393460
Phenotypes for gene: BSN were set to Seizures - different types
Penetrance for gene: BSN were set to unknown
Review for gene: BSN was set to AMBER
Added comment: There are a lot of cases to support an AD phenotype but unsure as to whether there is also an AR pheontype associated with disease...

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

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

PMID: 40393460 Guzman et al, 2025: cohort of 29 individuals with BSN variants including 14 with de novo vairants, 13 individuals with PTVs (protein truncating variants) of unknown inheritance and 2 individuals with PTVs with paternal inheritance. Affected individuals had diverse neurodevelopmental phenotypes including behavioural abnormalities; delayed speech, learning difficulties and variable seizure types.
Recruitment: 2/29 - enrolled in the Epilepsy genetics research project at Childrens Hospital Philadelphia (CHOP) confirmed de novo; 14/29 identified via gene matcher - 9/14 confirmed de novo by respective institutions; 7/29 identified through Penn medicine biobank; 1/29 missense de novo BSN variant identified from birth defects biorepositary at CHOP; 3/29 BSN PTVs idenitifed through the center for applied genomics at CHOP and a lit review identified 2/29 previously reported individuals with de novo PTVs in BSN.
Table 1 details the 14 individuals with de novo BSN variants - 8/14 had seizures (different types); 12/14 had developmental features.
They suggest haploinsuffucency as as a likely mechanism.
Sources: Other
Early onset or syndromic epilepsy v8.61 SETBP1 Ida Ertmanska Publications for gene: SETBP1 were set to 20436468
Early onset or syndromic epilepsy v8.60 SETBP1 Ida Ertmanska Phenotypes for gene: SETBP1 were changed from Schinzel-Giedion midface retraction syndrome 269150 to Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078; Schinzel-Giedion midface retraction syndrome, OMIM: 269150; Schinzel-Giedion syndrome, MONDO:0010010
Early onset or syndromic epilepsy v8.59 SETBP1 Ida Ertmanska reviewed gene: SETBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20436468, 21037274, 22473152, 23020937, 25217958, 25356899, 25028416, 25082129, 25663181, 26096993, 26188272, 28346496, 29463886, 32445275, 32460883; Phenotypes: Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078, Schinzel-Giedion midface retraction syndrome, OMIM: 269150, Schinzel-Giedion syndrome, MONDO:0010010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.59 BRSK1 Arina Puzriakova Classified gene: BRSK1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.59 BRSK1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated cases with early onset epilepsy and supportive data from functional and animal model studies (PMID: 41035394)
Early onset or syndromic epilepsy v8.59 BRSK1 Arina Puzriakova Gene: brsk1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.58 BRSK1 Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: BRSK1.
Early onset or syndromic epilepsy v8.58 BRSK1 Arina Puzriakova gene: BRSK1 was added
gene: BRSK1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: BRSK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK1 were set to 41035394
Phenotypes for gene: BRSK1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BRSK1 was set to AMBER
Added comment: Zhang et al. 2025 (PMID: 41035394) describe 7 unrelated individuals, born to non-consanguineous Chinese parents, with unexplained epilepsy and heterozygous variants in the BRSK1 gene identified by trio WES. Variants include four SNVs and two indels (2 frameshift, 1 nonsense, 3 missense) - five were de novo, one inherited from an affected parent and one recurrent. No other pathogenic variants in epilepsy genes were identified. BRSK1 is intolerant to LoF variants (pLI = 1 in gnomAD v4.1.0).

Clinical features in affected individuals include epilepsy (7/7) with age of onset before age 1 (with exception of 1 case with age of onset at 6 yrs), variable brain MRI abnormalities (3/7), developmental delay (2 GDD, 1 mental delay, 1 motor delay, 2 without DD). One individual also had ASD and ADHD.

Frameshift and nonsense variants led to complete loss of BRSK1 protein, while one missense variant reduced protein levels. Proteomic analyses demonstrated axonal and synaptic dysfunction. Brsk1 exon 4-7 knockout mice (heterozygous and homozygous) exhibited seizures, neuronal hyperexcitability and neurobehavioral impairments which recapitulated clinical features observed in humans.
Sources: Literature
Early onset or syndromic epilepsy v8.57 LAMC3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (six unrelated cases) for the association of biallelic LAMC3 variants with seizures. Hence, this gene should be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (six unrelated cases) for the association of biallelic LAMC3 variants with seizures. The 'Disputed' rating in ClinGen is only relevant to monoallelic MOI. Hence, this gene should be promoted to green rating with biallelic MOI in the next GMS update.
Early onset or syndromic epilepsy v8.57 CDK5 Eleanor Williams Phenotypes for gene: CDK5 were changed from Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342 to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342; lissencephaly 7 with cerebellar hypoplasia, MONDO:0014596
Early onset or syndromic epilepsy v8.56 TMEM167A Arina Puzriakova Classified gene: TMEM167A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.56 TMEM167A Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6 unrelated cases with a concordant phenotype caused by biallelic variants in this gene.
Early onset or syndromic epilepsy v8.56 TMEM167A Arina Puzriakova Gene: tmem167a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.55 TMEM167A Arina Puzriakova gene: TMEM167A was added
gene: TMEM167A was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: TMEM167A.
Mode of inheritance for gene: TMEM167A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM167A were set to 40924476
Phenotypes for gene: TMEM167A were set to Microcephaly, epilepsy, and diabetes syndrome, MONDO:0100328
Review for gene: TMEM167A was set to GREEN
Added comment: PMID: 40924476 (2025) - 6 individuals from 6 unrelated families with biallelic variants in the TMEM167A gene identified by WGS. Clinical features in all affected individuals include neonatal diabetes (diagnosed <6 months) and severe microcephaly. 5/6 also had epilepsy in the neonatal period. TMEM167A is highly expressed in the human pancreas and brain. Both the depletion of TMEM167A in EndoC-βH1 cells and knock-in of the p.Val59Glu patient variant in iPSC-derived β cells increased β cells sensitivity to ER stress. The p.Val59Glu variant disrupted proinsulin trafficking to the Golgi and led to dysfunction in iPSC-β cells.
Sources: Literature
Early onset or syndromic epilepsy v8.54 PPOX Arina Puzriakova Phenotypes for gene: PPOX were changed from Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577 to Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, childhood-onset, MONDO:0957577
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.; to: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska edited their review of gene: PPOX: Added comment: Comment on list classification: There are at least 4 unrelated individuals with biallelic variants in PPOX that presented with early onset (2-6 months after birth), syndromic epilepsy. Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; Changed publications to: 8290408, 9811936, 2004012, 30861571, 35164799, 37879139, 40114189
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
2 siblings with
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska changed review comment from: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PMID: 8290408 Hift et al., 1993
Male infant with Blistering and fragility of the skin of hands, face and ears; hypertrichosis; hyperpigmentation; scarring and milia; Epilepsy (onset at 5 months of age); developmental delay; nystagmus and clinodactyly.
Molecular diagnosis: homozygous for c.1279G>C, p.Ala433Pro - genotyped in PMID: 9811936 Roberts et al., 1998. Variant is rare in gnomAD v4, no homozygotes; Revel score = 0.71.

PMID: 30861571 Al-Hage et al., 2019
A 3-year-old girl presented with a history of recurrent blisters over sun-exposed areas from age 6 months; recurrent epileptic episodes from 2 months old; had a delay in speech and motor development; ocular nystagmus. Family members similarly affected. Patient and affected uncle both homozygous for p.Glu339Lys - variant not in gnomAD v4. Method: Exome seq.

PMID: 35164799 Vafaee-Shahi et al., 2022
Reported a 7-year-old boy with homozygous PPOX pathogenic variant (c.1072G>A, p.Gly358Arg) - rare in gnomAD v4, method: WES. He was admitted with three episodes of generalized tonic-clonic seizure in 6 months. He was presented with lesions, hyperpigmentation, fragility, and blistering of sun-exposed skin; weakness of limbs and brachydactyly, aggressive behaviour, learning disability and abdominal pain were also observed.

PMID: 40114189 Kaiser et al., 2025
2 siblings with
Patient 1, female, 7yo. Presented with neonatal hepatopathy and cutaneous lesions caused by light exposure; other symptoms include: nystagmus, global developmental delay, short stature, microcephaly, intellectual disability. She developed epileptic seizures, mainly bilateral tonic seizures with eye blinking, at the age of 3 months - treated with a combination of valproic acid and phenobarbital.
Patient 2 - similarly affected brother, 14yo - generalized epileptic seizures were reported before the age of 6 months; seizure-free with valproic acid treatment.
Both siblings homozygous for PPOX variant c.164A > C (p.Glu55Ala) - not in gnomAD v4, Revel score = 0.94.

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed phenotypes to: Variegate porphyria, childhood-onset, OMIM:620483, variegate porphyria, childhood-onset, MONDO:0957577
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska Classified gene: PPOX as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.53 PPOX Ida Ertmanska Gene: ppox has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.52 PPOX Ida Ertmanska Mode of inheritance for gene: PPOX was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.52 PPOX Ida Ertmanska Classified gene: PPOX as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.52 PPOX Ida Ertmanska Gene: ppox has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.51 PPOX Ida Ertmanska Publications for gene: PPOX were updated from to 8290408; 9811936; 2004012; 35164799; 37879139; 40114189
Tag Q3_25_promote_green tag was added to PPOX.
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed publications to: 8290408, 9811936, 2004012, 35164799, 37879139, 40114189
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska changed review comment from: Sources: Other; to: Comment on list classification: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms: nystagmus, epileptic seizures, developmental delay, intellectual disability, and sensory neuropathy (PMIDs: 8290408; 9811936; 2004012; 35164799; 37879139; 40114189).

PPOX is associated with AD Variegate porphyria (176200) and AR Variegate porphyria, childhood onset (620483) in OMIM - accessed 13th October 2025.

Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. The mode of inheritance should be set to BIALLELIC, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska edited their review of gene: PPOX: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.50 PPOX Ida Ertmanska gene: PPOX was added
gene: PPOX was added to Early onset or syndromic epilepsy. Sources: Other
Mode of inheritance for gene: PPOX was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PPOX were set to Variegate porphyria, OMIM:176200; Variegate porphyria, childhood-onset, OMIM:620483; variegate porphyria, MONDO:0008297; variegate porphyria, childhood-onset, MONDO:0957577
Review for gene: PPOX was set to GREEN
Added comment: Sources: Other
Early onset or syndromic epilepsy v8.49 LAMC3 Achchuthan Shanmugasundram Classified gene: LAMC3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.49 LAMC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (six unrelated cases) for the association of biallelic LAMC3 variants with seizures. Hence, this gene should be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.49 LAMC3 Achchuthan Shanmugasundram Gene: lamc3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.48 LAMC3 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LAMC3.
Early onset or syndromic epilepsy v8.48 LAMC3 Achchuthan Shanmugasundram changed review comment from: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. Childhood-onset seizures is the most common clinical manifestation that is reported in all patients except the foetal case.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene has also been rated green on the epilepsy panel in PanelApp Australia. Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Sources: Literature; to: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. Childhood-onset seizures is the most common clinical manifestation that is reported in all patients except the foetal case.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene has also been rated green with biallelic MOI on Genetic epilepsy panel in PanelApp Australia (https://panelapp-aus.org/panels/202/gene/LAMC3/). Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Sources: Literature
Early onset or syndromic epilepsy v8.48 LAMC3 Achchuthan Shanmugasundram gene: LAMC3 was added
gene: LAMC3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: LAMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMC3 were set to 21572413; 26802095; 29247375; 33639934; 34354730
Phenotypes for gene: LAMC3 were set to Cortical malformations, occipital, OMIM:614115; occipital pachygyria and polymicrogyria, MONDO:0013583
Review for gene: LAMC3 was set to GREEN
Added comment: There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. Childhood-onset seizures is the most common clinical manifestation that is reported in all patients except the foetal case.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene has also been rated green on the epilepsy panel in PanelApp Australia. Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Sources: Literature
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram commented on gene: RELN: Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Seizures are recorded as part of this phenotype in majority of the cases.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, this phenotype did not include the cases with autosomal-dominant lateral temporal epilepsy reported in PMID:26046367.

As there are sufficient monoallelic and biallelic cases reported with epilepsy as part of this phenotype, this gene can remain green with 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as the MOI.
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: Both monoallelic and biallelic variants in this gene has been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).; to: Comment on phenotypes: Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Both monoallelic and biallelic variants in this gene has been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; {Epilepsy, familial temporal lobe, 7}, OMIM:616436 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; Norman-Roberts syndrome, MONDO:0009760; {Epilepsy, familial temporal lobe, 7}, OMIM:616436; familial temporal lobe epilepsy 7, MONDO:0014639
Early onset or syndromic epilepsy v8.46 RELN Achchuthan Shanmugasundram Publications for gene: RELN were set to 26046367; 17431900; 10973257
Early onset or syndromic epilepsy v8.45 RELN Achchuthan Shanmugasundram changed review comment from: Monoallelic variants:
PMID:26046367 (2015) reported the identification of seven different heterozygous missense variants in RELN gene in seven unrelated families with autosomal-dominant lateral temporal epilepsy. These variants were identified by performing SNP-array linkage analysis and whole-exome sequencing. Of these seven variants, six of these are either absent or present with a very low allele frequency in gnomAD v4.1.0. However, c.2015C>T (p.Pro672Leu) variant is present in gnomAD with higher allele frequency.

Biallelic variants:

PMID:10973257 (2000) reported two unrelated consanguineous pedigrees segregating an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem. They were identified with homozygous variants in RELN gene and had seizures.

PMID:27000652 (2016) reported a Moroccan female patient with lissencephaly and with homozygous RELN variant. This patient presented with neonatal seizures that were controlled with medication.

PMID:35769015 (2022) reported the identification of biallelic RELN variants in seven patients from four unrelated families and monoalellic RELN variants from 13 individuals from seven families with frontotemporal or temporal-predominant lissencephaly. Five patients from three different families with biallelic variants presented with seizures as part of the phenotype, while detailed phenotypic information was not available in two patients from the first family with biallelic variants. However, seizure was only reported in three of 13 individuals with monoallelic variants (all three are unrelated).; to: Monoallelic variants:

PMID:26046367 (2015) reported the identification of seven different heterozygous missense variants in RELN gene in seven unrelated families with autosomal-dominant lateral temporal epilepsy. These variants were identified by performing SNP-array linkage analysis and whole-exome sequencing. Of these seven variants, six of these are either absent or present with a very low allele frequency in gnomAD v4.1.0. However, c.2015C>T (p.Pro672Leu) variant is present in gnomAD with higher allele frequency.

Biallelic variants:

PMID:10973257 (2000) reported two unrelated consanguineous pedigrees segregating an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem. They were identified with homozygous variants in RELN gene and had seizures.

PMID:27000652 (2016) reported a Moroccan female patient with lissencephaly and with homozygous RELN variant. This patient presented with neonatal seizures that were controlled with medication.

PMID:35769015 (2022) reported the identification of biallelic RELN variants in seven patients from four unrelated families and monoalellic RELN variants from 13 individuals from seven families with frontotemporal or temporal-predominant lissencephaly. Five patients from three different families with biallelic variants presented with seizures as part of the phenotype, while detailed phenotypic information was not available in two patients from the first family with biallelic variants. However, seizure was only reported in three of 13 individuals with monoallelic variants (all three are unrelated).
Early onset or syndromic epilepsy v8.45 RELN Achchuthan Shanmugasundram reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 10973257, 26046367, 27000652, 35769015; Phenotypes: Lissencephaly 2 (Norman-Roberts type), OMIM:257320, Norman-Roberts syndrome, MONDO:0009760, {Epilepsy, familial temporal lobe, 7}, OMIM:616436, familial temporal lobe epilepsy 7, MONDO:0014639; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As there are three unrelated cases reported with familial sleep-related hypermotor epilepsy phenotype despite limited rating in ClinGen, this gene can remain amber on this panel.; to: Comment on list classification: As there are three unrelated cases reported with familial sleep-related hypermotor epilepsy phenotype despite limited rating in ClinGen, this gene can remain green on this panel.
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram Classified gene: CHRNA2 as Green List (high evidence)
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are three unrelated cases reported with familial sleep-related hypermotor epilepsy phenotype despite limited rating in ClinGen, this gene can remain amber on this panel.
Early onset or syndromic epilepsy v8.45 CHRNA2 Achchuthan Shanmugasundram Gene: chrna2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.

This gene is also present with monoallelic MOI and green rating in Genetic Epilepsy panel of PanelApp Australia (https://panelapp-aus.org/panels/202/gene/CHRNA2/).; to: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.

This gene is also present with monoallelic MOI and green rating in Genetic Epilepsy panel of PanelApp Australia (https://panelapp-aus.org/panels/202/gene/CHRNA2/).
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.; to: Monoallelic variants in CHRNA2 gene have been associated with relevant phenotype in OMIM (MIM #610353, record accessed on 16 October 2025) and Gene2Phenotype (with strong rating on the DD panel).

Monoallelic variants in this gene have been associated with two different phenotypes by the Epilepsy GCEP expert panel in ClinGen:
- familial sleep-related hypermotor epilepsy (MONDO:0000030) - 'Limited' rating. There are three unrelated probands reported with monoallelic CHRNA2 variants and this phenotype.
- benign familial infantile epilepsy (MONDO:0017615) - 'Disputed' rating. There is only one proband reported with CHRNA2 variant and this phenotype.

This gene is also present with monoallelic MOI and green rating in Genetic Epilepsy panel of PanelApp Australia (https://panelapp-aus.org/panels/202/gene/CHRNA2/).
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram edited their review of gene: CHRNA2: Changed publications to: 16826524, 25770198, 25847220, 30809122
Early onset or syndromic epilepsy v8.44 CHRNA2 Achchuthan Shanmugasundram Publications for gene: CHRNA2 were set to 16826524; 2577019; 25847220; 30809122
Early onset or syndromic epilepsy v8.43 CHRNA2 Achchuthan Shanmugasundram Publications for gene: CHRNA2 were set to Aridon et al (2006) Am J Hum Genet 79: 342-350
Early onset or syndromic epilepsy v8.42 CHRNA2 Achchuthan Shanmugasundram Phenotypes for gene: CHRNA2 were changed from Epilepsy, nocturnal frontal lobe, type 4 to Epilepsy, nocturnal frontal lobe, type 4, OMIM:610353; autosomal dominant nocturnal frontal lobe epilepsy 4, MONDO:0012474
Early onset or syndromic epilepsy v8.41 CHRNA2 Achchuthan Shanmugasundram reviewed gene: CHRNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826524, 2577019, 25847220, 30809122; Phenotypes: Epilepsy, nocturnal frontal lobe, type 4, OMIM:610353, autosomal dominant nocturnal frontal lobe epilepsy 4, MONDO:0012474; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.41 OGDHL Ida Ertmanska changed review comment from: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes developmental delay / intellectual disability.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Early onset or syndromic epilepsy. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.; to: As reviewed by Arina Puzriakova, there are at least 10 individuals from 9 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases and includes childhood-onset seizures / epilepsy.

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14). Ataxia was explicitly noted in 1 patient. Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should remain Green for Early onset or syndromic epilepsy. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Early onset or syndromic epilepsy v8.41 OGDHL Ida Ertmanska reviewed gene: OGDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28017472, 34800363, 38031187; Phenotypes: Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.41 LSS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.; to: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

After seeking clinical opinion, it has been decided to recommend this gene for promotion to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.41 LGI1 Arina Puzriakova Publications for gene: LGI1 were set to 15079010; 11810107; 22496201
Early onset or syndromic epilepsy v8.40 LGI1 Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512 to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620
Early onset or syndromic epilepsy v8.39 LGI1 Arina Puzriakova Tag Q3_25_MOI tag was added to gene: LGI1.
Early onset or syndromic epilepsy v8.39 LGI1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; to: Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.
Early onset or syndromic epilepsy v8.39 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.39 EMX2 Arina Puzriakova Phenotypes for gene: EMX2 were changed from Schizencephaly, 269160 to Schizencephaly, OMIM:269160
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280). Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska edited their review of gene: LGI1: Added comment: Comment on mode of inheritance: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.; Changed publications to: 26773249, 40455867, 41000458
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska changed review comment from: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4

Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.

Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.

c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form); to: As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected (variable penetrance, estimated at 60% by ClinGen).

LGI1 is associated with AR Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v8.38 LGI1 Ida Ertmanska reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40455867, 41000458; Phenotypes: Epilepsy, familial temporal lobe, 600512, developmental and epileptic encephalopathy MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Tag dd_review tag was added to gene: KCND3.
Tag Q3_25_promote_green tag was added to gene: KCND3.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676, 39562497
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493; 28947073; 32823520; 32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient.
Knock-in mice (p.Phe227del equivalent) displayed defects in motor coordination and balance, and neuroinflammation. Knock-out Kcnd3 -/- mice showed no observable phenotype. Molecular evidence suggests that the misfolded protein induces a trafficking defect in the Golgi apparatus - a dominant negative effect (PMID: 39562497).
Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

Functional evidence: PMID: 39562497 Hung et al., 2025
A mouse model with a p.Phe227del-equivalent Kcnd3 knock-in displayed defects in motor coordination and balance, neuroinflammation, trafficking defect due to accumulation in the golgi apparatus, and a transcriptional effect: downregulation of genes involved in neurogenesis. Meanwhile, Kcnd3 knockout mice showed no observable phenotype. This evidence suggests a dominant negative effect of the mutation, and supports the association of KCND3 and neurodevelopmental disorders.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska commented on gene: KCND3: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493;28947073;32823520;32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.


PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.


PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska gene: KCND3 was added
gene: KCND3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCND3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND3 were set to 26189493; 28895081; 32823520; 31293010; 32921676
Phenotypes for gene: KCND3 were set to Spinocerebellar ataxia 19 (OMIM: 607346); spinocerebellar ataxia type 19/22, MONDO:0011819
Review for gene: KCND3 was set to GREEN
Added comment: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53).

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v8.37 EMX2 Eleanor Williams commented on gene: EMX2
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram Tag Q3_25_NHS_review was removed from gene: UGGT1.
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with intellectual disability (six families with severe ID). Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available for the association of biallelic UGGT1 variants with epilepsy (eight families and functional evidence). Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram changed review comment from: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.; to: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures (11 patients from eight unrelated families), characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram Entity copied from Intellectual disability v9.102
Early onset or syndromic epilepsy v8.37 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: UGGT1.
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to congenital disorder of glycosylation, MONDO:0015286
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: LSS.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Classified gene: LSS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene has previously been rated amber after clinical review despite having eight unrelated patients from six different families reported with seizures due to phenotypic variability. There is an additional patient reported with biallelic LSS variants and epilepsy.

Hence, clinical opinion is being sought on whether there is sufficient evidence available for the promotion of this gene to green rating.
Early onset or syndromic epilepsy v8.36 LSS Achchuthan Shanmugasundram Gene: lss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.35 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009 to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 29 September 2025.
Early onset or syndromic epilepsy v8.34 LSS Achchuthan Shanmugasundram Phenotypes for gene: LSS were changed from Alopecia; Abnormality of the skin; Microcephaly; Cataract 44, 616509, Hypotrichosis 14, 618275; Seizures; Abnormality of the genital system; Hypotonia; Intellectual disability; Global developmental delay to Alopecia-intellectual disability syndrome 4, OMIM:618840; alopecia-intellectual disability syndrome 4, MONDO:0030009
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram edited their review of gene: LSS: Changed publications to: 30723320, 37157980
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram changed review comment from: PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.; to: PMID:30723320 (2019) reported the identification of biallelic LSS variants in ten individuals from six unrelated families. In addition, one affected individual was identified with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. All 11 individuals presented with congenital alopecia and developmental delay, while eight individuals from six unrelated families had seizures.

PMID:37157980 (2023) reported trio exome sequencing on a family with a four-year-old male with global developmental delay, epilepsy and striking alopecia, and identified novel compound heterozygous LSS splice site (c.14+2T>C) and missense (c.1357 G>A; p.V453L) variants.
Early onset or syndromic epilepsy v8.33 LSS Achchuthan Shanmugasundram reviewed gene: LSS: Rating: GREEN; Mode of pathogenicity: None; Publications: 37157980; Phenotypes: Alopecia-intellectual disability syndrome 4, OMIM:618840, alopecia-intellectual disability syndrome 4, MONDO:0030009; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype comprising lissencephaly with seizures and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Classified gene: CDK5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 2 unrelated families with the same severe phenotype and supportive animal models. Inclusion on this panel would also enable inclusion on the R27 Paediatric disorders super panel.
Early onset or syndromic epilepsy v8.33 CDK5 Arina Puzriakova Gene: cdk5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.32 CDK5 Arina Puzriakova gene: CDK5 was added
gene: CDK5 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: CDK5.
Mode of inheritance for gene: CDK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK5 were set to 25560765; 40186457; 28854363; 8855328
Phenotypes for gene: CDK5 were set to Lissencephaly 7 with cerebellar hypoplasia, OMIM:616342
Review for gene: CDK5 was set to GREEN
Added comment: - PMID: 25560765 (2015) - Homozygous splice site variant g.IVS8+1G>A p.V162SfsX19 segregated with a lethal form of lissencephaly with cerebellar hypoplasia in 4 patients and 25 healthy relatives from one consanguineous family. Affected newborns had dysmorphic facial features, HC in normal-low range, lymphedema, arthrogryposis multiplex, and intractable seizures. Functional studies of the variant showed loss-of-function of the gene product.

- PMID: 40186457 (2025) - Homozygous missense variant c.149G>A (p.Arg50Gln) in an infant with diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. The disease course and severity were similar to those observed in the patients in the first report. Functional studies support deleterious effect of the variant.

Animal models:
Brains of Cdk5-null mice lacked cortical laminar structure and cerebellar foliation (PMID: 8855328). Cdk5 knockout in the ferret cerebral cortex also markedly impaired cortical folding (PMID: 28854363).
Sources: Literature
Early onset or syndromic epilepsy v8.31 SPOUT1 Arina Puzriakova Phenotypes for gene: SPOUT1 were changed from SPOUT1 Associated Development delay Microcephaly Seizures Short stature to Neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, OMIM:621154
Early onset or syndromic epilepsy v8.30 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Early onset or syndromic epilepsy v8.29 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from ?Arthrogryposis, mental retardation, and seizures (MIM 615553); Early onset epileptic encephalopathy with skeletal defects to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Early onset or syndromic epilepsy v8.28 PIGG Arina Puzriakova Phenotypes for gene: PIGG were changed from Mental retardation, autosomal recessive 53 616917 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917
Early onset or syndromic epilepsy v8.27 HNRNPU Arina Puzriakova Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 54, 617391 to Developmental and epileptic encephalopathy 54, OMIM:617391
Early onset or syndromic epilepsy v8.26 EEFSEC Arina Puzriakova Phenotypes for gene: EEFSEC were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to Neurodevelopmental disorder with progressive spasticity and brain abnormalities, OMIM:621102
Early onset or syndromic epilepsy v8.25 ELFN1 Arina Puzriakova Classified gene: ELFN1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.25 ELFN1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v8.25 ELFN1 Arina Puzriakova Gene: elfn1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.24 ELFN1 Arina Puzriakova gene: ELFN1 was added
gene: ELFN1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: ELFN1.
Mode of inheritance for gene: ELFN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELFN1 were set to 40576023; 34509675; 34452636
Phenotypes for gene: ELFN1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: ELFN1 was set to GREEN
Added comment: Total of 14 individuals from 7 unrelated families with biallelic loss of function variants in ELFN1 and a neurodevelopmental disorder comprising DD/ID ranging from moderate to severe (13/13) and epilepsy (12/13). Other features included dysmorphic features, behavioural disturbances, ADHD, ASD, hypotonia, muscle weakness, ataxia. Knockout and haploinsufficiency studies in mice resulted in detectable phenotypes compatible with ELFN1 deficiency disorder.
Sources: Literature
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Classified gene: UNC13A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated patients and functional studies) for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.23 UNC13A Achchuthan Shanmugasundram Gene: unc13a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.22 UNC13A Achchuthan Shanmugasundram gene: UNC13A was added
gene: UNC13A was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: UNC13A.
Mode of inheritance for gene: UNC13A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC13A were set to 28192369; 39634123
Phenotypes for gene: UNC13A were set to developmental and epileptic encephalopathy, MONDO:0100620
Review for gene: UNC13A was set to GREEN
Added comment: PMID:28192369 (2017) reported a 6-year-old male patient presenting with a disorder characterised by a dyskinetic movement disorder, developmental delay, and autism, and identified with a rare de novo heterozygous missense variant (p.Pro814Leu) in UNC13A gene. Sanger sequencing was done in parents and de novo inheritance was confirmed. This patient also presented with febrile seizures.

PMID:39634123 (2024) reported three unrelated patients presenting with clinical phenotypes consistent with developmental and epileptic encephalopathy including status epilepticus, focal onset seizures in both febrile and afebrile states, and intellectual disability. They were identified with three different de novo heterozygous missense variants (p.Met631Lys, p.Phe649Leu & p.Pro814Leu) based on trio exome sequencing. There is also functional evidence available from CRISPR/Cas9 zebrafish mutants in support of the association of UNC13A to epilepsy.

This gene is currently associated with congenital nervous system disorder (MONDO:0002320) in ClinGen with 'Limited' rating by Syndromic Disorders expert panel (https://search.clinicalgenome.org/CCID:008453).
Sources: Literature
Early onset or syndromic epilepsy v8.21 INPP4A Achchuthan Shanmugasundram Classified gene: INPP4A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.21 INPP4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are a total of 33 patients from 19 unrelated families reported with biallelic INPP4A variants and a neurodevelopmental disorder. Of these, 13 patients from 12 families presented with seizures. Hence, this gene should be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.21 INPP4A Achchuthan Shanmugasundram Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.20 INPP4A Achchuthan Shanmugasundram edited their review of gene: INPP4A: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v8.20 INPP4A Achchuthan Shanmugasundram Phenotypes for gene: INPP4A were changed from Intellectual disability; Seizures to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v8.19 INPP4A Achchuthan Shanmugasundram Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
Early onset or syndromic epilepsy v8.18 INPP4A Achchuthan Shanmugasundram reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39315527, 40748307, 40772914; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.18 MT-TK Arina Puzriakova Classified gene: MT-TK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.18 MT-TK Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Early onset or syndromic epilepsy v8.18 MT-TK Arina Puzriakova Gene: mt-tk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.17 MT-TK Arina Puzriakova Classified gene: MT-TK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.17 MT-TK Arina Puzriakova Gene: mt-tk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.16 MT-TK Arina Puzriakova gene: MT-TK was added
gene: MT-TK was added to Early onset or syndromic epilepsy. Sources: Literature
locus-type-rna-transfer, Q3_25_promote_green, Q3_25_NHS_review tags were added to gene: MT-TK.
Mode of inheritance for gene gene: MT-TK was set to MITOCHONDRIAL
Publications for gene: MT-TK were set to 1463006; 8228033; 18651333; 29663531; 33766967
Phenotypes for gene: MT-TK were set to MERRF syndrome, MONDO:0010790
Review for gene: MT-TK was set to GREEN
Added comment: Adding MT-TK to this panel by suggestion of North East and Yorkshire GLH where a patient was identified with a tier 3 diagnostic MT-TK variant due to absence of the gene on this applied panel.

MT-TK gene has been associated with severe mitochondrial diseases which includes myoclonic epilepsy - multiple (at least 8) unrelated cases with epilepsy as a presenting feature have been reported in the literature (PMID: 1463006; 8228033; 18651333; 29663531; 33766967)
Sources: Literature
Early onset or syndromic epilepsy v8.15 RNU5B-1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with variable degrees of intellectual disability reported in almost all cases. This disorder to relevant to the R27 Paediatric disorders superpanel, which will be added through inclusion on the Intellectual disability panel.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple unrelated individuals reported with de novo (several recurrent) variants in the RNU5B-1 gene that lead to splicing disruption. All individuals present with a neurodevelopmental disorder, with seizures reported in 6 unrelated cases which can be an early presenting feature.
Early onset or syndromic epilepsy v8.15 RNU5B-1 Arina Puzriakova Entity copied from Intellectual disability v9.51
Early onset or syndromic epilepsy v8.15 RNU5B-1 Arina Puzriakova gene: RNU5B-1 was added
gene: RNU5B-1 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
locus-type-rna-small-nuclear, dd_review, Q3_25_promote_green tags were added to gene: RNU5B-1.
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5B-1 were set to 40379786; 40442284
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.14 RNU5A-1 Arina Puzriakova Entity copied from Intellectual disability v9.51
Early onset or syndromic epilepsy v8.14 RNU5A-1 Arina Puzriakova gene: RNU5A-1 was added
gene: RNU5A-1 was added to Early onset or syndromic epilepsy. Sources: Expert Review Red,Literature
locus-type-rna-small-nuclear tags were added to gene: RNU5A-1.
Mode of inheritance for gene: RNU5A-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU5A-1 were set to 40379786
Phenotypes for gene: RNU5A-1 were set to Neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.13 RNU2-2P Arina Puzriakova Publications for gene: RNU2-2P were set to 40210679
Early onset or syndromic epilepsy v8.12 UBR5 Achchuthan Shanmugasundram Classified gene: UBR5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.12 UBR5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.12 UBR5 Achchuthan Shanmugasundram Gene: ubr5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.11 UBR5 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: UBR5.
Early onset or syndromic epilepsy v8.11 UBR5 Achchuthan Shanmugasundram gene: UBR5 was added
gene: UBR5 was added to Early onset or syndromic epilepsy. Sources: Literature
dd_review tags were added to gene: UBR5.
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: UBR5 was set to GREEN
Added comment: PMID:39721588 reported 29 unrelated individuals with a complex neurodevelopmental syndrome, which includes developmental delay (26/28), autism (16/26), intellectual disability (14/25), epilepsy (11/27), movement disorders (6/26) and/ or genital anomalies (4/25) as presenting phenotypes. They were all identified with variants in UBR5 gene, of which 28 had monoallelic inheritance (24 with de novo, 1 with maternal, 1 with maternal mosaic and 2 with unknown inheritance), while one had recessive inheritance.

Of the 28 patients with monoallelic variants, 16 had global developmental delay, 13 had ID and 10 patients had epilepsy/ seizures. The single patient with biallelic variant had severe/ profound ID, developmental delay and epileptic encephalopathy.

Functional evidence is also available from C. elegans and in vitro ubiquitination assays.

This gene is associated with phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v8.10 CRNKL1 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CRNKL1.
Early onset or syndromic epilepsy v8.10 FLVCR1 Eleanor Williams gene: FLVCR1 was added
gene: FLVCR1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_25_promote_green tags were added to gene: FLVCR1.
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 39306721
Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Review for gene: FLVCR1 was set to GREEN
Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Sources: Literature
Early onset or syndromic epilepsy v8.9 CRNKL1 Achchuthan Shanmugasundram Classified gene: CRNKL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.9 CRNKL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.9 CRNKL1 Achchuthan Shanmugasundram Gene: crnkl1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.8 CRNKL1 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: CRNKL1.
Early onset or syndromic epilepsy v8.8 CRNKL1 Achchuthan Shanmugasundram gene: CRNKL1 was added
gene: CRNKL1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.7 NOTCH3 Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.7 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic LoF variants in NOTCH3 gene with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.7 NOTCH3 Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.6 NOTCH3 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: NOTCH3.
Tag Q3_25_promote_green tag was added to gene: NOTCH3.
Early onset or syndromic epilepsy v8.6 NOTCH3 Achchuthan Shanmugasundram gene: NOTCH3 was added
gene: NOTCH3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOTCH3 were set to 39191170
Phenotypes for gene: NOTCH3 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: NOTCH3 was set to GREEN
Added comment: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

Of these 24 patients from 15 families had developmental delay, ranging from mild or only motor delay in 7 patients to global developmental impairment in 17 patients. 21 patents from 13 families had predominantly severe intellectual disability, of which five had mild ID. Seizures were reported in 10 patients from seven different families.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.5 CELF4 Achchuthan Shanmugasundram Classified gene: CELF4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.5 CELF4 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (nine unrelated cases with seizures) for the promotion of this gene to green rating on this panel in the next GMS update.
Early onset or syndromic epilepsy v8.5 CELF4 Achchuthan Shanmugasundram Gene: celf4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.4 CELF4 Achchuthan Shanmugasundram Tag dd_review tag was added to gene: CELF4.
Early onset or syndromic epilepsy v8.4 CELF4 Achchuthan Shanmugasundram gene: CELF4 was added
gene: CELF4 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_25_ promote_green tags were added to gene: CELF4.
Mode of inheritance for gene: CELF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF4 were set to 40108438
Phenotypes for gene: CELF4 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CELF4 was set to GREEN
Added comment: PMID:40108438 reported 15 patients with heterozygous missense or loss-of-function variants clustering in the N-terminal of the CELF4 gene. Most patients presented with neurodevelopmental disorders including global developmental delay (12 patients), intellectual disability (8, of which moderate in 2, mild in 3, and severity not defined in 3), seizures (9) and overweight/obesity (10) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.3 SYNGAP1 Arina Puzriakova Phenotypes for gene: SYNGAP1 were changed from Mental retardation, autosomal dominant 5 to Intellectual developmental disorder, autosomal dominant 5, OMIM:612621
Early onset or syndromic epilepsy v8.2 EPB41L3 Arina Puzriakova Entity copied from Intellectual disability v9.6
Early onset or syndromic epilepsy v8.2 EPB41L3 Arina Puzriakova gene: EPB41L3 was added
gene: EPB41L3 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q2_25_ promote_green, Q2_25_ NHS_review tags were added to gene: EPB41L3.
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to Developmental disorder with seizures and myelination defects
Early onset or syndromic epilepsy v8.1 Sarah Leigh Panel version 8.0 has been signed off on 2025-04-30
Early onset or syndromic epilepsy v8.0 Sarah Leigh promoted panel to version 8.0
Early onset or syndromic epilepsy v7.90 RNU4-2 Hayley Lees reviewed gene: RNU4-2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.90 RNU2-2P Achchuthan Shanmugasundram Classified gene: RNU2-2P as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.90 RNU2-2P Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with epilepsy. Hence, this gene can be promoted to green rating on the next GMS update.
Early onset or syndromic epilepsy v7.90 RNU2-2P Achchuthan Shanmugasundram Gene: rnu2-2p has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram Tag Q2_25_ promote_green tag was added to gene: RNU2-2P.
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram commented on gene: RNU2-2P: The "new-gene-name" tag has been added as the official HGNC symbol for RNU2-2P is RNU2-2.

In addition, "locus-type-rna-small-nuclear" tag has been added to highlight the biotype for this gene.
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: RNU2-2P.
Tag locus-type-rna-small-nuclear tag was added to gene: RNU2-2P.
Tag dd_review tag was added to gene: RNU2-2P.
Early onset or syndromic epilepsy v7.89 RNU2-2P Achchuthan Shanmugasundram Phenotypes for gene: RNU2-2P were changed from to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v7.88 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to
Early onset or syndromic epilepsy v7.87 RNU2-2P Achchuthan Shanmugasundram Mode of inheritance for gene: RNU2-2P was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v7.86 RNU2-2P Achchuthan Shanmugasundram reviewed gene: RNU2-2P: Rating: GREEN; Mode of pathogenicity: None; Publications: 40210679; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v7.86 STARD7_ATTTC Sarah Leigh commented on STR: STARD7_ATTTC: A long stretch ATTTC repeats is present in conjunction with ATTTT repeats in the intron 1 in the STARD7 gene in patients with OMIM:607876 (Corbett et al. 2019 PMID:31664034). In affected individuals the pathogenic configuration was defined as: (ATTTC)exp(ATTTT )exp. None of the control samples had any repeats of the pathogenic ATTTC motif (PMID:31664034).
Early onset or syndromic epilepsy v7.86 STARD7_ATTTC Sarah Leigh STR: STARD7_ATTTC was added
STR: STARD7_ATTTC was added to Early onset or syndromic epilepsy. Sources: Literature
STR, NGS Not Validated tags were added to STR: STARD7_ATTTC.
Mode of inheritance for STR: STARD7_ATTTC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: STARD7_ATTTC were set to 31664034
Phenotypes for STR: STARD7_ATTTC were set to Epilepsy, familial adult myoclonic, 2, OMIM:607876; epilepsy, familial adult myoclonic, 2, MONDO:0011930
Review for STR: STARD7_ATTTC was set to GREEN
Added comment: STARD7 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

STARD7_ATTTC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

STARD7_ATTTC is on https://stripy.org/database

STARD7_ATTTT is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were the same on DRAGON 4.02, https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database
The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Early onset or syndromic epilepsy v7.85 STARD7 Sarah Leigh Phenotypes for gene: STARD7 were changed from Epilepsy, familial adult myoclonic, 2, 607876; Familial adult myoclonic epilepsy-2; FAME-2 to Epilepsy, familial adult myoclonic, 2, OMIM:607876; epilepsy, familial adult myoclonic, 2, MONDO:0011930
Early onset or syndromic epilepsy v7.84 SAMD12_TTTCA Sarah Leigh changed review comment from: SAMD12 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

SAMD12_TTTCA is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

SAMD12_TTTCA is on https://stripy.org/database

SAMD12_TTTTA is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats shown above were obtained from DRAGON 4.02
The coordinates https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were 8:118366815-118366913 (hg38)

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature; to: SAMD12 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

SAMD12_TTTCA is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

SAMD12_TTTCA is on https://stripy.org/database

SAMD12_TTTTA is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02
The coordinates https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were 8:118366815-118366913 (hg38)

The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Early onset or syndromic epilepsy v7.84 SAMD12_TTTCA Sarah Leigh commented on STR: SAMD12_TTTCA: The TTTCA repeat is present in conjunction with TTTTA repeats in patients with OMIM:601068. Ishiura et al., 2018 (PMID: 29507423). In patients the expansions TTTCA and TTTTA combined was estimated to be in the range of 440 to 3680 repeats (one patient had 598 repeats of TTTTA and 458 repeats of TTTCA). In 82 patients the configuration of expansion was interpreted as: (TTTTA)exp(TTTCA)exp and in one family it was given as: (TTTTA)exp(TTTCA)exp(TTTTA)exp. There were no reports of TTTCA expansions in controls, however, 5.9% of healthy individuals had TTTTA expansions, therefore suggesting that the TTTTA expansion does no contribute to the disease (Ishiura et al., 2018).
Early onset or syndromic epilepsy v7.84 SAMD12_TTTCA Sarah Leigh Mode of inheritance for STR: SAMD12_TTTCA was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.83 SAMD12_TTTCA Sarah Leigh Phenotypes for STR: SAMD12_TTTCA were changed from to Epilepsy, familial adult myoclonic, 1, OMIM:601068; epilepsy, familial adult myoclonic, 1, MONDO:0010985
Early onset or syndromic epilepsy v7.82 SAMD12_TTTCA Sarah Leigh edited their review of STR: SAMD12_TTTCA: Changed rating: GREEN
Early onset or syndromic epilepsy v7.82 SAMD12_TTTCA Sarah Leigh STR: SAMD12_TTTCA was added
STR: SAMD12_TTTCA was added to Early onset or syndromic epilepsy. Sources: Literature
STR, NGS Not Validated tags were added to STR: SAMD12_TTTCA.
Mode of inheritance for STR: SAMD12_TTTCA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for STR: SAMD12_TTTCA were set to 30194086; 29507423; 29939203; 32203200
Review for STR: SAMD12_TTTCA was set to AMBER
Added comment: SAMD12 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

SAMD12_TTTCA is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3

SAMD12_TTTCA is on https://stripy.org/database

SAMD12_TTTTA is on DRAGON 4.02.

The coordinates and pathogenic ranges of the sequence repeats shown above were obtained from DRAGON 4.02
The coordinates https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4 and https://stripy.org/database were 8:118366815-118366913 (hg38)

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Early onset or syndromic epilepsy v7.81 FUT2 Arina Puzriakova Added comment: Comment on publications: PMID: 39350204 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.81 FUT2 Arina Puzriakova Publications for gene: FUT2 were set to 39350204
Early onset or syndromic epilepsy v7.80 FUT2 Arina Puzriakova gene: FUT2 was added
gene: FUT2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: FUT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FUT2 were set to 39350204
Phenotypes for gene: FUT2 were set to Developmental and epileptic encephalopathy
Added comment: PMID: 39350204 (2024) - homozygous missense variant (NC_000019.10:g.48703291C>T) in the FUT2 gene was identified in an infant with vitamin B12-responsive developmental and epileptic encephalopathy and megaloblastic anemia. Although the mechanism of how the FUT2 gene variant affects vitamin B12 absorption is unclear.

Additional evidence is required before conclusively implicating FUT2 in human disease and therefore rating Red for now.
Sources: Literature
Early onset or syndromic epilepsy v7.79 EPM2A Arina Puzriakova Phenotypes for gene: EPM2A were changed from Epilepsy, progressive myoclonic 2A (Lafora) 254780 to Myoclonic epilepsy of Lafora 1, OMIM:254780
Early onset or syndromic epilepsy v7.78 KCNH8 Sarah Leigh Added comment: Comment on publications: PMID: 39156922 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.78 KCNH8 Sarah Leigh Publications for gene: KCNH8 were set to 39156922
Early onset or syndromic epilepsy v7.77 RTEL1 Sarah Leigh Added comment: Comment on publications: PMID: 39156922 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.77 RTEL1 Sarah Leigh Publications for gene: RTEL1 were set to 39156922
Early onset or syndromic epilepsy v7.76 RTEL1 Sarah Leigh gene: RTEL1 was added
gene: RTEL1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RTEL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RTEL1 were set to 39156922
Phenotypes for gene: RTEL1 were set to Familial Progressive Myoclonus Epilepsy
Review for gene: RTEL1 was set to RED
Added comment: PMID: 39156922 reports two sibling from a consanguineous family who had familial progressive myoclonus epilepsy. Both of the sibling were homozygous for a KCNH8 variant (NM_144633.3:c.298T>C; p.Tyr100His) and a RTEL1 variant (NM_032957.5:c.691G>T; p.Asp231Tyr).
Sources: Literature
Early onset or syndromic epilepsy v7.75 KCNH8 Sarah Leigh gene: KCNH8 was added
gene: KCNH8 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCNH8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNH8 were set to 39156922
Phenotypes for gene: KCNH8 were set to Familial Progressive Myoclonus Epilepsy
Review for gene: KCNH8 was set to RED
Added comment: PMID: 39156922 reports two sibling from a consanguineous family who had familial progressive myoclonus epilepsy. Both of the sibling were homozygous for a KCNH8 variant (NM_144633.3:c.298T>C; p.Tyr100His) and a RTEL1 variant (NM_032957.5:c.691G>T; p.Asp231Tyr).
Sources: Literature
Early onset or syndromic epilepsy v7.74 PPP2R2B Sarah Leigh Classified gene: PPP2R2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.74 PPP2R2B Sarah Leigh Gene: ppp2r2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.73 PPP2R2B Sarah Leigh Added comment: Comment on publications: PMID: 39565297 and 25356899 were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.73 PPP2R2B Sarah Leigh Publications for gene: PPP2R2B were set to 39565297; 25356899
Early onset or syndromic epilepsy v7.72 PPP2R2B Sarah Leigh Added comment: Comment on phenotypes: The PPP2R2B_CAG variant is associated with Spinocerebellar ataxia 12, OMIM:604326
Early onset or syndromic epilepsy v7.72 PPP2R2B Sarah Leigh Phenotypes for gene: PPP2R2B were changed from neurodevelopmental syndrome to neurodevelopmental syndrome
Early onset or syndromic epilepsy v7.71 PPP2R2B Sarah Leigh gene: PPP2R2B was added
gene: PPP2R2B was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: PPP2R2B.
Mode of inheritance for gene: PPP2R2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP2R2B were set to 39565297; 25356899
Phenotypes for gene: PPP2R2B were set to neurodevelopmental syndrome
Review for gene: PPP2R2B was set to GREEN
Added comment: Sources: Literature
Early onset or syndromic epilepsy v7.70 RYR3 Sarah Leigh Added comment: Comment on publications: PMID: 39220738 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.70 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327; 29498452; 31230720; 39220738; 39840699
Early onset or syndromic epilepsy v7.69 RYR3 Sarah Leigh Phenotypes for gene: RYR3 were changed from Epileptic encephalopathy to idiopathic(non-lesional) partial epilepsy/susceptibility of seizures
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh edited their review of gene: RYR3: Changed phenotypes to: idiopathic(non-lesional) partial epilepsy/susceptibility of seizures
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh Classified gene: RYR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.68 RYR3 Sarah Leigh Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: RYR3.
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh edited their review of gene: RYR3: Added comment: Previously there have been four reports of seizures in patients with biallelic RYR3 variants (PMID: 25262651; 29667327; 39220738). Using a cohort of patients with idiopathic(non-lesional) partial epilepsy/susceptibility of seizures, authors of PMID: 39840699 report thirteen RYR3 variants in seven cases. In all but one of the cases, the variants are compound heterozygotes, with the remaining case having a de novo heterozygous RYR3 variant. Seizure onset was in childhood (1 to 7 years), brain MRIs were normal in all cases, there was no evidence of myopathy and there was a single case of intellectual disability (table 1, PMID: 39840699).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.67 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327; 39220738; 39840699
Early onset or syndromic epilepsy v7.66 RYR3 Sarah Leigh Publications for gene: RYR3 were set to 25262651; 29667327
Early onset or syndromic epilepsy v7.65 GTF3C3 Arina Puzriakova Entity copied from Intellectual disability v8.151
Early onset or syndromic epilepsy v7.65 GTF3C3 Arina Puzriakova gene: GTF3C3 was added
gene: GTF3C3 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Victorian Clinical Genetics Services,Literature
Q1_25_ promote_green tags were added to gene: GTF3C3.
Mode of inheritance for gene: GTF3C3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C3 were set to 28940097; 28097321; 30552426; 40040844
Phenotypes for gene: GTF3C3 were set to Global developmental delay; Intellectual disability; Seizures
Early onset or syndromic epilepsy v7.64 C12orf66 Arina Puzriakova Classified gene: C12orf66 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.64 C12orf66 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green the next GMS panel update.
Early onset or syndromic epilepsy v7.64 C12orf66 Arina Puzriakova Gene: c12orf66 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.63 C12orf66 Arina Puzriakova commented on gene: C12orf66: Added new-gene-name tag, new approved HGNC gene symbol for C12orf66 is KICS2
Early onset or syndromic epilepsy v7.63 C12orf66 Arina Puzriakova commented on gene: C12orf66: PMID: 39824192 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.63 C12orf66 Arina Puzriakova gene: C12orf66 was added
gene: C12orf66 was added to Early onset or syndromic epilepsy. Sources: Literature
new-gene-name, Q1_25_ promote_green tags were added to gene: C12orf66.
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C12orf66 were set to 39824192
Phenotypes for gene: C12orf66 were set to Intellectual developmental disorder, autosomal recessive 83, OMIM:621100
Review for gene: C12orf66 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM (MIM# 621100)

- PMID: 39824192 (2025) - biallelic variants in KICS2 in 11 individuals from 8 families with intellectual disability. All affected individuals had mild to severe intellectual disability, with 8 individuals also presenting with seizures and 3 (2 families) with hearing impairment. Functional studies in cell culture and zebrafish models provided evidence of pathogenicity, showing impaired mTORC1 regulation and effects on ciliogenesis.
Sources: Literature
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Classified gene: SPOUT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Gene: spout1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Added comment: Comment on publications: PMID: 39962046 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.62 SPOUT1 Sarah Leigh Publications for gene: SPOUT1 were set to 39962046
Early onset or syndromic epilepsy v7.61 SPOUT1 Sarah Leigh gene: SPOUT1 was added
gene: SPOUT1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: SPOUT1.
Mode of inheritance for gene: SPOUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPOUT1 were set to 39962046
Phenotypes for gene: SPOUT1 were set to SPOUT1 Associated Development delay Microcephaly Seizures Short stature
Review for gene: SPOUT1 was set to GREEN
Added comment: PMID: 39962046 reports the association of biallelic SPOUT1 variants with SPOUT1 Associated Development delay Microcephaly Seizures Short stature. In this study, a total of 18 SPOUT1 variants were found in 28 individuals from 21 unrelated families. Intellectual disability was evident in 10/10 families where it could be ascertained, seizures were reported in 16/21 of the families and short stature was seen in 13/15 families where it could be measured.
SPOUT1 variant zebra fish models showed reduction in larval head size with concomitant apoptosis and the human SPOUT1 missense variants were pathogenic in complementation assays in zebrafish (PMID: 39962046).
Sources: Literature
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Tag watchlist tag was added to gene: DALRD3.
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Added comment: Comment on list classification: Maintaining Amber rating as only 2 families have been reported to date.
Early onset or syndromic epilepsy v7.60 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.59 DALRD3 Arina Puzriakova Added comment: Comment on publications: PMID: 39482881 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.59 DALRD3 Arina Puzriakova Publications for gene: DALRD3 were set to 32427860
Early onset or syndromic epilepsy v7.58 DALRD3 Arina Puzriakova commented on gene: DALRD3: PMID: 39482881 - second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.
Early onset or syndromic epilepsy v7.58 DALRD3 Arina Puzriakova Deleted their comment
Early onset or syndromic epilepsy v7.58 SPR Arina Puzriakova Added comment: Comment on mode of inheritance: Sepiapterin reductase deficiency typically follows an autosomal recessive pattern of inheritance. Two cases with different heterozygous variants have been reported (PMID: 29147684, 15241655) although with reduced penetrance in the familial cases and mild form of the disorder in the singleton.

Overall additional evidence is required to conclusively make an association with monoallelic variants and therefore updating the MOI from 'Both mono- and biallelic' to 'Biallelic'
Early onset or syndromic epilepsy v7.58 SPR Arina Puzriakova Mode of inheritance for gene: SPR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.57 SPR Arina Puzriakova Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Early onset or syndromic epilepsy v7.56 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.56 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.55 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Early onset or syndromic epilepsy. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Early onset or syndromic epilepsy v7.54 MARK2 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MARK2.
Early onset or syndromic epilepsy v7.54 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620851).
Early onset or syndromic epilepsy v7.54 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related to ReNU syndrome, OMIM:620851
Early onset or syndromic epilepsy v7.53 DHRSX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #301133).
Early onset or syndromic epilepsy v7.53 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286; epilepsy, MONDO:0005027 to Congenital disorder of glycosylation, type 1DD, OMIM:301133
Early onset or syndromic epilepsy v7.52 DHRSX Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DHRSX.
Early onset or syndromic epilepsy v7.52 CTSF Sarah Leigh Added comment: Comment on publications: PMID: 39720560 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.52 CTSF Sarah Leigh Publications for gene: CTSF were set to 16508006; 39720560
Early onset or syndromic epilepsy v7.51 CTSF Sarah Leigh Tag Q1_25_ promote_green tag was added to gene: CTSF.
Early onset or syndromic epilepsy v7.51 CTSF Sarah Leigh reviewed gene: CTSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 39720560; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.51 MARK2 Arina Puzriakova Classified gene: MARK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.51 MARK2 Arina Puzriakova Gene: mark2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.50 MARK2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v7.50 MARK2 Arina Puzriakova Tag Q1_25_ promote_green tag was added to gene: MARK2.
Early onset or syndromic epilepsy v7.50 MARK2 Arina Puzriakova Entity copied from Intellectual disability v8.126
Early onset or syndromic epilepsy v7.50 MARK2 Arina Puzriakova gene: MARK2 was added
gene: MARK2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Green,NHS GMS,Literature
Mode of inheritance for gene: MARK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK2 were set to 39419027; 39436150
Phenotypes for gene: MARK2 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v7.49 CTSF Sarah Leigh Publications for gene: CTSF were set to 16508006
Early onset or syndromic epilepsy v7.48 CTSF Sarah Leigh Phenotypes for gene: CTSF were changed from Ceroid lipofuscinosis, neuronal, 13, Kufs type, 615362 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362; neuronal ceroid lipofuscinosis 13, MONDO:0014147
Early onset or syndromic epilepsy v7.47 INPP4A Arina Puzriakova Entity copied from Intellectual disability v8.124
Early onset or syndromic epilepsy v7.47 INPP4A Arina Puzriakova gene: INPP4A was added
gene: INPP4A was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber
Q1_25_ promote_green tags were added to gene: INPP4A.
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678
Phenotypes for gene: INPP4A were set to Intellectual disability; Seizures
Penetrance for gene: INPP4A were set to Complete
Early onset or syndromic epilepsy v7.46 PPP2R5C Sarah Leigh Classified gene: PPP2R5C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.46 PPP2R5C Sarah Leigh Gene: ppp2r5c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.45 PPP2R5C Sarah Leigh Added comment: Comment on publications: PMID: 39696819 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.45 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39696819; 39978342
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh edited their review of gene: PPP2R5C: Changed publications to: 25972378, 39696819, 39978342
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh changed review comment from: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature; to: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39696819 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh changed review comment from: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature; to: PMIDs 25972378; 39696819; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Early onset or syndromic epilepsy v7.44 PPP2R5C Sarah Leigh Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Early onset or syndromic epilepsy v7.43 PPP2R5C Sarah Leigh gene: PPP2R5C was added
gene: PPP2R5C was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: PPP2R5C.
Mode of inheritance for gene: PPP2R5C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2R5C were set to 25972378; 39500882; 39978342
Phenotypes for gene: PPP2R5C were set to neurodevelopmental disorder
Review for gene: PPP2R5C was set to GREEN
Added comment: PMIDs 25972378; 39500882; 39978342 report twenty one PPP2R5C variants in 30 unrelated individuals with macrocephaly, intellectual disability, seizures and hypotonia (PMIDs 39500882 table 1 & 39978342 table 1 ). Most of these heterozygous variants were de novo (there was one case where this could not be established, PMID: 39696819).
Sources: Literature
Early onset or syndromic epilepsy v7.42 PNPLA8 Sarah Leigh Added comment: Comment on publications: PMID: 39082157 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.42 PNPLA8 Sarah Leigh Publications for gene: PNPLA8 were set to 39082157
Early onset or syndromic epilepsy v7.41 PNPLA8 Sarah Leigh Classified gene: PNPLA8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.41 PNPLA8 Sarah Leigh Gene: pnpla8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.40 PNPLA8 Sarah Leigh gene: PNPLA8 was added
gene: PNPLA8 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: PNPLA8.
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to 39082157
Phenotypes for gene: PNPLA8 were set to ?Mitochondrial myopathy with lactic acidosis, OMIM:251950; mitochondrial myopathy-lactic acidosis-deafness syndrome MONDO:0016825
Review for gene: PNPLA8 was set to GREEN
Added comment: Biallelic PNPLA8 variants have previously been associated with Mitochondrial myopathy with lactic acidosis, (OMIM:251950). PMID: 39082157 reports a study were microcephaly, global delay and seizures are associated with biallelic PNPLA8 variants. Amongst the unrelated individuals studied, 8/11 had severe microcephaly, 9/11 had epileptic seizures and 8/11 had severe global delay and intellectual disability where it could be measured, 3/11 cases died in childhood and affected siblings (but not genotyped) had died in two other families. Using cerebral organoids generated from human induced pluripotent stem cells, the authors were able to assert that the loss of PNPLA8 led to
developmental defects by reducing the number of basal radial glial cells and upper-layer neurons (PMID: 39082157).
Sources: Literature
Early onset or syndromic epilepsy v7.39 TRPM7 Achchuthan Shanmugasundram Tag Q1_23_promote_green was removed from gene: TRPM7.
Tag Q1_25_ promote_green tag was added to gene: TRPM7.
Early onset or syndromic epilepsy v7.39 CUX1 Sarah Leigh Tag Q3_24_promote_green was removed from gene: CUX1.
Tag Q3_24_NHS_review was removed from gene: CUX1.
Early onset or syndromic epilepsy v7.39 FUK Sarah Leigh Tag Q3_24_promote_green was removed from gene: FUK.
Early onset or syndromic epilepsy v7.39 FZR1 Sarah Leigh Tag Q3_24_promote_green was removed from gene: FZR1.
Early onset or syndromic epilepsy v7.39 LNPK Sarah Leigh Tag Q3_24_promote_green was removed from gene: LNPK.
Early onset or syndromic epilepsy v7.39 PI4K2A Sarah Leigh Tag Q3_24_promote_green was removed from gene: PI4K2A.
Tag Q3_24_NHS_review was removed from gene: PI4K2A.
Early onset or syndromic epilepsy v7.39 SLC13A3 Sarah Leigh Tag Q3_24_promote_green was removed from gene: SLC13A3.
Early onset or syndromic epilepsy v7.39 SLC4A10 Sarah Leigh Tag Q3_24_promote_green was removed from gene: SLC4A10.
Early onset or syndromic epilepsy v7.39 AASS Sarah Leigh Tag Q3_24_promote_green was removed from gene: AASS.
Early onset or syndromic epilepsy v7.39 CCDC88A Sarah Leigh Tag Q3_24_promote_green was removed from gene: CCDC88A.
Early onset or syndromic epilepsy v7.39 CNTN2 Sarah Leigh Tag Q3_24_promote_green was removed from gene: CNTN2.
Tag Q3_24_NHS_review was removed from gene: CNTN2.
Early onset or syndromic epilepsy v7.39 SLC4A10 Sarah Leigh reviewed gene: SLC4A10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.39 SLC13A3 Sarah Leigh reviewed gene: SLC13A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.39 PI4K2A Sarah Leigh reviewed gene: PI4K2A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.39 LNPK Sarah Leigh edited their review of gene: LNPK: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.39 FZR1 Sarah Leigh reviewed gene: FZR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v7.39 FUK Sarah Leigh reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.39 CUX1 Sarah Leigh commented on gene: CUX1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v7.39 CNTN2 Sarah Leigh reviewed gene: CNTN2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.39 CCDC88A Sarah Leigh edited their review of gene: CCDC88A: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.39 AASS Sarah Leigh reviewed gene: AASS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.38 SLC4A10 Sarah Leigh Source NHS GMS was added to SLC4A10.
Source Expert Review Green was added to SLC4A10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 SLC13A3 Sarah Leigh Source NHS GMS was added to SLC13A3.
Source Expert Review Green was added to SLC13A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 PI4K2A Sarah Leigh Source Expert Review Green was added to PI4K2A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 LNPK Sarah Leigh Source Expert Review Green was added to LNPK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 FZR1 Sarah Leigh Source NHS GMS was added to FZR1.
Source Expert Review Green was added to FZR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 FUK Sarah Leigh Source Expert Review Green was added to FUK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 CUX1 Sarah Leigh Source NHS GMS was added to CUX1.
Source Expert Review Green was added to CUX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 CNTN2 Sarah Leigh Source Expert Review Green was added to CNTN2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 CCDC88A Sarah Leigh Source Expert Review Green was added to CCDC88A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.38 AASS Sarah Leigh Source NHS GMS was added to AASS.
Source Expert Review Green was added to AASS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v7.37 GABBR2 Arina Puzriakova Added comment: Comment on publications: PMID: 39028675 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI
Early onset or syndromic epilepsy v7.37 GABBR2 Arina Puzriakova Publications for gene: GABBR2 were set to 29100083; 28061363; 28135719; 28856709; 39028675
Early onset or syndromic epilepsy v7.36 GABBR2 Arina Puzriakova Publications for gene: GABBR2 were set to EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11; 29100083; 28061363; 28135719; 28856709
Early onset or syndromic epilepsy v7.35 GABBR2 Arina Puzriakova Phenotypes for gene: GABBR2 were changed from EPILEPTIC ENCEPHALOPATHY; Rett syndrome; Epileptic encephalopathy, early infantile, 59, 617904 to Developmental and epileptic encephalopathy 59, OMIM:617904
Early onset or syndromic epilepsy v7.34 TARS2 Sarah Leigh Added comment: Comment on publications: PMID: 39394138 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.34 TARS2 Sarah Leigh Publications for gene: TARS2 were set to 39394138; 33153448; 34508595; 37454282
Early onset or syndromic epilepsy v7.33 TARS2 Sarah Leigh Classified gene: TARS2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.33 TARS2 Sarah Leigh Gene: tars2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.32 TARS2 Sarah Leigh gene: TARS2 was added
gene: TARS2 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_25_ promote_green tags were added to gene: TARS2.
Mode of inheritance for gene: TARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS2 were set to 39394138; 33153448; 34508595; 37454282
Phenotypes for gene: TARS2 were set to Combined oxidative phosphorylation deficiency 21, OMIM: 615918; combined oxidative phosphorylation defect type 21,NDO:0014398
Review for gene: TARS2 was set to GREEN
Added comment: Numerous biallelic TARS2 variants have been associated with Combined oxidative phosphorylation deficiency 21 (OMIM: 615918) in cases from around the world. A summary of TARS2 variants and associated clinical features is presented in Supplementary Table 1, in PMID: 39394138. There at least 30 variants in 32 cases within 27 families. In eight of the families, the children had died before their second birthdays, all of the cases in the remaining 19 families were in special care, with a maximum age of 27 years. Epilepsy was evident in 15/24 families where an assessment was possible, psychomotor delay was evident in 25/26 families and brain MRI anomalies were apparent in 21/23 families.
Sources: Literature
Early onset or syndromic epilepsy v7.31 TRPM7 Sarah Leigh Classified gene: TRPM7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.31 TRPM7 Sarah Leigh Gene: trpm7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.30 TRPM7 Sarah Leigh gene: TRPM7 was added
gene: TRPM7 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_23_promote_green tags were added to gene: TRPM7.
Mode of inheritance for gene: TRPM7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRPM7 were set to 39099563; 35712613; 35561741
Phenotypes for gene: TRPM7 were set to hypomagnesaemia with secondary hypocalcaemia
Review for gene: TRPM7 was set to GREEN
Added comment: Heterozygous TRPM7 variants are associated with hypomagnesaemia with secondary hypocalcaemia (HSH)(PMID: 39099563; 35712613; 35561741). Six TRPM7 variants have been identified in six unrelated cases of HSH, one of the variants was found in three members of one family. The remaining variants were de novo. In addition to HSH, other phenotypic feature have been seen in those carrying TRPM7 variants, including seizures (4/6), motor skill defects (5/6), autism spectrum disorder (4/6) (PMID: 39099563; 35712613; 35561741). Functional studies suggest a loss of function effect of the TRPM7 variants (PMID: 39099563; 35561741).
Sources: Literature
Early onset or syndromic epilepsy v7.29 GLS Achchuthan Shanmugasundram Classified gene: GLS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.29 GLS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with biallelic GLS variants and with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v7.29 GLS Achchuthan Shanmugasundram Gene: gls has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.28 GLS Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: GLS.
Early onset or syndromic epilepsy v7.28 GLS Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39559284 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.28 GLS Achchuthan Shanmugasundram Publications for gene: GLS were set to 30575854
Early onset or syndromic epilepsy v7.27 GLS Achchuthan Shanmugasundram reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: 39559284; Phenotypes: Developmental and epileptic encephalopathy 71, OMIM:618328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.27 EEFSEC Achchuthan Shanmugasundram changed review comment from: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. Seizures were reported in seven patients from six families.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. Seizures were reported in seven patients from six families.

In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v7.27 EEFSEC Achchuthan Shanmugasundram Classified gene: EEFSEC as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.27 EEFSEC Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (six unrelated families) for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v7.27 EEFSEC Achchuthan Shanmugasundram Gene: eefsec has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.26 EEFSEC Achchuthan Shanmugasundram changed review comment from: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. Seizures were reported in seven patients from six families.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v7.26 EEFSEC Achchuthan Shanmugasundram Phenotypes for gene: EEFSEC were changed from neuroseselopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v7.25 EEFSEC Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: EEFSEC.
Early onset or syndromic epilepsy v7.25 EEFSEC Achchuthan Shanmugasundram changed review comment from: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v7.25 EEFSEC Achchuthan Shanmugasundram edited their review of gene: EEFSEC: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v7.25 EEFSEC Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39753114 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.25 EEFSEC Achchuthan Shanmugasundram Publications for gene: EEFSEC were set to 39753114
Early onset or syndromic epilepsy v7.24 EEFSEC Achchuthan Shanmugasundram gene: EEFSEC was added
gene: EEFSEC was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEFSEC were set to 39753114
Phenotypes for gene: EEFSEC were set to neuroseselopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: EEFSEC was set to GREEN
Added comment: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy.

This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v7.23 WDR47 Achchuthan Shanmugasundram Classified gene: WDR47 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.23 WDR47 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (five unrelated families) for the promotion of this gene to green rating on the next GMS update.
Early onset or syndromic epilepsy v7.23 WDR47 Achchuthan Shanmugasundram Gene: wdr47 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.22 WDR47 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: WDR47.
Early onset or syndromic epilepsy v7.22 WDR47 Achchuthan Shanmugasundram changed review comment from: PMID:39609633 reported seven patients from five unrelated families with either homozygous or compound heterozygous variants in WDR47 gene. They all presented with a complex neurodevelopmental syndrome comprising corpus callosum dysgenesis, microcephaly, intellectual disability and epilepsy. Profound intellectual disability was present in four of five reported families.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature; to: PMID:39609633 reported seven patients from five unrelated families with either homozygous or compound heterozygous variants in WDR47 gene. They all presented with a complex neurodevelopmental syndrome comprising corpus callosum dysgenesis, microcephaly, intellectual disability and epilepsy. Seizures were present in all five reported families.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v7.22 WDR47 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39609633 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Early onset or syndromic epilepsy v7.22 WDR47 Achchuthan Shanmugasundram Publications for gene: WDR47 were set to 39609633
Early onset or syndromic epilepsy v7.21 WDR47 Achchuthan Shanmugasundram Phenotypes for gene: WDR47 were changed from neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v7.20 WDR47 Achchuthan Shanmugasundram edited their review of gene: WDR47: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v7.20 WDR47 Achchuthan Shanmugasundram gene: WDR47 was added
gene: WDR47 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: WDR47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR47 were set to 39609633
Phenotypes for gene: WDR47 were set to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: WDR47 was set to GREEN
Added comment: PMID:39609633 reported seven patients from five unrelated families with either homozygous or compound heterozygous variants in WDR47 gene. They all presented with a complex neurodevelopmental syndrome comprising corpus callosum dysgenesis, microcephaly, intellectual disability and epilepsy. Profound intellectual disability was present in four of five reported families.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v7.19 ADPRHL2 Eleanor Williams Publications for gene: ADPRHL2 were set to 30100084; 30401461
Early onset or syndromic epilepsy v7.18 PABPC1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: PMID:35511136 reported 4 unrelated individuals with de novo PABPC1 variants and with a phenotype of global developmental delay including intellectual disability, movement coordination disorders, seizures, behavioral disorders and mild facial dysmorphisms. There are no biallelic cases reported so far. Hence, the MOI should be updated to "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" in the next GMS review.
Early onset or syndromic epilepsy v7.18 PABPC1 Achchuthan Shanmugasundram Mode of inheritance for gene: PABPC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.17 PABPC1 Achchuthan Shanmugasundram Tag Q4_24_MOI tag was added to gene: PABPC1.
Early onset or syndromic epilepsy v7.17 PABPC1 Achchuthan Shanmugasundram reviewed gene: PABPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35511136; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v7.17 CRELD1 Sarah Leigh Tag Q4_24_NHS_review tag was added to gene: CRELD1.
Tag Q4_24_MOI tag was added to gene: CRELD1.
Early onset or syndromic epilepsy v7.17 CRELD1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for CRELD1 on this panel should be changed from "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" to "BIALLELIC, autosomal or pseudoautosomal".
Early onset or syndromic epilepsy v7.17 CRELD1 Sarah Leigh Mode of inheritance for gene: CRELD1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.16 CRELD1 Sarah Leigh edited their review of gene: CRELD1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v7.16 CRELD1 Sarah Leigh Phenotypes for gene: CRELD1 were changed from effries-Lakhani neurodevelopmental syndrome, OMIM:620771; Jeffries-Lakhani neurodevelopmental syndrome, MONDO:0958329 to Jeffries-Lakhani neurodevelopmental syndrome, OMIM:620771; Jeffries-Lakhani neurodevelopmental syndrome, MONDO:0958329
Early onset or syndromic epilepsy v7.15 CRELD1 Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants are associated with Atrioventricular septal defect, partial, with heterotaxy syndrome, OMIM:606217;{Atrioventricular septal defect, susceptibility to, 2}, OMIM:606217;atrioventricular septal defect, susceptibility to, 2, MONDO:0011650. However, this condition is not relevant to Early onset or syndromic epilepsy panel.
Early onset or syndromic epilepsy v7.15 CRELD1 Sarah Leigh Phenotypes for gene: CRELD1 were changed from Atrioventricular septal defect, partial, with heterotaxy syndrome, OMIM:606217; {Atrioventricular septal defect, susceptibility to, 2}, OMIM:606217; atrioventricular septal defect, susceptibility to, 2, MONDO:0011650 to effries-Lakhani neurodevelopmental syndrome, OMIM:620771; Jeffries-Lakhani neurodevelopmental syndrome, MONDO:0958329
Early onset or syndromic epilepsy v7.14 CRELD1 Sarah Leigh edited their review of gene: CRELD1: Added comment: Biallelic CRELD1 variants have been associated with Jeffries-Lakhani neurodevelopmental syndrome (OMIM:620771) and it is a moderate G2P gene for CRELD1-related neurodevelopmental disorder with hypotonia and seizures. At least four CRELD1 variants have been reported in at least 14 patients from 10 unrelated families (PMID: 37947183).; Changed publications to: 37947183
Early onset or syndromic epilepsy v7.14 CRELD1 Sarah Leigh Publications for gene: CRELD1 were set to 32437232
Early onset or syndromic epilepsy v7.13 CRELD1 Tracy Lester reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v7.13 AASS Arina Puzriakova Classified gene: AASS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.13 AASS Arina Puzriakova Gene: aass has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.12 AASS Arina Puzriakova gene: AASS was added
gene: AASS was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_24_promote_green tags were added to gene: AASS.
Mode of inheritance for gene: AASS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AASS were set to 23890588; 10775527; 27604308; 23570448
Phenotypes for gene: AASS were set to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
Review for gene: AASS was set to GREEN
Added comment: AASS associated with hyperlysinemia in ClinGen (definitive), G2P (strong) and OMIM. At least 10 probands in 4 publications (PMIDs: 23890588, 10775527, 27604308, 23570448), of which at least 4 cases had epilepsy. Seizures can represent an early feature of the disorder which supports inclusion of AASS on this panel.

This gene-disease relationship is supported by its biochemical function in lysine catabolism and a knock-in mouse model which recapitulates the human phenotype of hyperlysinemia (PMID: 35135854).
Sources: Literature
Early onset or syndromic epilepsy v7.11 SLC4A10 Arina Puzriakova Entity copied from Intellectual disability v8.25
Early onset or syndromic epilepsy v7.11 SLC4A10 Arina Puzriakova gene: SLC4A10 was added
gene: SLC4A10 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Other
Q3_24_promote_green tags were added to gene: SLC4A10.
Mode of inheritance for gene: SLC4A10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A10 were set to 37459438; 38054405; 31130284
Phenotypes for gene: SLC4A10 were set to Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities, OMIM:620746
Early onset or syndromic epilepsy v7.10 SLC13A3 Arina Puzriakova Tag Q3_24_promote_green tag was added to gene: SLC13A3.
Early onset or syndromic epilepsy v7.10 SLC13A3 Arina Puzriakova Publications for gene: SLC13A3 were set to 38235040; 34966709; 30635937
Early onset or syndromic epilepsy v7.9 SLC13A3 Arina Puzriakova Classified gene: SLC13A3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.9 SLC13A3 Arina Puzriakova Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM (MIM# 618384). At least 9 unrelated cases with biallelic variants in this gene and acute reversible leukoencephalopathy with increased urinary α-ketoglutarate, arising in the context of a febrile illness (PMID: 30635937; 34966709; 35527102; 37290914; 38235040).

Sufficient evidence to promote SLC13A3 to Green at the next GMS panel update.
Early onset or syndromic epilepsy v7.9 SLC13A3 Arina Puzriakova Gene: slc13a3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.8 SLC13A3 Arina Puzriakova Phenotypes for gene: SLC13A3 were changed from to Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate, OMIM:618384
Early onset or syndromic epilepsy v7.7 AJAP1 Achchuthan Shanmugasundram Classified gene: AJAP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.7 AJAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are five unrelated cases, the epilepsy phenotype is broad and there is contradictory functional evidence. Hence, this gene is currently rated as amber.

The 'watchlist' tag has been added to keep track of any new evidence.
Early onset or syndromic epilepsy v7.7 AJAP1 Achchuthan Shanmugasundram Gene: ajap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.6 AJAP1 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: AJAP1.
Early onset or syndromic epilepsy v7.6 AJAP1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Hannah Knight, PMID:38985877 reported five unrelated individuals with monoallelic variants or a deletion in AJAP1 gene, of which four patients presented with epilepsy.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: As reviewed by Hannah Knight, PMID:38985877 reported five unrelated individuals with monoallelic variants or a deletion in AJAP1 gene. Although four of these patients presented with seizures, the type of seizures varied across these individuals.

Two of these five cases had a conclusion of either 'benign' or 'unknown' in their evaluation of pathogenicity, where 'benign' was one of the four cases with seizures, where 'unknown' was the fifth case without seizures. One of the cases (Individual 1) has a missense variant that was evaluated as 'pathogenic'. But, functional studies in monoallelic knock in mice was not clearly supportive of this conclusion and the EEG in this mice appeared equivalent to wild type mouse. In addition, all missense variants of this gene in ClinVar are rated as VUS / benign.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Early onset or syndromic epilepsy v7.6 AJAP1 Achchuthan Shanmugasundram edited their review of gene: AJAP1: Changed rating: AMBER
Early onset or syndromic epilepsy v7.6 AJAP1 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: AJAP1.
Tag Q3_24_NHS_review was removed from gene: AJAP1.
Early onset or syndromic epilepsy v7.6 AJAP1 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v7.6 CCDC88A Arina Puzriakova Publications for gene: CCDC88A were set to 26917597; 30392057
Early onset or syndromic epilepsy v7.5 CCDC88A Arina Puzriakova Phenotypes for gene: CCDC88A were changed from ?PEHO syndrome-like 617507 to PEHO syndrome-like, OMIM:617507
Early onset or syndromic epilepsy v7.4 CCDC88A Arina Puzriakova Tag watchlist was removed from gene: CCDC88A.
Tag Q3_24_promote_green tag was added to gene: CCDC88A.
Early onset or syndromic epilepsy v7.4 CCDC88A Arina Puzriakova Classified gene: CCDC88A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.4 CCDC88A Arina Puzriakova Added comment: Comment on list classification: There are now at least 7 individuals from 4 unrelated families with biallelic variants in the CCDC88A gene (PMID: 26917597; 30392057; 37798908; 39334473), described to a PEHO-like syndrome with universal features including ID, epilepsy, microcephaly and optic nerve/cerebellar atrophy.

Sufficient unrelated cases with the same phenotype to promote this gene to green at the next GMS panel update.
Early onset or syndromic epilepsy v7.4 CCDC88A Arina Puzriakova Gene: ccdc88a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.3 PI4K2A Achchuthan Shanmugasundram Classified gene: PI4K2A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v7.3 PI4K2A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester, there are four unrelated cases reported with a neurodevelopmental disorder. Of these, epilepsy was present in three unrelated cases. Hence, this gene should be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v7.3 PI4K2A Achchuthan Shanmugasundram Gene: pi4k2a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v7.2 PI4K2A Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v7.2 PI4K2A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Tracy Lester, there are four unrelated cases reported with global developmental delay and/ or profound intellectual disability. Hence, this gene should be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Tracy Lester, there are four unrelated cases reported with a neurodevelopmental disorder . Hence, this gene should be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v7.2 PI4K2A Achchuthan Shanmugasundram Entity copied from Intellectual disability v8.13
Early onset or syndromic epilepsy v7.2 PI4K2A Achchuthan Shanmugasundram gene: PI4K2A was added
gene: PI4K2A was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,NHS GMS
Q3_24_promote_green, Q3_24_NHS_review tags were added to gene: PI4K2A.
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 30564627; 32418222; 35880319
Phenotypes for gene: PI4K2A were set to Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, OMIM:620732
Penetrance for gene: PI4K2A were set to unknown
Early onset or syndromic epilepsy v7.1 SLC13A3 Cassandra Smith gene: SLC13A3 was added
gene: SLC13A3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: SLC13A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A3 were set to 38235040; 34966709; 30635937
Review for gene: SLC13A3 was set to GREEN
Added comment: Febrile seizures reported in >3 families with biallelic variants in SLC13A3
Sources: Literature
Early onset or syndromic epilepsy v7.1 Eleanor Williams Panel version 7.0 has been signed off on 2024-10-30
Early onset or syndromic epilepsy v7.0 Eleanor Williams promoted panel to version 7.0
Early onset or syndromic epilepsy v6.15 CCDC88A Cassandra Smith reviewed gene: CCDC88A: Rating: GREEN; Mode of pathogenicity: None; Publications: 39334473, 37798908, 26917597; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v6.15 BORCS8 Arina Puzriakova Phenotypes for gene: BORCS8 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, OMIM:620987
Early onset or syndromic epilepsy v6.14 BORCS8 Arina Puzriakova Tag gene-checked was removed from gene: BORCS8.
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Classified gene: AJAP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Gene: ajap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Classified gene: AJAP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Gene: ajap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Classified gene: AJAP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene with green rating in the next GMS update.
Early onset or syndromic epilepsy v6.14 AJAP1 Achchuthan Shanmugasundram Gene: ajap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v6.13 AJAP1 Achchuthan Shanmugasundram Phenotypes for gene: AJAP1 were changed from Epileptic seizures; developmental disorder; intellectual disability to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v6.12 AJAP1 Achchuthan Shanmugasundram Publications for gene: AJAP1 were set to 38985877
Early onset or syndromic epilepsy v6.12 AJAP1 Achchuthan Shanmugasundram Publications for gene: AJAP1 were set to PMID: 38985877
Early onset or syndromic epilepsy v6.11 AJAP1 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: AJAP1.
Tag Q3_24_NHS_review tag was added to gene: AJAP1.
Early onset or syndromic epilepsy v6.11 AJAP1 Achchuthan Shanmugasundram edited their review of gene: AJAP1: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v6.11 AJAP1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Hannah Knight, there are five unrelated individuals reported with monoallelic variants or a deletion in AJAP1 gene, of which four patients presented with epilepsy.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: As reviewed by Hannah Knight, PMID:38985877 reported five unrelated individuals with monoallelic variants or a deletion in AJAP1 gene, of which four patients presented with epilepsy.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Early onset or syndromic epilepsy v6.11 AJAP1 Achchuthan Shanmugasundram reviewed gene: AJAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38985877; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v6.11 AJAP1 Hannah Knight gene: AJAP1 was added
gene: AJAP1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: AJAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AJAP1 were set to PMID: 38985877
Phenotypes for gene: AJAP1 were set to Epileptic seizures; developmental disorder; intellectual disability
Review for gene: AJAP1 was set to GREEN
Added comment: PMID: 38985877 (2024) identified five individuals with monoallelic variants or a deletion in AJAP1, who present with epilepsy, neurodevelopmental problems, or intellectual disability
Also included functional work
Sources: Literature
Early onset or syndromic epilepsy v6.11 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286; epilepsy, MONDO:0005027 to congenital disorder of glycosylation, MONDO:0015286; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v6.11 DHRSX Achchuthan Shanmugasundram Phenotypes for gene: DHRSX were changed from to congenital disorder of glycosylation, MONDO:0015286; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v6.10 DHRSX Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: DHRSX.
Early onset or syndromic epilepsy v6.10 DHRSX Achchuthan Shanmugasundram edited their review of gene: DHRSX: Changed rating: AMBER
Early onset or syndromic epilepsy v6.10 DHRSX Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with intellectual disability and hence there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.; to: Comment on list classification: There are two unrelated families reported with epilepsy and hence this gene should be promoted to amber.
Early onset or syndromic epilepsy v6.10 DHRSX Achchuthan Shanmugasundram edited their review of gene: DHRSX: Changed phenotypes to: congenital disorder of glycosylation, MONDO:0015286, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v6.10 DHRSX Achchuthan Shanmugasundram Entity copied from Intellectual disability v7.60
Early onset or syndromic epilepsy v6.10 DHRSX Achchuthan Shanmugasundram gene: DHRSX was added
gene: DHRSX was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber
Q3_24_promote_green, Pseudoautosomal region 1 tags were added to gene: DHRSX.
Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRSX were set to 38821050
Penetrance for gene: DHRSX were set to Complete
Early onset or syndromic epilepsy v6.9 YIF1B Arina Puzriakova Added comment: Comment on phenotypes: Relevant phenotype has now been added to OMIM - Kaya-Barakat-Masson syndrome, OMIM:619125
Early onset or syndromic epilepsy v6.9 YIF1B Arina Puzriakova Phenotypes for gene: YIF1B were changed from Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement to Kaya-Barakat-Masson syndrome, OMIM:619125
Early onset or syndromic epilepsy v6.8 TUBGCP2 Arina Puzriakova Phenotypes for gene: TUBGCP2 were changed from Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737 to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM:618737
Early onset or syndromic epilepsy v6.7 RNU4-2 Arina Puzriakova Tag gene-checked tag was added to gene: RNU4-2.
Early onset or syndromic epilepsy v6.7 KCNB2 Arina Puzriakova Tag gene-checked tag was added to gene: KCNB2.
Early onset or syndromic epilepsy v6.7 KCNA3 Arina Puzriakova Tag gene-checked tag was added to gene: KCNA3.
Early onset or syndromic epilepsy v6.7 DENND5B Arina Puzriakova Tag gene-checked tag was added to gene: DENND5B.
Early onset or syndromic epilepsy v6.7 CAMK2D Arina Puzriakova Tag gene-checked tag was added to gene: CAMK2D.
Early onset or syndromic epilepsy v6.7 BORCS8 Arina Puzriakova Tag gene-checked tag was added to gene: BORCS8.
Early onset or syndromic epilepsy v6.7 ANO4 Arina Puzriakova Tag gene-checked tag was added to gene: ANO4.
Early onset or syndromic epilepsy v6.7 BORCS8 Sarah Leigh Tag watchlist tag was added to gene: BORCS8.
Early onset or syndromic epilepsy v6.7 BORCS8 Sarah Leigh reviewed gene: BORCS8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v6.7 BORCS8 Sarah Leigh Tag Q3_24_promote_green was removed from gene: BORCS8.
Early onset or syndromic epilepsy v6.7 BORCS8 Sarah Leigh Entity copied from Intellectual disability v7.41
Early onset or syndromic epilepsy v6.7 BORCS8 Sarah Leigh gene: BORCS8 was added
gene: BORCS8 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q3_24_promote_green tags were added to gene: BORCS8.
Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS8 were set to 38128568
Phenotypes for gene: BORCS8 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v6.6 RNU4-2 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: RNU4-2.
Early onset or syndromic epilepsy v6.6 MAST3 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: MAST3.
Tag Q2_24_MOI was removed from gene: MAST3.
Tag Q2_24_NHS_review was removed from gene: MAST3.
Early onset or syndromic epilepsy v6.6 ANO4 Achchuthan Shanmugasundram Tag Q2_24_promote_green was removed from gene: ANO4.
Tag Q2_24_MOI was removed from gene: ANO4.
Early onset or syndromic epilepsy v6.6 PRICKLE1 Achchuthan Shanmugasundram Tag Q1_24_demote_amber was removed from gene: PRICKLE1.
Tag Q1_24_expert_review was removed from gene: PRICKLE1.
Early onset or syndromic epilepsy v6.6 ZNFX1 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: ZNFX1.
Tag Q1_24_NHS_review was removed from gene: ZNFX1.
Early onset or syndromic epilepsy v6.6 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: KCNA3.
Tag Q1_24_NHS_review was removed from gene: KCNA3.
Early onset or syndromic epilepsy v6.6 KCNA1 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: KCNA1.
Tag Q1_24_NHS_review was removed from gene: KCNA1.
Early onset or syndromic epilepsy v6.6 HSD17B10 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: HSD17B10.
Early onset or syndromic epilepsy v6.6 COL4A3BP Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: COL4A3BP.
Early onset or syndromic epilepsy v6.6 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: CAMSAP1.
Early onset or syndromic epilepsy v6.6 ANK2 Achchuthan Shanmugasundram Tag Q1_24_promote_green was removed from gene: ANK2.
Early onset or syndromic epilepsy v6.6 ZNFX1 Achchuthan Shanmugasundram reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v6.6 RNU4-2 Achchuthan Shanmugasundram reviewed gene: RNU4-2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v6.6 PRICKLE1 Achchuthan Shanmugasundram reviewed gene: PRICKLE1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v6.6 MAST3 Achchuthan Shanmugasundram reviewed gene: MAST3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v6.6 KCNA3 Achchuthan Shanmugasundram commented on gene: KCNA3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v6.6 KCNA1 Achchuthan Shanmugasundram commented on gene: KCNA1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v6.6 HSD17B10 Achchuthan Shanmugasundram reviewed gene: HSD17B10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v6.6 COL4A3BP Achchuthan Shanmugasundram reviewed gene: COL4A3BP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v6.6 CAMSAP1 Achchuthan Shanmugasundram commented on gene: CAMSAP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v6.6 ANO4 Achchuthan Shanmugasundram reviewed gene: ANO4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v6.6 ANK2 Achchuthan Shanmugasundram commented on gene: ANK2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v6.5 ZNFX1 Achchuthan Shanmugasundram Source NHS GMS was added to ZNFX1.
Source Expert Review Green was added to ZNFX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 RNU4-2 Achchuthan Shanmugasundram Source NHS GMS was added to RNU4-2.
Source Expert Review Green was added to RNU4-2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 PRICKLE1 Achchuthan Shanmugasundram Source Expert Review Amber was added to PRICKLE1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v6.5 MAST3 Achchuthan Shanmugasundram Source NHS GMS was added to MAST3.
Source Expert Review Green was added to MAST3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 KCNA3 Achchuthan Shanmugasundram Source NHS GMS was added to KCNA3.
Source Expert Review Green was added to KCNA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 KCNA1 Achchuthan Shanmugasundram Source Expert Review Green was added to KCNA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 HSD17B10 Achchuthan Shanmugasundram Source NHS GMS was added to HSD17B10.
Source Expert Review Green was added to HSD17B10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 COL4A3BP Achchuthan Shanmugasundram Source NHS GMS was added to COL4A3BP.
Source Expert Review Green was added to COL4A3BP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 CAMSAP1 Achchuthan Shanmugasundram Source NHS GMS was added to CAMSAP1.
Source Expert Review Green was added to CAMSAP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 ANO4 Achchuthan Shanmugasundram Source NHS GMS was added to ANO4.
Source Expert Review Green was added to ANO4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.5 ANK2 Achchuthan Shanmugasundram Source NHS GMS was added to ANK2.
Source Expert Review Green was added to ANK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v6.4 RNU2-2P Eleanor Williams gene: RNU2-2P was added
gene: RNU2-2P was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: RNU2-2P was set to RED
Added comment: PRE-PRINT article https://doi.org/10.1101/2024.09.03.24312863

Greene et al 2024 - report 15 cases in which recurrent germline variants in RNU2-2P are found in patients with a severe neurodevelopmental disorder.

9 cases were from the 100,000 Genomes Project, all of which were annotated with Intellectual disability and displayed severe epilepsy usually from the first few months of life. Among these 9 two recurrent variants were found; n.4G>A and n.35A>G. Trio sequencing of 4/5 of the cases with n.4G>A and 3/4 of the cases with n.35A>G showed that the variants were de novo in all cases.

A variant with a different alternate allele at nucleotide 35, n.35A>T, was identified in
8 unaffected participants but further analysis suggests that this is a recurring somatic mosaic
variant.

A further 6 cases were identified in additional datasets of patients with neurodevelopmental abnormalities with de novo variants and no unaffected carriers of either variant; 4 cases had n.4G>A, 1 case had n.35A>G and 1 case had a different alternate allele, n.35A>C.

RNU2-2P is currently annotated as a pseudogene in Ensembl, but there is evidence that it is a transcribed gene from PMID.: 35288589
Sources: Literature
Early onset or syndromic epilepsy v6.3 CUX1 Sarah Leigh Tag Q3_24_promote_green tag was added to gene: CUX1.
Tag Q3_24_NHS_review tag was added to gene: CUX1.
Early onset or syndromic epilepsy v6.3 CUX1 Sarah Leigh Classified gene: CUX1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v6.3 CUX1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be green on this panel.
Early onset or syndromic epilepsy v6.3 CUX1 Sarah Leigh Gene: cux1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v6.2 CUX1 Sarah Leigh gene: CUX1 was added
gene: CUX1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CUX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUX1 were set to 37644171
Phenotypes for gene: CUX1 were set to Global developmental delay with or without impaired intellectual development, OMIM:618330; global developmental delay with or without impaired intellectual development, MONDO:0032680
Review for gene: CUX1 was set to GREEN
Added comment: Variants in CUX1 have been associated with Global developmental delay with or without impaired intellectual development (OMIM:618330). PMID: 37644171 reports epileptic seizures in 8/34 individuals carrying different CUX1 variants (supplementary table 1).
Sources: Literature
Early onset or syndromic epilepsy v6.1 Eleanor Williams Panel version 6.0 has been signed off on 2024-08-07
Early onset or syndromic epilepsy v6.0 Eleanor Williams promoted panel to version 6.0
Early onset or syndromic epilepsy v5.30 MT-TL1 Sarah Leigh Tag locus-type-rna-transfer tag was added to gene: MT-TL1.
Early onset or syndromic epilepsy v5.30 SNORD118 Sarah Leigh Tag locus-type-small-nucleolar tag was added to gene: SNORD118.
Early onset or syndromic epilepsy v5.30 RNU4ATAC Sarah Leigh Tag locus-type-rna-small-nuclear tag was added to gene: RNU4ATAC.
Early onset or syndromic epilepsy v5.30 LNPK Achchuthan Shanmugasundram Classified gene: LNPK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.30 LNPK Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v5.30 LNPK Achchuthan Shanmugasundram Gene: lnpk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.29 LNPK Achchuthan Shanmugasundram Phenotypes for gene: LNPK were changed from Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, OMIM:618090 to Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, OMIM:618090
Early onset or syndromic epilepsy v5.29 LNPK Achchuthan Shanmugasundram Phenotypes for gene: LNPK were changed from Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum 618090 to Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, OMIM:618090
Early onset or syndromic epilepsy v5.29 LNPK Achchuthan Shanmugasundram Publications for gene: LNPK were set to 30032983
Early onset or syndromic epilepsy v5.28 LNPK Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: LNPK.
Early onset or syndromic epilepsy v5.28 LNPK Achchuthan Shanmugasundram reviewed gene: LNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: 35599435; Phenotypes: Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, OMIM:618090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.28 FZR1 Achchuthan Shanmugasundram Classified gene: FZR1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.28 FZR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v5.28 FZR1 Achchuthan Shanmugasundram Gene: fzr1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.27 FZR1 Achchuthan Shanmugasundram changed review comment from: PMID:31318984 reported the identification of a novel heterozygous missense FZR1 variant (c.560A>G/ p.Asp187Gly) in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, global developmental delay, and refractory epilepsy. There is some functional evidence available for this variant.

PMID:34788397 reported the identification of three de novo missense FZR1 variants (c.559G>A/ p.Asp187Asn, c.999C>G/ p.Asn333Lys & c.999C>A/ p.Asn333Lys) in three unrelated individuals from different descents (Turkish, Moroccan and Afghan) presenting with childhood-onset generalized epilepsy, intellectual disability, and mild ataxia.

This gene has been associated with relevant phenotypes in OMIM (MIM #620145) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature; to: PMID:31318984 reported the identification of a novel heterozygous missense FZR1 variant (c.560A>G/ p.Asp187Gly) in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, global developmental delay, and refractory epilepsy. There is some functional evidence available for this variant.

PMID:34788397 reported the identification of three de novo missense FZR1 variants (c.559G>A/ p.Asp187Asn, c.999C>G/ p.Asn333Lys & c.999C>A/ p.Asn333Lys) in three unrelated individuals from different descents (Turkish, Moroccan and Afghan) presenting with childhood-onset generalized epilepsy, intellectual disability, and mild ataxia. There is functional evidence available for variants reported in this study.

This gene has been associated with relevant phenotypes in OMIM (MIM #620145) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature
Early onset or syndromic epilepsy v5.27 FZR1 Achchuthan Shanmugasundram gene: FZR1 was added
gene: FZR1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_24_promote_green tags were added to gene: FZR1.
Mode of inheritance for gene: FZR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FZR1 were set to 31318984; 34788397
Phenotypes for gene: FZR1 were set to Developmental and epileptic encephalopathy 109, OMIM:620145
Review for gene: FZR1 was set to GREEN
Added comment: PMID:31318984 reported the identification of a novel heterozygous missense FZR1 variant (c.560A>G/ p.Asp187Gly) in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, global developmental delay, and refractory epilepsy. There is some functional evidence available for this variant.

PMID:34788397 reported the identification of three de novo missense FZR1 variants (c.559G>A/ p.Asp187Asn, c.999C>G/ p.Asn333Lys & c.999C>A/ p.Asn333Lys) in three unrelated individuals from different descents (Turkish, Moroccan and Afghan) presenting with childhood-onset generalized epilepsy, intellectual disability, and mild ataxia.

This gene has been associated with relevant phenotypes in OMIM (MIM #620145) and Gene2Phenotype (with 'strong' rating on the DD panel).
Sources: Literature
Early onset or syndromic epilepsy v5.26 FUK Achchuthan Shanmugasundram Classified gene: FUK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.26 FUK Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with seizures and hence this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v5.26 FUK Achchuthan Shanmugasundram Gene: fuk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.25 FUK Achchuthan Shanmugasundram Publications for gene: FUK were set to 30503518
Early onset or syndromic epilepsy v5.24 FUK Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: FUK.
Early onset or syndromic epilepsy v5.24 FUK Achchuthan Shanmugasundram reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: None; Publications: 35718084, 36426412; Phenotypes: Congenital disorder of glycosylation with defective fucosylation 2, OMIM:618324; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.24 CNTN2 Achchuthan Shanmugasundram Classified gene: CNTN2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.24 CNTN2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Sarah Graham, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Early onset or syndromic epilepsy v5.24 CNTN2 Achchuthan Shanmugasundram Gene: cntn2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.23 CNTN2 Achchuthan Shanmugasundram Phenotypes for gene: CNTN2 were changed from Epilepsy, familial adult myoclonic, 5 to Epilepsy, early-onset, 5, with or without developmental delay, OMIM:615400
Early onset or syndromic epilepsy v5.22 CNTN2 Achchuthan Shanmugasundram Publications for gene: CNTN2 were set to
Early onset or syndromic epilepsy v5.21 CNTN2 Achchuthan Shanmugasundram Mode of inheritance for gene: CNTN2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.20 CNTN2 Achchuthan Shanmugasundram Tag Q3_24_promote_green tag was added to gene: CNTN2.
Tag Q3_24_NHS_review tag was added to gene: CNTN2.
Early onset or syndromic epilepsy v5.20 CNTN2 Achchuthan Shanmugasundram edited their review of gene: CNTN2: Added comment: PMID:23518707 reported a consanguineous Egyptian family in which five siblings aged 11 to 14 years had seizures and were identified with a homozygous frameshift CNTN2 variant (p.Trp168fs).

PMID:34691156 reported a 10-year old boy born of unrelated parents of Han Chinese descent, with developmental delay and onset of generalised tonic-clonic seizures at 5 years of age and identified with a homozygous frameshift CNTN2 variant (p.Thr958Thrfs).

PMID:36553572 reported a 13-year-old boy with global developmental delay and epileptic encephalopathy and was associated with a homozygous nonsense variant (p.Arg314Ter) in the CNTN2 gene.

PMID:37359369 reported a consanguineous Pakistani family in which four siblings developed various types of seizures late in the first decade of their life and had global developmental,ental delay with mild intellectual disability. They were identified with a homozygous nonsense CNTN2 variant (p.Glu567Ter)

This gene has been associated with relevant phenotypes in OMIM (MIM #615400), but not yet in Gene2Phenotype.; Changed publications to: 23518707, 34691156, 36553572, 37359369
Early onset or syndromic epilepsy v5.20 CNTN2 Achchuthan Shanmugasundram reviewed gene: CNTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, early-onset, 5, with or without developmental delay, OMIM:615400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.20 CNTN2 Sarah Graham reviewed gene: CNTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37359369, 34691156, 28397838, 36553572; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.20 RNU4-2 Arina Puzriakova changed review comment from: Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings in PMID:38645094 (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.; to: Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings in PMID: 38645094 (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.
Early onset or syndromic epilepsy v5.20 RNU4-2 Arina Puzriakova changed review comment from: Comment on list classification: The two papers (PMID: 38821540; 38645094) corroborate mutual findings and report over 100 unrelated individuals with a clinically overlapping neurological disorder and variants the non-coding gene RNU4-2.

Overall there is sufficient evidence to promote this gene to Green status at the next GMS panel update.; to: Comment on list classification: Multiple individuals have been identified in PMID: 38821540 with a clinically overlapping neurological disorder and variants the non-coding gene RNU4-2. Additional cases with mutual findings have also been reported in PMID: 38645094, corroborating this gene-disease association - however, PMID: 38645094 is still in preprint at this time.

Overall there is sufficient evidence to promote this gene to Green status at the next GMS panel update.
Early onset or syndromic epilepsy v5.20 RNU4-2 Arina Puzriakova changed review comment from: Second paper by Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings with the PMID: 38645094 paper (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.; to: Greene et al. 2024 (PMID: 38821540) reported on 73 unrelated cases with a neurodevelopmental disorder associated with heterozygous variants in the RNU4-2 gene, overlapping findings in PMID:38645094 (still currently in preprint). Participants were identified through their enrolment in various cohorts including the 100,000 Genomes Project, NHSE Genomic Medicine Service (GMS), and NIHR BioResource.

Almost all variants were acquired de novo, with the exception of one variant that was inherited from an affected mother and 16 probands with unknown inheritance due to lack of parental genotype data.
Variants cluster in two regions of RNU4-2 (n.62–70 and n.73–79) but the majority of cases harboured a recurrent variant, n.64_65insT.

Clinical presentation was predominantly characterised by intellectual disability, but other observed features include microcephaly, proportionate short stature, hypotonia, seizures and motor delay.
Early onset or syndromic epilepsy v5.20 ADGRL1 Achchuthan Shanmugasundram Classified gene: ADGRL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.20 ADGRL1 Achchuthan Shanmugasundram Gene: adgrl1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.20 ADGRL1 Achchuthan Shanmugasundram Classified gene: ADGRL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.20 ADGRL1 Achchuthan Shanmugasundram Gene: adgrl1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.19 ADGRL1 Achchuthan Shanmugasundram gene: ADGRL1 was added
gene: ADGRL1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADGRL1 were set to 35907405
Phenotypes for gene: ADGRL1 were set to Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, OMIM:620065
Review for gene: ADGRL1 was set to AMBER
Added comment: PMID:35907405 reported the identification of monoallelic ADGRL1 variants in ten individuals with a neurodevelopmental disorder comprising developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy. This includes a case that was previously reported in PMID:30504930. Epilepsy was reported in two of these cases. This gene has been associated with relevant phenotype in OMIM (MIM #620065), but not yet in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v5.18 KCNB2 Achchuthan Shanmugasundram Classified gene: KCNB2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.18 KCNB2 Achchuthan Shanmugasundram Gene: kcnb2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.18 KCNB2 Achchuthan Shanmugasundram Classified gene: KCNB2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.18 KCNB2 Achchuthan Shanmugasundram Gene: kcnb2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.17 KCNB2 Achchuthan Shanmugasundram gene: KCNB2 was added
gene: KCNB2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNB2 were set to 38503299
Phenotypes for gene: KCNB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: KCNB2 was set to AMBER
Added comment: PMID:38503299 reported seven unrelated individuals with monoallelic KCNB2 variants and neurodevelopmental disorder, of which two of them had seizures.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v5.16 CAMK2D Achchuthan Shanmugasundram Classified gene: CAMK2D as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.16 CAMK2D Achchuthan Shanmugasundram Gene: camk2d has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.16 CAMK2D Achchuthan Shanmugasundram Classified gene: CAMK2D as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.16 CAMK2D Achchuthan Shanmugasundram Gene: camk2d has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.16 CAMK2D Achchuthan Shanmugasundram Classified gene: CAMK2D as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.16 CAMK2D Achchuthan Shanmugasundram Gene: camk2d has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.15 CAMK2D Achchuthan Shanmugasundram gene: CAMK2D was added
gene: CAMK2D was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CAMK2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK2D were set to 38272033
Phenotypes for gene: CAMK2D were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: CAMK2D was set to AMBER
Added comment: PMID:38272033 reported eight unrelated individuals with monoallelic CAMK2D variants and presenting with a neurodevelopmental disorder. Clinical phenotypes include intellectual disability (ID), delayed speech, behavioral problems and dilated cardiomyopathy.

The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms.

Epilepsy was reported as one of the clinical manifestations in 3 out of eight reported cases.

This gene has been associated with relevant phenotype in Gene2Phenotype ('moderate' rating on the DD panel), but not yet in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v5.14 RNU4-2 Arina Puzriakova Entity copied from Intellectual disability v6.18
Early onset or syndromic epilepsy v5.14 RNU4-2 Arina Puzriakova gene: RNU4-2 was added
gene: RNU4-2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
locus-type-rna-small-nuclear, Q2_24_promote_green tags were added to gene: RNU4-2.
Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU4-2 were set to 38821540; 38645094
Phenotypes for gene: RNU4-2 were set to Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related
Early onset or syndromic epilepsy v5.13 ANO4 Sarah Leigh commented on gene: ANO4: To date, no phenotype has been associated with ANO4 variants in OMIM, Gen2Phen or Mondo.
Early onset or syndromic epilepsy v5.13 ANO4 Sarah Leigh Phenotypes for gene: ANO4 were changed from to sporadic encephalopathic and familial epilepsy
Early onset or syndromic epilepsy v5.12 ANO4 Sarah Leigh Classified gene: ANO4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.12 ANO4 Sarah Leigh Gene: ano4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.11 ANO4 Sarah Leigh gene: ANO4 was added
gene: ANO4 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_24_promote_green, Q2_24_MOI tags were added to gene: ANO4.
Mode of inheritance for gene: ANO4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ANO4 were set to 38744284
Mode of pathogenicity for gene: ANO4 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: ANO4 was set to GREEN
Added comment: PMID: 38744284 reports five de novo ANO4 missense variants in patients (I1–I5) with a phenotype that includes intellectual disability, developmental and epileptic or epileptic encephalopathy (DEE/EE) and hypotonia. A further two ANO4 missenses variants were observed, one had been inherited from unaffected mother (patient F7) and with a penetrance of 73% in members of a large pedigree with a milder phenotype (PMID: 38744284: Supplementary figure S2). Febrile seizures plus (GEFS+) or temporal lobe epilepsy were associated with these inherited variants. A dominant negative mechanism was proposed by Yang et al (PMID: 38744284) as a result of functional studies of one of the variants causing DEE/EE and one causing GEFS+.
Sources: Literature
Early onset or syndromic epilepsy v5.10 ZBTB47 Eleanor Williams Tag gene-checked tag was added to gene: ZBTB47.
Early onset or syndromic epilepsy v5.10 TMEM63B Eleanor Williams Tag gene-checked tag was added to gene: TMEM63B.
Early onset or syndromic epilepsy v5.10 PPP1R3F Eleanor Williams Tag gene-checked tag was added to gene: PPP1R3F.
Early onset or syndromic epilepsy v5.10 MAST4 Eleanor Williams Tag gene-checked tag was added to gene: MAST4.
Early onset or syndromic epilepsy v5.10 RAB5C Eleanor Williams Tag gene-checked tag was added to gene: RAB5C.
Early onset or syndromic epilepsy v5.10 PABPC1 Eleanor Williams Tag gene-checked tag was added to gene: PABPC1.
Early onset or syndromic epilepsy v5.10 CNOT9 Eleanor Williams Tag gene-checked tag was added to gene: CNOT9.
Early onset or syndromic epilepsy v5.10 ARF3 Eleanor Williams Tag gene-checked tag was added to gene: ARF3.
Early onset or syndromic epilepsy v5.10 MAST3 Sarah Leigh Tag Q2_24_NHS_review tag was added to gene: MAST3.
Early onset or syndromic epilepsy v5.10 MAST3 Sarah Leigh changed review comment from: MAST3 variants have been associated with Developmental and epileptic encephalopathy 108 (OMIM:620115). PMID:34185323 reports five de novo missense MAST3 variants in eleven unrelated individuals with developmental and epileptic encephalopathy, with a range of seizure types. Functional studies suggest that the MAST3 variants have a gain-of-function effect.
Sources: Literature; to: MAST3 variants have been associated with Developmental and epileptic encephalopathy 108 (OMIM:620115). PMID:34185323 reports five de novo missense MAST3 variants in eleven unrelated individuals with developmental and epileptic encephalopathy, with a range of seizure types. These variants are within the serine-threonine kinases (STK) domain. PMID: 35095415 reports a further four de novo missense MAST3 variants, within the domain of unknown function (DUF). It would appear that the variants within the STK domain are associated with a neurodevelopmental disorder with a epilepsy phenotype, while variants within the DUF domain have a autistic spectrum disorder phenotype (PMID: 35095415)
Functional studies suggest that the MAST3 variants have a gain-of-function effect (PMID:34185323; 35095415).
Early onset or syndromic epilepsy v5.10 MAST3 Sarah Leigh Publications for gene: MAST3 were set to 34185323
Early onset or syndromic epilepsy v5.9 MAST3 Sarah Leigh Added comment: Comment on mode of pathogenicity: It would appear that MAST3 variants have a gain-of-function effect (PMID:34185323).
Early onset or syndromic epilepsy v5.9 MAST3 Sarah Leigh Mode of pathogenicity for gene: MAST3 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v5.8 MAST3 Sarah Leigh Classified gene: MAST3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v5.8 MAST3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v5.8 MAST3 Sarah Leigh Gene: mast3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v5.7 MAST3 Sarah Leigh Tag Q2_24_promote_green tag was added to gene: MAST3.
Tag Q2_24_MOI tag was added to gene: MAST3.
Early onset or syndromic epilepsy v5.7 MAST3 Sarah Leigh gene: MAST3 was added
gene: MAST3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST3 were set to 34185323
Mode of pathogenicity for gene: MAST3 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: MAST3 was set to GREEN
Added comment: MAST3 variants have been associated with Developmental and epileptic encephalopathy 108 (OMIM:620115). PMID:34185323 reports five de novo missense MAST3 variants in eleven unrelated individuals with developmental and epileptic encephalopathy, with a range of seizure types. Functional studies suggest that the MAST3 variants have a gain-of-function effect.
Sources: Literature
Early onset or syndromic epilepsy v5.6 SLC5A6 Eleanor Williams changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remainsred.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains red.
Early onset or syndromic epilepsy v5.6 ZBTB47 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 U2AF2 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 TRIT1 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 TMEM63B Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 SHQ1 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 SHQ1 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated togreenand the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 SCN8A 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 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 RAB5C Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 PTCD3 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 PPP1R3F Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'X-LINKED: hemizygous mutation in males, biallelic mutations in females'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, biallelic mutations in females' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 PLA2G6 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 PIP5K1C Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 PIGM Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 PABPC1 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'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.
Early onset or syndromic epilepsy v5.6 MAST4 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 LETM1 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 KDM6B Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 KCNH5 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 HECTD4 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 ESAM Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 EIF4A2 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'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.
Early onset or syndromic epilepsy v5.6 DNAJC6 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 CRELD1 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set 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 rating of this gene has been updated to green and the mode of inheritance set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 ATP6V0C Eleanor Williams 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 ASL Eleanor Williams changed review comment from: The rating of this gene has been updated to green and the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 ARF3 Eleanor Williams 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, imprinted status unknown' following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 AGO1 Eleanor Williams 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, imprinted status unknown' following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 CNOT9 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 ATP6V0C Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand 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'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 ASL Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 ARF3 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 AGO1 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 CACNB4 Eleanor Williams edited their review of gene: CACNB4: Changed rating: RED
Early onset or syndromic epilepsy v5.6 CACNB4 Eleanor Williams changed review comment from: The rating of this gene has been updated from green to redfollowing NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated from green to red following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 SCN8A Achchuthan Shanmugasundram Tag for-review was removed from gene: SCN8A.
Tag to_be_confirmed_NHSE was removed from gene: SCN8A.
Early onset or syndromic epilepsy v5.6 CACNB4 Achchuthan Shanmugasundram Tag Q4_23_demote_red was removed from gene: CACNB4.
Tag Q4_23_expert_review was removed from gene: CACNB4.
Early onset or syndromic epilepsy v5.6 ZBTB47 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ZBTB47.
Early onset or syndromic epilepsy v5.6 TRIT1 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: TRIT1.
Early onset or syndromic epilepsy v5.6 SHQ1 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: SHQ1.
Early onset or syndromic epilepsy v5.6 PTCD3 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: PTCD3.
Early onset or syndromic epilepsy v5.6 PLA2G6 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: PLA2G6.
Early onset or syndromic epilepsy v5.6 PIGM Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: PIGM.
Early onset or syndromic epilepsy v5.6 MAST4 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: MAST4.
Early onset or syndromic epilepsy v5.6 HECTD4 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: HECTD4.
Early onset or syndromic epilepsy v5.6 ASL Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ASL.
Tag Q4_23_NHS_review was removed from gene: ASL.
Early onset or syndromic epilepsy v5.6 ARF3 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: ARF3.
Early onset or syndromic epilepsy v5.6 AGO1 Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: AGO1.
Early onset or syndromic epilepsy v5.6 U2AF2 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: U2AF2.
Early onset or syndromic epilepsy v5.6 TMEM63B Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: TMEM63B.
Early onset or syndromic epilepsy v5.6 RAB5C Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: RAB5C.
Early onset or syndromic epilepsy v5.6 PPP1R3F Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: PPP1R3F.
Early onset or syndromic epilepsy v5.6 PIP5K1C Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: PIP5K1C.
Early onset or syndromic epilepsy v5.6 PABPC1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: PABPC1.
Tag Q3_23_MOI was removed from gene: PABPC1.
Early onset or syndromic epilepsy v5.6 LETM1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: LETM1.
Tag Q3_23_MOI was removed from gene: LETM1.
Early onset or syndromic epilepsy v5.6 KDM6B Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: KDM6B.
Early onset or syndromic epilepsy v5.6 KCNH5 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: KCNH5.
Early onset or syndromic epilepsy v5.6 ESAM Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: ESAM.
Early onset or syndromic epilepsy v5.6 EIF4A2 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: EIF4A2.
Early onset or syndromic epilepsy v5.6 DNAJC6 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: DNAJC6.
Early onset or syndromic epilepsy v5.6 CRELD1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: CRELD1.
Early onset or syndromic epilepsy v5.6 CNOT9 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: CNOT9.
Early onset or syndromic epilepsy v5.6 ATP6V0C Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: ATP6V0C.
Tag Q3_23_NHS_review was removed from gene: ATP6V0C.
Early onset or syndromic epilepsy v5.6 SLC5A6 Eleanor Williams reviewed gene: SLC5A6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v5.6 ZBTB47 Eleanor Williams reviewed gene: ZBTB47: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 U2AF2 Eleanor Williams reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 TRIT1 Eleanor Williams edited their review of gene: TRIT1: Added comment: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v5.6 TMEM63B Eleanor Williams reviewed gene: TMEM63B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 SHQ1 Eleanor Williams reviewed gene: SHQ1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 SCN8A Eleanor Williams reviewed gene: SCN8A: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 RAB5C Eleanor Williams reviewed gene: RAB5C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 PTCD3 Eleanor Williams reviewed gene: PTCD3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 PPP1R3F Eleanor Williams reviewed gene: PPP1R3F: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v5.6 PLA2G6 Eleanor Williams reviewed gene: PLA2G6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 PIP5K1C Eleanor Williams reviewed gene: PIP5K1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 PIGM Eleanor Williams reviewed gene: PIGM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 PABPC1 Eleanor Williams reviewed gene: PABPC1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 MAST4 Eleanor Williams reviewed gene: MAST4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 LETM1 Eleanor Williams reviewed gene: LETM1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 KDM6B Eleanor Williams reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 KCNH5 Eleanor Williams reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 HECTD4 Eleanor Williams reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 ESAM Eleanor Williams reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 EIF4A2 Eleanor Williams reviewed gene: EIF4A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 DNAJC6 Eleanor Williams reviewed gene: DNAJC6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 CRELD1 Eleanor Williams reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 CNOT9 Eleanor Williams reviewed gene: CNOT9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 CACNB4 Eleanor Williams reviewed gene: CACNB4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v5.6 ATP6V0C Eleanor Williams reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v5.6 ASL Eleanor Williams edited their review of gene: ASL: Added comment: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.6 ARF3 Eleanor Williams reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v5.6 AGO1 Eleanor Williams reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v5.5 ZBTB47 Achchuthan Shanmugasundram Source NHS GMS was added to ZBTB47.
Source Expert Review Green was added to ZBTB47.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 U2AF2 Achchuthan Shanmugasundram Source NHS GMS was added to U2AF2.
Source Expert Review Green was added to U2AF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 TRIT1 Achchuthan Shanmugasundram Source NHS GMS was added to TRIT1.
Source Expert Review Green was added to TRIT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 TMEM63B Achchuthan Shanmugasundram Source NHS GMS was added to TMEM63B.
Source Expert Review Green was added to TMEM63B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 SLC5A6 Achchuthan Shanmugasundram Source NHS GMS was added to SLC5A6.
Early onset or syndromic epilepsy v5.5 SHQ1 Achchuthan Shanmugasundram Source NHS GMS was added to SHQ1.
Source Expert Review Green was added to SHQ1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 SCN8A Achchuthan Shanmugasundram Mode of inheritance for gene SCN8A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.5 RAB5C Achchuthan Shanmugasundram Source NHS GMS was added to RAB5C.
Source Expert Review Green was added to RAB5C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 PTCD3 Achchuthan Shanmugasundram Source NHS GMS was added to PTCD3.
Source Expert Review Green was added to PTCD3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 PPP1R3F Achchuthan Shanmugasundram Source NHS GMS was added to PPP1R3F.
Source Expert Review Green was added to PPP1R3F.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 PLA2G6 Achchuthan Shanmugasundram Source NHS GMS was added to PLA2G6.
Source Expert Review Green was added to PLA2G6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 PIP5K1C Achchuthan Shanmugasundram Source NHS GMS was added to PIP5K1C.
Source Expert Review Green was added to PIP5K1C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 PIGM Achchuthan Shanmugasundram Source Expert Review Green was added to PIGM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 PABPC1 Achchuthan Shanmugasundram Source NHS GMS was added to PABPC1.
Source Expert Review Green was added to PABPC1.
Mode of inheritance for gene PABPC1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 MAST4 Achchuthan Shanmugasundram Source NHS GMS was added to MAST4.
Source Expert Review Green was added to MAST4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 LETM1 Achchuthan Shanmugasundram Source NHS GMS was added to LETM1.
Source Expert Review Green was added to LETM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 KDM6B Achchuthan Shanmugasundram Source Expert Review Green was added to KDM6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 KCNH5 Achchuthan Shanmugasundram Source Expert Review Green was added to KCNH5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 HECTD4 Achchuthan Shanmugasundram Source Expert Review Green was added to HECTD4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 ESAM Achchuthan Shanmugasundram Source NHS GMS was added to ESAM.
Source Expert Review Green was added to ESAM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 EIF4A2 Achchuthan Shanmugasundram Source NHS GMS was added to EIF4A2.
Source Expert Review Green was added to EIF4A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 DNAJC6 Achchuthan Shanmugasundram Source Expert Review Green was added to DNAJC6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 CRELD1 Achchuthan Shanmugasundram Source NHS GMS was added to CRELD1.
Source Expert Review Green was added to CRELD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 CNOT9 Achchuthan Shanmugasundram Source NHS GMS was added to CNOT9.
Source Expert Review Green was added to CNOT9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 CACNB4 Achchuthan Shanmugasundram Source Expert Review Red was added to CACNB4.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v5.5 ATP6V0C Achchuthan Shanmugasundram Source NHS GMS was added to ATP6V0C.
Source Expert Review Green was added to ATP6V0C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 ASL Achchuthan Shanmugasundram Source NHS GMS was added to ASL.
Source Expert Review Green was added to ASL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 ARF3 Achchuthan Shanmugasundram Source NHS GMS was added to ARF3.
Source Expert Review Green was added to ARF3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.5 AGO1 Achchuthan Shanmugasundram Source NHS GMS was added to AGO1.
Source Expert Review Green was added to AGO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v5.4 SPTBN4 Arina Puzriakova Phenotypes for gene: SPTBN4 were changed from Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519 to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, OMIM:617519
Early onset or syndromic epilepsy v5.3 ISCA-46743-Gain Arina Puzriakova changed review comment from: The rating of this region has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval. Evidence: multiple unrelated cases curated in ClinGen plus several others - sufficient evidence for this region. Phenotype: syndromic intellectual disability (congenital anomalies, behavioural problems and facial dysmorphism). Modulated phenotype in females is reported.; to: The rating of this region has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' following NHS Genomic Medicine Service approval. Evidence: multiple unrelated cases curated in ClinGen plus several others - sufficient evidence for this region. Phenotype: syndromic intellectual disability (congenital anomalies, behavioural problems and facial dysmorphism), seizures in about 30%. Modulated phenotype in females is reported.
Early onset or syndromic epilepsy v5.3 ISCA-46743-Gain Arina Puzriakova reviewed Region: ISCA-46743-Gain: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v5.3 ISCA-46743-Gain Arina Puzriakova Publications for Region: ISCA-46743-Gain were set to
Early onset or syndromic epilepsy v5.2 ISCA-46743-Gain Arina Puzriakova Region: ISCA-46743-Gain was added
Region: ISCA-46743-Gain was added to Early onset or syndromic epilepsy. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46743-Gain was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2024-05-01
Early onset or syndromic epilepsy v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Early onset or syndromic epilepsy v4.196 ZNFX1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: ZNFX1.
Early onset or syndromic epilepsy v4.196 YIF1B Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: YIF1B.
Early onset or syndromic epilepsy v4.196 TRIT1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: TRIT1.
Early onset or syndromic epilepsy v4.196 OTUD7A Achchuthan Shanmugasundram Tag gene-checked was removed from gene: OTUD7A.
Early onset or syndromic epilepsy v4.196 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Microcephalic osteodysplastic primordial dwarfism, type I 210710 to Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710
Early onset or syndromic epilepsy v4.195 GLI3 Arina Puzriakova Mode of inheritance for gene: GLI3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.194 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Early onset or syndromic epilepsy v4.193 DENND5B Sarah Leigh Classified gene: DENND5B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.193 DENND5B Sarah Leigh Gene: dennd5b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.192 DENND5B Sarah Leigh edited their review of gene: DENND5B: Changed rating: AMBER
Early onset or syndromic epilepsy v4.192 DENND5B Sarah Leigh gene: DENND5B was added
gene: DENND5B was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: DENND5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DENND5B were set to 38387458
Phenotypes for gene: DENND5B were set to DENND5B associated neurodevelopmental disorder
Review for gene: DENND5B was set to GREEN
Added comment: DENND5B variants have not previously been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38387458 reports five de novo missense variants in five unrelated cases. The carriers of these DENND5B variants have a neurodevelopmental disorder, which is characterized by psychomotor delay (5/5 cases), intellectual disability, ranging from severe to mild (3/5 cases, although one of the negative cases was a 2 year old child, who was considered to be too young to make the assessment, although the DD/intellectual disability phenotype was considered to be moderate in this case), epilepsy (2/5 cases) and hypotonia (4/5 cases). The authors of PMID: 38387458 also report the functional effects of the DENND5B variants, which revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. They conclude that this effect is likely to be caused by the predicted disruption of protein folding in the variant DENND5B peptide.
Sources: Literature
Early onset or syndromic epilepsy v4.191 TBC1D2B Sarah Leigh edited their review of gene: TBC1D2B: Added comment: TBC1D2B variants have been associated with Neurodevelopmental disorder with seizures and gingival overgrowth (OMIM:619323) and as definitive Gen2Phen gene for TBC1D2B-related neurodevelopmental disorder. So far, 11 TBC1D2B variants have been reported in 8 unrelated families. Global developmental delay (HP:0001263) was reported in 5/8 families, mental deterioration (HP:0001268) was seen in 5/8 families and seizures (HP:0001250) were reported in 8/8 families (four of these were controlled with medication)(PMID: 38374468).; Changed rating: GREEN
Early onset or syndromic epilepsy v4.191 TBC1D2B Sarah Leigh Publications for gene: TBC1D2B were set to 32623794
Early onset or syndromic epilepsy v4.190 TBC1D2B Sarah Leigh Phenotypes for gene: TBC1D2B were changed from Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality to Neurodevelopmental disorder with seizures and gingival overgrowth, OMIM:619323; neurodevelopmental disorder with seizures and gingival overgrowth, MONDO:0859148
Early onset or syndromic epilepsy v4.188 SLC32A1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has relevant phenotypes listed in OMIM (Developmental and epileptic encephalopathy 114, OMIM:620774 and Generalized epilepsy with febrile seizures plus, type 12, OMIM:620755)
Early onset or syndromic epilepsy v4.188 SLC32A1 Arina Puzriakova Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214 to Developmental and epileptic encephalopathy 114, OMIM:620774; Generalized epilepsy with febrile seizures plus, type 12, OMIM:620755
Early onset or syndromic epilepsy v4.187 SLC32A1 Arina Puzriakova Tag gene-checked was removed from gene: SLC32A1.
Early onset or syndromic epilepsy v4.187 CAPRIN1 Arina Puzriakova Publications for gene: CAPRIN1 were set to 35979925
Early onset or syndromic epilepsy v4.186 CAPRIN1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636)
Early onset or syndromic epilepsy v4.186 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behavior; Seizures to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
Early onset or syndromic epilepsy v4.185 CAPRIN1 Arina Puzriakova Tag gene-checked was removed from gene: CAPRIN1.
Early onset or syndromic epilepsy v4.185 WNK3 Arina Puzriakova Tag gene-checked was removed from gene: WNK3.
Early onset or syndromic epilepsy v4.185 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from X-linked intellectual disability, MONDO:0100284 to Prieto syndrome, OMIM:309610; Intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v4.184 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, 308300 to Incontinentia pigmenti, OMIM:308300
Early onset or syndromic epilepsy v4.183 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from Microcephaly-capillary malformation syndrome 614261 to Microcephaly-capillary malformation syndrome, OMIM:614261
Early onset or syndromic epilepsy v4.182 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 603387 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Early onset or syndromic epilepsy v4.181 SNF8 Achchuthan Shanmugasundram Classified gene: SNF8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.181 SNF8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated patients reported with seizures and hence this gene should be rated amber with current evidence.
Early onset or syndromic epilepsy v4.181 SNF8 Achchuthan Shanmugasundram Gene: snf8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.180 SNF8 Achchuthan Shanmugasundram gene: SNF8 was added
gene: SNF8 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNF8 were set to 38423010
Phenotypes for gene: SNF8 were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: SNF8 was set to AMBER
Added comment: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8.

The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous.

Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v4.179 SPATA5 Arina Puzriakova Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome 616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Early onset or syndromic epilepsy v4.178 PCLO Sarah Leigh Classified gene: PCLO as Red List (low evidence)
Early onset or syndromic epilepsy v4.178 PCLO Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be Amber on this panel.
Early onset or syndromic epilepsy v4.178 PCLO Sarah Leigh Gene: pclo has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.177 ZNFX1 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.492
Early onset or syndromic epilepsy v4.177 ZNFX1 Sarah Leigh gene: ZNFX1 was added
gene: ZNFX1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q1_24_promote_green, Q1_24_NHS_review tags were added to gene: ZNFX1.
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNFX1 were set to 33876776; 33872655
Phenotypes for gene: ZNFX1 were set to Immunodeficiency 91 and hyperinflammation, OMIM:619644; immunodeficiency 91 and hyperinflammation, MONDO:0030491
Early onset or syndromic epilepsy v4.176 SRPX2 Arina Puzriakova Phenotypes for gene: SRPX2 were changed from ?Rolandic epilepsy, mental retardation, and speech dyspraxia 300643 to ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, OMIM:300643
Early onset or syndromic epilepsy v4.175 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219
Early onset or syndromic epilepsy v4.174 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Red List (low evidence)
Early onset or syndromic epilepsy v4.174 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.173 SLC5A6 Sarah Leigh edited their review of gene: SLC5A6: Added comment: There is insufficient evidence of epilepsy associated with SLC5A6 variants (PMID: 35013551; 38036278; 38012394; 37391029; 31754459) for this gene to be rated as Amber on the Early onset or syndromic epilepsy, therefore it have been demoted to Red.; Changed rating: RED
Early onset or syndromic epilepsy v4.173 SLC5A6 Sarah Leigh Tag watchlist was removed from gene: SLC5A6.
Tag for-review was removed from gene: SLC5A6.
Tag to_be_confirmed_NHSE was removed from gene: SLC5A6.
Early onset or syndromic epilepsy v4.173 ANK2 Achchuthan Shanmugasundram Classified gene: ANK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.173 ANK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.173 ANK2 Achchuthan Shanmugasundram Gene: ank2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.172 ANK2 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: ANK2.
Early onset or syndromic epilepsy v4.172 ANK2 Achchuthan Shanmugasundram changed review comment from: PMID:37195288 reported 12 individuals with heterozygous de novo LoF variants in ANK2, of which seven patients had early-onset epilepsy, with an onset of epilepsy before the age of 2 years. 4 patients had neonatal onset epilepsy. 1 patient had bilateral tonic-clinic seizures at 3 years of age. Another patient had focal epilepsy with focal motor seizures.
Sources: Literature; to: PMID:37195288 reported 12 individuals with heterozygous de novo LoF variants in ANK2 and with a complex neurodevelopmental disorder comprising intellectual disability, autism spectrum disorder and early-onset epilepsy. Seven of 12 patients had early-onset epilepsy, with an onset of epilepsy before the age of 2 years. 4 patients had neonatal onset epilepsy. 1 patient had bilateral tonic-clinic seizures at 3 years of age. Another patient had focal epilepsy with focal motor seizures.
Sources: Literature
Early onset or syndromic epilepsy v4.172 ANK2 Achchuthan Shanmugasundram gene: ANK2 was added
gene: ANK2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 37195288
Phenotypes for gene: ANK2 were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: ANK2 was set to GREEN
Added comment: PMID:37195288 reported 12 individuals with heterozygous de novo LoF variants in ANK2, of which seven patients had early-onset epilepsy, with an onset of epilepsy before the age of 2 years. 4 patients had neonatal onset epilepsy. 1 patient had bilateral tonic-clinic seizures at 3 years of age. Another patient had focal epilepsy with focal motor seizures.
Sources: Literature
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram changed review comment from: PMID:30055040 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE). PMID:34778950 reported the comparison of these variants with a de novo variant in the voltage sensor (p.Ala261Ter) that was identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).; to: PMID:30055040 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE). PMID:34778950 reported the comparison of the three variants from PMID:30055040 with a de novo variant in the voltage sensor (p.Ala261Ter) that was identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram changed review comment from: PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:34778950 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE) and a de novo variant in the voltage sensor (p.Ala261Ter) identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).; to: PMID:30055040 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE). PMID:34778950 reported the comparison of these variants with a de novo variant in the voltage sensor (p.Ala261Ter) that was identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram Classified gene: KCNA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic KCNA1 variants with epilepsy/ epileptic encephalopathy and hence this gene can be promoted to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram Gene: kcna1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.170 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771; 24578548; 31586945; 32316562; 34778950
Early onset or syndromic epilepsy v4.169 KCNA1 Achchuthan Shanmugasundram edited their review of gene: KCNA1: Changed publications to: 30055040, 31586945, 32316562, 34778950
Early onset or syndromic epilepsy v4.169 KCNA1 Achchuthan Shanmugasundram changed review comment from: PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:34778950 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients with severe developmental and epileptic encephalopathy (DEE) and a de novo variant in the voltage sensor (p.Ala261Ter) identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).; to: PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:34778950 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE) and a de novo variant in the voltage sensor (p.Ala261Ter) identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).
Early onset or syndromic epilepsy v4.169 KCNA1 Achchuthan Shanmugasundram Phenotypes for gene: KCNA1 were changed from Episodic ataxia/myokymia syndrome 160120 to Episodic ataxia/ myokymia syndrome, OMIM:160120; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.168 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771; 24578548
Early onset or syndromic epilepsy v4.167 KCNA1 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.166 KCNA1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNA1.
Tag Q1_24_NHS_review tag was added to gene: KCNA1.
Early onset or syndromic epilepsy v4.166 KCNA1 Achchuthan Shanmugasundram reviewed gene: KCNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31586945, 32316562, 34778950; Phenotypes: epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.166 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.166 CAMSAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.166 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.165 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: CAMSAP1.
Early onset or syndromic epilepsy v4.165 CAMSAP1 Achchuthan Shanmugasundram gene: CAMSAP1 was added
gene: CAMSAP1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to Cortical dysplasia, complex, with other brain malformations 12, OMIM:620316
Review for gene: CAMSAP1 was set to GREEN
Added comment: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Early onset or syndromic epilepsy v4.164 KCNA1 Tracy Lester Deleted their comment
Early onset or syndromic epilepsy v4.164 KCNA1 Tracy Lester edited their review of gene: KCNA1: Added comment: There have been several recent reports that show de novo missense variants in specific regions of this gene are associated with epileptic encephalopathy, supported by functional studies, and gene now meets criteria to be green for this phenotype; Changed rating: GREEN; Changed publications to: 24578548, 3055040, 34778950; Changed phenotypes to: epilep
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh commented on gene: MADD: Apnoea is a feature of DEEAH syndrome (OMIM:619004) and Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (OMIM:619005), both of which are caused by biallelic MADD variants (PMID: 32761064).
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562
Early onset or syndromic epilepsy v4.163 SLC5A6 Helen Lord edited their review of gene: SLC5A6: Added comment: PMID 35013551 Holling et al, 2022 - reporting 5 individuals from 3 families with motor neuropathies. Hom variant c.1285A>G p.(Ser429Gly) in 3 aff siblings and a simplex patient; and a third family where proband had a mat inherited c.280C>T p.(Arg94*) and a pat inherited c.485A>G p.(Tyr162Cys). in silico tools suggest missense variants affect function. No mention of epilepsy in any of these individuals.

PMID 38036278 Hsieh et al 2023 - Family with compound het SLC5A6 missense variants reported. No mention of epilepsy in affected individuals.

PMID 38012394 Utsuno et al 2024 - 3 sibs from a Japanese family with periventricular brain cysts and motor developmental delay - all compund het for SLC5A6 missense variants - no mention of epilepsy/seizure in any of these sibs.

PMID 37391029 Montomoli et al 2023 - 3 members of the same family - Patient 2 had a generalised tonic-clonic seizre and EEG showed sharp waves in left centro-temporal region. No mention of seizures at follow up at 24 years of age, and no mention prior to this seizure but lots of other clinical features. All affecteds had a hom fs SLC5A6 variant, parents het. Table summarising cases showed epilepsy in 2/13 case - patient 2 in this paper and the Byrne et al paper.

PMID 31754459 Byrne et al - see review 31/01/2021.

No new evidence to support a stronger link with SLC5A6 and an epilepsy phenotype.; Changed publications to: 35013551, 38036278, 38012394, 37391029, 31754459, 27904971
Early onset or syndromic epilepsy v4.163 CACNB4 Helen Lord edited their review of gene: CACNB4: Added comment: PMID 35813387 - Naseer et al, 2022: WES i one family and targeted sequencing of SCN1A and CACNB4 in 25 sporadic epilepsy patients. 3 different unrelated patients found to have the c.78_79insG variant in CACNB4. Do mention that tecently het CACNB4 mutations are not linked with epilepsy [Heyne et al 2019] and that het mutated animal model did not show any tyoe of deformities [Coba et al, 2012].

Also PMID32176688 - see previous occurence where identifed homozygously.; Changed rating: AMBER; Changed publications to: 35813387
Early onset or syndromic epilepsy v4.163 MADD Sarah Leigh edited their review of gene: MADD: Added comment: Comments from Karen Stals (Royal Devon and Exeter Hospital), 4 Dec 2023: Apnoea a presenting feature in 13/14 patients with MADD-related disorder with biallelic MADD variants in Schneeberger et al 2020 PMID: 32761064. Identified biallelic variants in this gene in a patient with a consistent phenotype.; Changed rating: GREEN; Changed publications to: 32761064
Early onset or syndromic epilepsy v4.163 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Leukodystrophy, hypomyelinating, 9 616140 to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Early onset or syndromic epilepsy v4.162 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to 21834044; 20890278; 20729831; 28377545
Early onset or syndromic epilepsy v4.161 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317 to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Early onset or syndromic epilepsy v4.160 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Classified gene: HSD17B10 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - seizures can be a reported feature of HSD10 disease (PMID: 12872843; 22132097; 26950678; 27295195; 34765396)
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Gene: hsd17b10 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.158 HSD17B10 Arina Puzriakova gene: HSD17B10 was added
gene: HSD17B10 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_24_promote_green tags were added to gene: HSD17B10.
Mode of inheritance for gene: HSD17B10 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: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Phenotypes for gene: HSD17B10 were set to HSD10 mitochondrial disease, OMIM:300438
Review for gene: HSD17B10 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for 2-methyl-3-hydroxybutyrylL-coA dehydrogenase deficiency and for intellectual development disorder syndromic X-linked type 10. Multiple unrelated individuals (at least 8 variants) with supportive functional studies reported in the literature, including some affected female carriers presenting with mild to moderate developmental delay or intellectual disability.
Phenotype in severely affected males comprises developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation.
Sources: Literature
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Classified gene: COL4A3BP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Gene: col4a3bp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova commented on gene: COL4A3BP: Added new-gene-name tag, new approved HGNC gene symbol for COL4A3BP is CERT1
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova Tag new-gene-name tag was added to gene: COL4A3BP.
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova gene: COL4A3BP was added
gene: COL4A3BP was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_24_promote_green tags were added to gene: COL4A3BP.
Mode of inheritance for gene: COL4A3BP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL4A3BP were set to 25533962; 33347465; 34688657; 36976648; 37892645
Phenotypes for gene: COL4A3BP were set to Intellectual developmental disorder, autosomal dominant 34, OMIM:616351
Review for gene: COL4A3BP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and in Gene2Phenotype (definitive disease confidence category for CERT1-related INTELLECTUAL DISABILITY)

At least 35 cases have been reported in literature with heterozygous variants. Seizures were observed in at least 19 individuals.
Sources: Literature
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Classified gene: KCNA3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:37964487 and reviewed by Gavin Ryan, epilepsy was present in eight of twelve patients for whom detailed clinical information was available. Hence, this gene can be promoted to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Gene: kcna3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.154 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Intellectual disability; Developmental Delay; Epilepsy to Neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.153 KCNA3 Achchuthan Shanmugasundram Publications for gene: KCNA3 were set to PMID: 37964487
Early onset or syndromic epilepsy v4.152 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNA3.
Tag Q1_24_NHS_review tag was added to gene: KCNA3.
Early onset or syndromic epilepsy v4.152 KCNA3 Achchuthan Shanmugasundram reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.152 KCNA3 Gavin Ryan gene: KCNA3 was added
gene: KCNA3 was added to Early onset or syndromic epilepsy. Sources: Expert Review
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA3 were set to PMID: 37964487
Phenotypes for gene: KCNA3 were set to Intellectual disability; Developmental Delay; Epilepsy
Penetrance for gene: KCNA3 were set to unknown
Review for gene: KCNA3 was set to GREEN
Added comment: Soldovieri et al identified 14 de novo missense variants in KCNA3 gene. The majority of individuals presented with ID, developmental delay, and epilepsy, amongst other features. Functional studies showed loss-of-function effects for some variants and possible gain-of-function for others. One of these variants has also been identified in NHS GMS WGS patient with consistent features.
Sources: Expert Review
Early onset or syndromic epilepsy v4.152 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400 to Hyperprolinemia, type I, OMIM:239500; hyperprolinemia type 1, MONDO:0009400
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified to date in Genomics England's Clinical Variant Archive (CVA) dataset are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variants (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova Publications for gene: PRICKLE1 were set to 18976727; 21276947
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova edited their review of gene: PRICKLE1: Changed publications to: 30564977, 30345727, 21276947, 26727662, 29790814, 31875159, 31035234, 15634728, 15642921, 16376507, 18976727, 20301774
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Tag Q1_24_demote_amber tag was added to gene: PRICKLE1.
Tag Q1_24_expert_review tag was added to gene: PRICKLE1.
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Classified gene: PRICKLE1 as Green List (high evidence)
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Added comment: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variants (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Gene: prickle1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v4.149 PRICKLE1 Arina Puzriakova Tag disputed tag was added to gene: PRICKLE1.
Early onset or syndromic epilepsy v4.149 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904 to Epilepsy, progressive myoclonic 1B, OMIM:612437
Early onset or syndromic epilepsy v4.148 MTOR Sarah Leigh Publications for gene: MTOR were set to
Early onset or syndromic epilepsy v4.147 MTOR Sarah Leigh Phenotypes for gene: MTOR were changed from Focal cortical dysplasia, type II, somatic to Smith-Kingsmore syndrome, OMIM:616638; macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, MONDO:0014716; Focal cortical dysplasia, type II, somatic, OMIM:607341isolated focal cortical dysplasia type II, MONDO:0011818
Early onset or syndromic epilepsy v4.146 CACNB4 Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v4.146 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Epilepsy, generalized, with febrile seizures plus, type 1 604233 AD; Epileptic encephalopathy, early infantile, 52 617350 AR to Developmental and epileptic encephalopathy 52, OMIM:617350 (AR); Generalized epilepsy with febrile seizures plus, type 1, OMIM:604233 (AD)
Early onset or syndromic epilepsy v4.145 SCN1B Arina Puzriakova Publications for gene: SCN1B were set to 12011299; 16205844; 9697698
Early onset or syndromic epilepsy v4.144 TRIP13 Achchuthan Shanmugasundram Tag founder-effect was removed from gene: TRIP13.
Early onset or syndromic epilepsy v4.144 TRIP13 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: TRIP13.
Early onset or syndromic epilepsy v4.144 PCLO Dmitrijs Rots reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh edited their review of gene: COX11: Added comment: Epileptic seizures have been seen in 2/3 unrelated cases of Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275) carrying two different COX11 variants (PMID: 36030551;38068960).; Changed rating: AMBER
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh Tag Q4_23_promote_green was removed from gene: COX11.
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh Entity copied from Mitochondrial disorders v4.142
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh gene: COX11 was added
gene: COX11 was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber
Q4_23_promote_green tags were added to gene: COX11.
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551; 38068960
Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Classified gene: TRIT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Gene: trit1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.142 TRIT1 Eleanor Williams gene: TRIT1 was added
gene: TRIT1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q4_23_promote_green tags were added to gene: TRIT1.
Mode of inheritance for gene: TRIT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIT1 were set to 28185376; 24901367
Phenotypes for gene: TRIT1 were set to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Added comment: Associated with Combined oxidative phosphorylation deficiency 35, OMIM: 617873 (AR)

4 cases reported with biallelic variants in this gene and a syndromic phenotype that includes epilepsy.

PMID: 28185376 - Kernohan et al 2017 - report 4 individuals from 3 unrelated families with recessive mutations in TRIT1 identified by WES and confirmed by Sanger sequencing. Parents were heterozygous for the variants. All patients presented with syndrome features which included microcephaly, profound developmental delay, hypotonia, epilepsy, and brain anomalies.

PMID: 24901367 - Yarham et al 2014 - used WES to identify a homozygous p.Arg323Gln mutation in the TRIT1 gene in 2 affected children that segregates within a consanguineous UK-Pakistani family. The children encephalopathy and myoclonic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v4.141 ASL Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ASL.
Tag Q4_23_NHS_review tag was added to gene: ASL.
Early onset or syndromic epilepsy v4.141 ASL Eleanor Williams Publications for gene: ASL were set to 36994644; 21744316; 28251416
Early onset or syndromic epilepsy v4.140 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815 to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; seizure, HP:0001250
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Classified gene: ASL as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation of green rating subject to GMS review. 13 cases reported with ASA with epilepsy as a feature and variants in the ASL gene.
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Gene: asl has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.138 ASL Eleanor Williams commented on gene: ASL
Early onset or syndromic epilepsy v4.138 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Seizure; Neurodevelopmental delay; Intellectual disability; Autism; Abnormality of movement; Ataxia; Hepatomegaly; Elevated hepatic transaminase; Renal tubular dysfunction; Abnormal hair morphology to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Early onset or syndromic epilepsy v4.136 SHQ1 Sarah Leigh Entity copied from Childhood onset dystonia, chorea or related movement disorder v3.61
Early onset or syndromic epilepsy v4.136 SHQ1 Sarah Leigh gene: SHQ1 was added
gene: SHQ1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: SHQ1.
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611; 36189577
Phenotypes for gene: SHQ1 were set to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Early onset or syndromic epilepsy v4.135 ALPL Achchuthan Shanmugasundram Tag drug-indication was removed from gene: ALPL.
Early onset or syndromic epilepsy v4.135 TEFM Achchuthan Shanmugasundram Classified gene: TEFM as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.135 TEFM Achchuthan Shanmugasundram Gene: tefm has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram changed review comment from: Three patients from two unrelated families with biallelic TEFM variants had seizures.; to: PMID:36823193 reported seven individuals from five unrelated families presenting with mitochondrial respiratory chain deficiency and they were identified with biallelic TEFM variants. Three of these patients from two unrelated families had seizures.
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram reviewed gene: TEFM: Rating: AMBER; Mode of pathogenicity: None; Publications: 36823193; Phenotypes: Combined oxidative phosphorylation deficiency 58, OMIM:620451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v4.116
Early onset or syndromic epilepsy v4.134 TEFM Achchuthan Shanmugasundram gene: TEFM was added
gene: TEFM was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Combined oxidative phosphorylation deficiency 58, OMIM:620451
Early onset or syndromic epilepsy v4.133 ASL Nour Elkhateeb changed review comment from: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60% (PMID 36994644, 21744316, 28251416). The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients (PMID: 36994644).
Sources: Literature, ClinGen; to: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60% (PMID 36994644, 21744316, 28251416). The epilepsy phenotype occurs early in the natural history of ASA, with a median between at 2-5.5 years (PMID 36994644, 21744316, 28251416). The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients (PMID: 36994644).
Sources: Literature, ClinGen
Early onset or syndromic epilepsy v4.133 ASL Nour Elkhateeb changed review comment from: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60%. The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients.
Sources: Literature, ClinGen; to: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60% (PMID 36994644, 21744316, 28251416). The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients (PMID: 36994644).
Sources: Literature, ClinGen
Early onset or syndromic epilepsy v4.133 ASL Nour Elkhateeb gene: ASL was added
gene: ASL was added to Early onset or syndromic epilepsy. Sources: Literature,ClinGen
Mode of inheritance for gene: ASL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASL were set to 36994644; 21744316; 28251416
Phenotypes for gene: ASL were set to Seizure; Neurodevelopmental delay; Intellectual disability; Autism; Abnormality of movement; Ataxia; Hepatomegaly; Elevated hepatic transaminase; Renal tubular dysfunction; Abnormal hair morphology
Penetrance for gene: ASL were set to Complete
Review for gene: ASL was set to GREEN
Added comment: Epilepsy is reported as a common phenotype in individuals with argininosuccinic aciduria (ASA) with incidence between 42%-60%. The epilepsy phenotype occurs early in the natural history of ASA. The epilepsy phenotype is severe, with a significant cohort of patients presenting with pharmacoresistant seizures, and with status epilepticus. Epilepsy onset preceded ASA diagnosis in several reported patients.
Sources: Literature, ClinGen
Early onset or syndromic epilepsy v4.133 CLCN2 Sarah Leigh commented on gene: CLCN2: The association between CLCN2 and epilepsy has been refuted by ClinGen Epilepsy Expert Panel on the meeting date March 15, 2022 (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba2a1616-b3d7-4762-a546-c838333db683-2022-03-15T040000.000Z)
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh commented on gene: MAGI2: Sarah Leigh commented on gene: MAGI2: Clingen refuted association with epilepsy https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d622b88-9c77-47f8-93b1-808517da0cff-2023-10-17T190000.000Z?page=1&size=25&search=
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v4.133 CACNB4 Sarah Leigh Tag refuted tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v4.133 CACNB4 Sarah Leigh Tag Q4_23_demote_red tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v4.133 CACNB4 Sarah Leigh edited their review of gene: CACNB4: Added comment: The gene disease association between CACNB4 and epilepsy has been refuted by ClinGen Epilepsy Gene Curation Expert Panel on July 5, 2022 (SOP Version 9)(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2fad131-8e91-4874-9394-8b86d6d62abb-2022-07-05T160000.000Z?page=1&size=25&search= ); Changed rating: RED
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh Tag disputed was removed from gene: MAGI2.
Tag refuted tag was added to gene: MAGI2.
Early onset or syndromic epilepsy v4.133 MAGI2 Sarah Leigh commented on gene: MAGI2: Clingen refuted association with epilepsy https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d622b88-9c77-47f8-93b1-808517da0cff-2023-10-17T190000.000Z?page=1&size=25&search=
Early onset or syndromic epilepsy v4.133 ZBTB47 Sarah Leigh changed review comment from: Asked the opinion of Helen Brittain (Genomics England, Clinical Fellow), regarding the recommended rating of ZBTB47.; to: The opinion of Helen Brittain (Genomics England, Clinical Fellow), was that ZBTB47 should be green on the Intellectual disability and Early onset or syndromic epilepsy panels.
Early onset or syndromic epilepsy v4.133 ZBTB47 Sarah Leigh edited their review of gene: ZBTB47: Added comment: ZBTB47 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37743782 reports five unrelated patients with de novo missense variants in ZBTB47 (c.2039A>G, p.(Glu680Gly) in one patient and c.1429G>A, p.(Glu477Lys) in four others), with a phenotype that included developmental delay, intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities.; Changed rating: GREEN
Early onset or syndromic epilepsy v4.133 ZBTB47 Sarah Leigh Phenotypes for gene: ZBTB47 were changed from Neurodevelopmental disorder, MONDO; 0700092 to Neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v4.132 ZBTB47 Sarah Leigh Phenotypes for gene: ZBTB47 were changed from Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related to Neurodevelopmental disorder, MONDO; 0700092
Early onset or syndromic epilepsy v4.131 ZBTB47 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ZBTB47.
Early onset or syndromic epilepsy v4.131 ZBTB47 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.337
Early onset or syndromic epilepsy v4.131 ZBTB47 Sarah Leigh gene: ZBTB47 was added
gene: ZBTB47 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: ZBTB47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB47 were set to 37743782
Phenotypes for gene: ZBTB47 were set to Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related
Early onset or syndromic epilepsy v4.130 MAST4 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.337
Early onset or syndromic epilepsy v4.130 MAST4 Sarah Leigh gene: MAST4 was added
gene: MAST4 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: MAST4.
Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST4 were set to 36910266; 33057194
Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh Tag Q4_23_NHS_review was removed from gene: PIGM.
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).
Absence seizures were apparent in 5/7 individuals from 5/6 families with OMIM:610293 biallelic for rs587776528 (table 1, PMID: 31445883).
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.77
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh gene: PIGM was added
gene: PIGM was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber,London North GLH
promoter, non-coding-known-pathogenic, Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: PIGM.
Mode of inheritance for gene: PIGM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGM were set to 27604308; 16767100; 25293775; 17442906; 31445883
Phenotypes for gene: PIGM were set to Glycosylphosphatidylinositol deficiency, OMIM:610293
Early onset or syndromic epilepsy v4.128 PTCD3 Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.64
Early onset or syndromic epilepsy v4.128 PTCD3 Sarah Leigh gene: PTCD3 was added
gene: PTCD3 was added to Early onset or syndromic epilepsy. Sources: Expert list,Expert Review Amber
Q4_23_promote_green tags were added to gene: PTCD3.
Mode of inheritance for gene: PTCD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCD3 were set to 30607703; 30706245; 36450274
Phenotypes for gene: PTCD3 were set to ?Combined oxidative phosphorylation deficiency 51, OMIM:619057; combined oxidative phosphorylation deficiency 51, MONDO:0033631
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>3 unrelated cases and supporting functional evidence) for the promotion of this gene to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.127 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>3 unrelated cases and supporting functional evidence) for the promotion of this gene to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (>3 unrelated cases and supporting functional evidence) for the promotion of this gene to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.126 ARF3 Achchuthan Shanmugasundram Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.125 ARF3 Achchuthan Shanmugasundram Tag watchlist was removed from gene: ARF3.
Tag Q4_23_promote_green tag was added to gene: ARF3.
Early onset or syndromic epilepsy v4.125 ARF3 Achchuthan Shanmugasundram Publications for gene: ARF3 were set to 34346499
Early onset or syndromic epilepsy v4.124 ARF3 Achchuthan Shanmugasundram reviewed gene: ARF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34346499, 36369169; Phenotypes: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.122 KCNH5 Arina Puzriakova Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; epilepsy, MONDO:0005027 to Developmental and epileptic encephalopathy 112, OMIM:620537
Early onset or syndromic epilepsy v4.120 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing was removed from gene: MT-CO3.
Early onset or syndromic epilepsy v4.120 PLA2G6 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: PLA2G6.
Early onset or syndromic epilepsy v4.120 PLA2G6 Sarah Leigh edited their review of gene: PLA2G6: Changed rating: GREEN
Early onset or syndromic epilepsy v4.120 PLA2G6 Sarah Leigh commented on gene: PLA2G6: Sixteen cases of PLA2G6-associated neurodegeneration (PLAN) were examined in PMID: 30340910. Seizures were evident in 5/10 cases with infantile PLAN and in 3/6 cases with childhood PLAN. A total of nine PLA2G6 variants were associated with a phenotype that included seizures.
Early onset or syndromic epilepsy v4.120 PLA2G6 Sarah Leigh Classified gene: PLA2G6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.120 PLA2G6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.120 PLA2G6 Sarah Leigh Gene: pla2g6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.119 PLA2G6 Sarah Leigh Added comment: Comment on phenotypes: PLA2G6-associated neurodegeneration (PLAN)
Early onset or syndromic epilepsy v4.119 PLA2G6 Sarah Leigh Phenotypes for gene: PLA2G6 were changed from PLA2G6-associated neurodegeneration (PLAN); Familial cortical myoclonic tremor with epilepsy (FCMTE); Infantile neuroaxonal dystrophy 1, 256600; Neurodegeneration with brain iron accumulation 2B, 610217 to Infantile neuroaxonal dystrophy 1, OMIM:256600; neurodegeneration with brain iron accumulation 2A, MONDO:0024457; Neurodegeneration with brain iron accumulation 2B, OMIM:610217; neurodegeneration with brain iron accumulation 2B, MONDO:0012444; Parkinson disease 14, autosomal recessive, OMIM:612953; autosomal recessive Parkinson disease 14, MONDO:0013060
Early onset or syndromic epilepsy v4.118 PLA2G6 Sarah Leigh Tag watchlist_moi tag was added to gene: PLA2G6.
Early onset or syndromic epilepsy v4.118 HECTD4 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: HECTD4.
Early onset or syndromic epilepsy v4.118 HECTD4 Achchuthan Shanmugasundram commented on gene: HECTD4: The OMIM entry for this gene is OMIM:620209, which has been cross-checked with both Ensembl and HGNC. Hence, gene-checked tag has been added.
Early onset or syndromic epilepsy v4.118 TRA2B Eleanor Williams Tag gene-checked tag was added to gene: TRA2B.
Early onset or syndromic epilepsy v4.118 TRA2B Eleanor Williams commented on gene: TRA2B
Early onset or syndromic epilepsy v4.118 SLC32A1 Eleanor Williams Tag gene-checked tag was added to gene: SLC32A1.
Early onset or syndromic epilepsy v4.118 SLC32A1 Eleanor Williams commented on gene: SLC32A1
Early onset or syndromic epilepsy v4.118 RHEB Eleanor Williams Tag gene-checked tag was added to gene: RHEB.
Early onset or syndromic epilepsy v4.118 RHEB Eleanor Williams commented on gene: RHEB: This gene is not currently associated with a disease phenotype in OMIM, but checked PMID: 33434304 to make sure it is the same gene listed in the publication as on this panel and it is, so added the gene-checked tag
Early onset or syndromic epilepsy v4.118 PLK1 Eleanor Williams commented on gene: PLK1
Early onset or syndromic epilepsy v4.118 PLK1 Eleanor Williams Tag gene-checked tag was added to gene: PLK1.
Early onset or syndromic epilepsy v4.118 OTUD7A Eleanor Williams Tag gene-checked tag was added to gene: OTUD7A.
Early onset or syndromic epilepsy v4.118 OTUD7A Eleanor Williams commented on gene: OTUD7A
Early onset or syndromic epilepsy v4.118 KLHL20 Eleanor Williams Tag gene-checked tag was added to gene: KLHL20.
Early onset or syndromic epilepsy v4.118 KLHL20 Eleanor Williams commented on gene: KLHL20
Early onset or syndromic epilepsy v4.118 C2orf69 Achchuthan Shanmugasundram changed review comment from: The OMIM entry for this gene is OMIM:619219, which has been crossed checked with both Ensembl and HGNC. Hence, gene-checked tag has been added.; to: The OMIM entry for this gene is OMIM:619219, which has been cross-checked with both Ensembl and HGNC. Hence, gene-checked tag has been added.
Early onset or syndromic epilepsy v4.118 C2orf69 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: C2orf69.
Early onset or syndromic epilepsy v4.118 C2orf69 Achchuthan Shanmugasundram commented on gene: C2orf69
Early onset or syndromic epilepsy v4.118 SPATA5 Achchuthan Shanmugasundram commented on gene: SPATA5
Early onset or syndromic epilepsy v4.118 SPATA5L1 Achchuthan Shanmugasundram commented on gene: SPATA5L1
Early onset or syndromic epilepsy v4.118 SCAF4 Arina Puzriakova Phenotypes for gene: SCAF4 were changed from SCAF4-related Neurodevelopmental Disorder; Intellectual disability; Seizures; Behavioural abnormalities to Fliedner-Zweier syndrome, OMIM:620511
Early onset or syndromic epilepsy v4.117 SCAF4 Arina Puzriakova Tag gene-checked was removed from gene: SCAF4.
Early onset or syndromic epilepsy v4.117 CLDN5 Eleanor Williams Tag gene-checked tag was added to gene: CLDN5.
Early onset or syndromic epilepsy v4.117 CLDN5 Eleanor Williams commented on gene: CLDN5
Early onset or syndromic epilepsy v4.117 AGO1 Arina Puzriakova Classified gene: AGO1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.117 AGO1 Arina Puzriakova Gene: ago1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.116 AGO1 Arina Puzriakova gene: AGO1 was added
gene: AGO1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q4_23_promote_green tags were added to gene: AGO1.
Mode of inheritance for gene: AGO1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AGO1 were set to 25356899; 30213762; 34930816
Phenotypes for gene: AGO1 were set to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, OMIM:620292
Review for gene: AGO1 was set to GREEN
Added comment: Multiple individuals reported with de novo variants in this gene. About half of patients develop seizures, which may be controlled or refractory.

Given that in some patients seizures are a prominent component of their phenotype and there are a sufficient number of individuals to support this gene-disease association, there is enough evidence to promote AGO1 to green status at the next GMS panel update.
Sources: Literature
Early onset or syndromic epilepsy v4.115 CAPRIN1 Eleanor Williams Tag gene-checked tag was added to gene: CAPRIN1.
Early onset or syndromic epilepsy v4.115 CAPRIN1 Eleanor Williams commented on gene: CAPRIN1
Early onset or syndromic epilepsy v4.115 UBAP2L Arina Puzriakova Tag Q1_23_promote_green was removed from gene: UBAP2L.
Early onset or syndromic epilepsy v4.115 TRA2B Arina Puzriakova Tag Q2_23_promote_green was removed from gene: TRA2B.
Early onset or syndromic epilepsy v4.115 STXBP1 Arina Puzriakova Phenotypes for gene: STXBP1 were changed from Developmental and epileptic encephalopathy 4, OMIM:612164; developmental and epileptic encephalopathy, 4, MONDO:0012812 to Developmental and epileptic encephalopathy 4, OMIM:612164
Early onset or syndromic epilepsy v4.114 STXBP1 Arina Puzriakova Tag Q1_23_MOI was removed from gene: STXBP1.
Early onset or syndromic epilepsy v4.114 ST3GAL3 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: ST3GAL3.
Early onset or syndromic epilepsy v4.114 SLC39A8 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: SLC39A8.
Early onset or syndromic epilepsy v4.114 SLC32A1 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: SLC32A1.
Early onset or syndromic epilepsy v4.114 SATB2 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: SATB2.
Early onset or syndromic epilepsy v4.114 SARS Arina Puzriakova Tag Q1_23_promote_green was removed from gene: SARS.
Early onset or syndromic epilepsy v4.114 RHEB Arina Puzriakova Tag Q2_23_promote_green was removed from gene: RHEB.
Early onset or syndromic epilepsy v4.114 RAC3 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: RAC3.
Early onset or syndromic epilepsy v4.114 PPFIBP1 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: PPFIBP1.
Early onset or syndromic epilepsy v4.114 PLXNA1 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: PLXNA1.
Early onset or syndromic epilepsy v4.114 PLK1 Arina Puzriakova Phenotypes for gene: PLK1 were changed from Epilepsy; microcephaly; intellectual disability to developmental and epileptic encephalopathy, MONDO:0100062
Early onset or syndromic epilepsy v4.113 PLK1 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: PLK1.
Early onset or syndromic epilepsy v4.113 OTUD7A Arina Puzriakova Phenotypes for gene: OTUD7A were changed from Epileptic encephalopathy, intellectual disability to developmental and epileptic encephalopathy, MONDO:0100062
Early onset or syndromic epilepsy v4.112 OTUD7A Arina Puzriakova Tag Q2_23_promote_green was removed from gene: OTUD7A.
Early onset or syndromic epilepsy v4.112 NUP214 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: NUP214.
Early onset or syndromic epilepsy v4.112 NEDD4L Arina Puzriakova Tag Q1_23_promote_green was removed from gene: NEDD4L.
Early onset or syndromic epilepsy v4.112 MED11 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: MED11.
Early onset or syndromic epilepsy v4.112 MAGI2 Arina Puzriakova Tag disputed tag was added to gene: MAGI2.
Early onset or syndromic epilepsy v4.112 MAGI2 Arina Puzriakova Tag Q1_23_demote_red was removed from gene: MAGI2.
Early onset or syndromic epilepsy v4.112 KPTN Arina Puzriakova Tag Q1_23_promote_green was removed from gene: KPTN.
Early onset or syndromic epilepsy v4.112 KLHL20 Arina Puzriakova Tag Q4_22_promote_green was removed from gene: KLHL20.
Early onset or syndromic epilepsy v4.112 GRM7 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: GRM7.
Early onset or syndromic epilepsy v4.112 GRIA2 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: GRIA2.
Early onset or syndromic epilepsy v4.112 GCSH Arina Puzriakova Phenotypes for gene: GCSH were changed from ?Glycine encephalopathy, OMIM:605899; Neurodevelopmental disorder, MONDO:0700092 to Multiple mitochondrial dysfunctions syndrome 7, OMIM:620423; Glycine encephalopathy; Transient neonatal hyperglycinemia
Early onset or syndromic epilepsy v4.111 GCSH Arina Puzriakova Tag Q1_23_promote_green was removed from gene: GCSH.
Early onset or syndromic epilepsy v4.111 GABRB1 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: GABRB1.
Early onset or syndromic epilepsy v4.111 FRMD5 Arina Puzriakova Tag Q4_22_promote_green was removed from gene: FRMD5.
Early onset or syndromic epilepsy v4.111 FOXRED1 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: FOXRED1.
Early onset or syndromic epilepsy v4.111 FGFR3 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: FGFR3.
Early onset or syndromic epilepsy v4.111 EXT2 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: EXT2.
Early onset or syndromic epilepsy v4.111 ENTPD1 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: ENTPD1.
Early onset or syndromic epilepsy v4.111 DPH5 Arina Puzriakova Phenotypes for gene: DPH5 were changed from DPH5-related neurodevelopmental disorder to Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties, OMIM:620070
Early onset or syndromic epilepsy v4.110 DPH5 Arina Puzriakova Tag Q4_22_promote_green was removed from gene: DPH5.
Early onset or syndromic epilepsy v4.110 DOLK Arina Puzriakova Tag watchlist was removed from gene: DOLK.
Tag Q1_23_promote_green was removed from gene: DOLK.
Early onset or syndromic epilepsy v4.110 DEPDC5 Arina Puzriakova Tag Q1_23_MOI was removed from gene: DEPDC5.
Early onset or syndromic epilepsy v4.110 CUX2 Arina Puzriakova Tag Q1_23_MOI was removed from gene: CUX2.
Tag Q1_23_NHS_review was removed from gene: CUX2.
Early onset or syndromic epilepsy v4.110 CPLX1 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: CPLX1.
Early onset or syndromic epilepsy v4.110 CLDN5 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: CLDN5.
Early onset or syndromic epilepsy v4.110 CHD4 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: CHD4.
Early onset or syndromic epilepsy v4.110 CAPRIN1 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: CAPRIN1.
Early onset or syndromic epilepsy v4.110 C2orf69 Arina Puzriakova Tag Q2_23_promote_green was removed from gene: C2orf69.
Early onset or syndromic epilepsy v4.110 BAP1 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: BAP1.
Early onset or syndromic epilepsy v4.110 ATP5O Arina Puzriakova Tag Q2_23_promote_green was removed from gene: ATP5O.
Early onset or syndromic epilepsy v4.110 ASXL3 Arina Puzriakova Tag Q1_23_promote_green was removed from gene: ASXL3.
Early onset or syndromic epilepsy v4.110 CPA6 Arina Puzriakova Tag for-review was removed from gene: CPA6.
Tag Q2_23_demote_red was removed from gene: CPA6.
Tag Q2_23_NHS_review was removed from gene: CPA6.
Tag Q2_23_expert_review was removed from gene: CPA6.
Tag refuted tag was added to gene: CPA6.
Early onset or syndromic epilepsy v4.110 UBAP2L Arina Puzriakova reviewed gene: UBAP2L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 TRA2B Arina Puzriakova reviewed gene: TRA2B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 STXBP1 Arina Puzriakova reviewed gene: STXBP1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 ST3GAL3 Arina Puzriakova reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 SLC39A8 Arina Puzriakova reviewed gene: SLC39A8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 SLC32A1 Arina Puzriakova reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 SATB2 Arina Puzriakova reviewed gene: SATB2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 SARS Arina Puzriakova commented on gene: SARS: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v4.110 RHEB Arina Puzriakova edited their review of gene: RHEB: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 RAC3 Arina Puzriakova edited their review of gene: RAC3: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 PPFIBP1 Arina Puzriakova reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 PLXNA1 Arina Puzriakova reviewed gene: PLXNA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 PLK1 Arina Puzriakova reviewed gene: PLK1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 OTUD7A Arina Puzriakova reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 NUP214 Arina Puzriakova reviewed gene: NUP214: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 NEDD4L Arina Puzriakova reviewed gene: NEDD4L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 MED11 Arina Puzriakova reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 MAGI2 Arina Puzriakova reviewed gene: MAGI2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v4.110 KPTN Arina Puzriakova reviewed gene: KPTN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 KLHL20 Arina Puzriakova edited their review of gene: KLHL20: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 GRM7 Arina Puzriakova reviewed gene: GRM7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 GRIA2 Arina Puzriakova reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 GCSH Arina Puzriakova reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 GABRB1 Arina Puzriakova reviewed gene: GABRB1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 FRMD5 Arina Puzriakova commented on gene: FRMD5: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v4.110 FOXRED1 Arina Puzriakova reviewed gene: FOXRED1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 FGFR3 Arina Puzriakova reviewed gene: FGFR3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 EXT2 Arina Puzriakova reviewed gene: EXT2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 ENTPD1 Arina Puzriakova reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 DPH5 Arina Puzriakova reviewed gene: DPH5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 DOLK Arina Puzriakova reviewed gene: DOLK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 DEPDC5 Arina Puzriakova reviewed gene: DEPDC5: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 CUX2 Arina Puzriakova reviewed gene: CUX2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 CPLX1 Arina Puzriakova reviewed gene: CPLX1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 CPA6 Arina Puzriakova reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v4.110 CLDN5 Arina Puzriakova reviewed gene: CLDN5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.110 CHD4 Arina Puzriakova reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 CAPRIN1 Arina Puzriakova reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 C2orf69 Arina Puzriakova edited their review of gene: C2orf69: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.110 BAP1 Arina Puzriakova reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.110 ATP5O Arina Puzriakova commented on gene: ATP5O: The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v4.110 ASXL3 Arina Puzriakova reviewed gene: ASXL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.109 UBAP2L Arina Puzriakova Source NHS GMS was added to UBAP2L.
Source Expert Review Green was added to UBAP2L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 TRA2B Arina Puzriakova Source NHS GMS was added to TRA2B.
Source Expert Review Green was added to TRA2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 STXBP1 Arina Puzriakova Mode of inheritance for gene STXBP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.109 ST3GAL3 Arina Puzriakova Source Expert Review Green was added to ST3GAL3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 SLC39A8 Arina Puzriakova Source NHS GMS was added to SLC39A8.
Source Expert Review Green was added to SLC39A8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 SLC32A1 Arina Puzriakova Source NHS GMS was added to SLC32A1.
Source Expert Review Green was added to SLC32A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 SATB2 Arina Puzriakova Source NHS GMS was added to SATB2.
Source Expert Review Green was added to SATB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 SARS Arina Puzriakova Source NHS GMS was added to SARS.
Source Expert Review Green was added to SARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 RHEB Arina Puzriakova Source NHS GMS was added to RHEB.
Source Expert Review Green was added to RHEB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 RAC3 Arina Puzriakova Source NHS GMS was added to RAC3.
Source Expert Review Green was added to RAC3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 PPFIBP1 Arina Puzriakova Source NHS GMS was added to PPFIBP1.
Source Expert Review Green was added to PPFIBP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 PLXNA1 Arina Puzriakova Source NHS GMS was added to PLXNA1.
Source Expert Review Green was added to PLXNA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 PLK1 Arina Puzriakova Source NHS GMS was added to PLK1.
Source Expert Review Green was added to PLK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 OTUD7A Arina Puzriakova Source NHS GMS was added to OTUD7A.
Source Expert Review Green was added to OTUD7A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 NUP214 Arina Puzriakova Source NHS GMS was added to NUP214.
Source Expert Review Green was added to NUP214.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 NEDD4L Arina Puzriakova Source Expert Review Green was added to NEDD4L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 MED11 Arina Puzriakova Source NHS GMS was added to MED11.
Source Expert Review Green was added to MED11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 MAGI2 Arina Puzriakova Source Expert Review Red was added to MAGI2.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v4.109 KPTN Arina Puzriakova Source Expert Review Green was added to KPTN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 KLHL20 Arina Puzriakova Source NHS GMS was added to KLHL20.
Source Expert Review Green was added to KLHL20.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 GRM7 Arina Puzriakova Source NHS GMS was added to GRM7.
Source Expert Review Green was added to GRM7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 GRIA2 Arina Puzriakova Source Expert Review Green was added to GRIA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 GCSH Arina Puzriakova Source Expert Review Green was added to GCSH.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 GABRB1 Arina Puzriakova Source Expert Review Green was added to GABRB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 FRMD5 Arina Puzriakova Source NHS GMS was added to FRMD5.
Source Expert Review Green was added to FRMD5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 FOXRED1 Arina Puzriakova Source Expert Review Green was added to FOXRED1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 FGFR3 Arina Puzriakova Source Expert Review Green was added to FGFR3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 EXT2 Arina Puzriakova Source NHS GMS was added to EXT2.
Source Expert Review Green was added to EXT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 ENTPD1 Arina Puzriakova Source NHS GMS was added to ENTPD1.
Source Expert Review Green was added to ENTPD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 DPH5 Arina Puzriakova Source NHS GMS was added to DPH5.
Source Expert Review Green was added to DPH5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 DOLK Arina Puzriakova Source Expert Review Green was added to DOLK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 DEPDC5 Arina Puzriakova Mode of inheritance for gene DEPDC5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.109 CUX2 Arina Puzriakova Mode of inheritance for gene CUX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.109 CPLX1 Arina Puzriakova Source NHS GMS was added to CPLX1.
Source Expert Review Green was added to CPLX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 CPA6 Arina Puzriakova Source Expert Review Red was added to CPA6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v4.109 CLDN5 Arina Puzriakova Source NHS GMS was added to CLDN5.
Source Expert Review Green was added to CLDN5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 CHD4 Arina Puzriakova Source NHS GMS was added to CHD4.
Source Expert Review Green was added to CHD4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 CAPRIN1 Arina Puzriakova Source NHS GMS was added to CAPRIN1.
Source Expert Review Green was added to CAPRIN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 C2orf69 Arina Puzriakova Source NHS GMS was added to C2orf69.
Source Expert Review Green was added to C2orf69.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 BAP1 Arina Puzriakova Source NHS GMS was added to BAP1.
Source Expert Review Green was added to BAP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 ATP5O Arina Puzriakova Source Expert Review Green was added to ATP5O.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.109 ASXL3 Arina Puzriakova Source NHS GMS was added to ASXL3.
Source Expert Review Green was added to ASXL3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.108 UBAP2L Arina Puzriakova Phenotypes for gene: UBAP2L were changed from Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system to Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, OMIM:620494
Early onset or syndromic epilepsy v4.107 MED11 Arina Puzriakova Phenotypes for gene: MED11 were changed from MED11-associated neurodevelopmental disorder to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, OMIM:620327
Early onset or syndromic epilepsy v4.106 IQSEC2 Arina Puzriakova Publications for gene: IQSEC2 were set to Shoubridge et al (2010) Nat Genet 42(6): 486-8
Early onset or syndromic epilepsy v4.105 IQSEC2 Arina Puzriakova Phenotypes for gene: IQSEC2 were changed from Mental retardation, X-linked 1 to Intellectual developmental disorder, X-linked 1, OMIM:309530
Early onset or syndromic epilepsy v4.104 HECTD4 Arina Puzriakova Classified gene: HECTD4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.104 HECTD4 Arina Puzriakova Gene: hectd4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.103 HECTD4 Arina Puzriakova Deleted their comment
Early onset or syndromic epilepsy v4.103 HECTD4 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: HECTD4.
Early onset or syndromic epilepsy v4.103 HECTD4 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.292
Early onset or syndromic epilepsy v4.103 HECTD4 Arina Puzriakova gene: HECTD4 was added
gene: HECTD4 was added to Early onset or syndromic epilepsy. Sources: Literature,NHS GMS,Expert Review Green
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, OMIM:620250
Early onset or syndromic epilepsy v4.102 SPATA5L1 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: SPATA5L1.
Early onset or syndromic epilepsy v4.102 SPATA5 Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: SPATA5.
Early onset or syndromic epilepsy v4.102 CRELD1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: CRELD1.
Early onset or syndromic epilepsy v4.102 CRELD1 Sarah Leigh edited their review of gene: CRELD1: Changed rating: GREEN
Early onset or syndromic epilepsy v4.102 CRELD1 Sarah Leigh Classified gene: CRELD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.102 CRELD1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.102 CRELD1 Sarah Leigh Gene: creld1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.101 CRELD1 Sarah Leigh changed review comment from: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

This data has been submitted for publication

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.; to: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

This data has been accepted for publication.

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.
Early onset or syndromic epilepsy v4.101 RAB5C Achchuthan Shanmugasundram Classified gene: RAB5C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.101 RAB5C Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is sufficient evidence (4 unrelated cases) for this gene to be promoted to green rating in this panel at the next GMS update.
Early onset or syndromic epilepsy v4.101 RAB5C Achchuthan Shanmugasundram Gene: rab5c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.100 RAB5C Achchuthan Shanmugasundram Deleted their review
Early onset or syndromic epilepsy v4.100 RAB5C Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.285
Early onset or syndromic epilepsy v4.100 RAB5C Achchuthan Shanmugasundram gene: RAB5C was added
gene: RAB5C was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q3_23_promote_green tags were added to gene: RAB5C.
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5C were set to 37552066
Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related
Early onset or syndromic epilepsy v4.99 ESAM Achchuthan Shanmugasundram Tag Q3_23_NHS_review was removed from gene: ESAM.
Early onset or syndromic epilepsy v4.99 ESAM Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.284
Early onset or syndromic epilepsy v4.99 ESAM Achchuthan Shanmugasundram gene: ESAM was added
gene: ESAM was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature,Expert Review
Q3_23_promote_green, Q3_23_NHS_review tags were added to gene: ESAM.
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, OMIM:620371
Early onset or syndromic epilepsy v4.98 PPP1R3F Achchuthan Shanmugasundram Phenotypes for gene: PPP1R3F were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are at least nine patients reported with intellectual disability and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.; to: Comment on list classification: There are at least six patients reported with epilepsy and with hemizygious PPP1R3F variants and hence this gene should be promoted to green rating at the next GMS review.
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram changed review comment from: PMID:37531237 - 13 unrelated males were identified with hemizygous variants in PPP1R3F gene and were reported with a novel X-linked recessive neurodevelopmental disorder. Intellectual disability was formally tested in 10 individuals of which 5 had mild ID, two had severe ID, one had moderate ID, one had ID for which severity was not stated and one had no ID.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:37531237 - 13 unrelated males were identified with hemizygous variants in PPP1R3F gene and were reported with a novel X-linked recessive neurodevelopmental disorder. Six of these 13 patients were reported with heterogeneous seizure types including generalized, nocturnal, tonic, atonic, focal, myoclonic, and atypical absence.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram edited their review of gene: PPP1R3F: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.281
Early onset or syndromic epilepsy v4.97 PPP1R3F Achchuthan Shanmugasundram gene: PPP1R3F was added
gene: PPP1R3F was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q3_23_promote_green tags were added to gene: PPP1R3F.
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram Tag Q3_23_NHS_review was removed from gene: U2AF2.
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram edited their review of gene: U2AF2: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram Entity copied from Intellectual disability - microarray and sequencing v5.274
Early onset or syndromic epilepsy v4.96 U2AF2 Achchuthan Shanmugasundram gene: U2AF2 was added
gene: U2AF2 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q3_23_promote_green, Q3_23_NHS_review tags were added to gene: U2AF2.
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 28135719; 31785789; 33057194; 34112922; 36747105; 37092751; 37134193
Phenotypes for gene: U2AF2 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v4.95 MT-CO3 Achchuthan Shanmugasundram Tag limit of detection for heteroplasmic variants is not validated for WGS testing tag was added to gene: MT-CO3.
Early onset or syndromic epilepsy v4.95 STARD7 Sarah Leigh Tag STR tag was added to gene: STARD7.
Early onset or syndromic epilepsy v4.95 SAMD12 Sarah Leigh Publications for gene: SAMD12 were set to 30194086; 29507423; 29939203; 32203200
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh changed review comment from: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.; to: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

This data has been submitted for publication

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh changed review comment from: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :
16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.; to: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh commented on gene: CRELD1: Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :
16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh reviewed gene: CRELD1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh Classified gene: CRELD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.94 CRELD1 Sarah Leigh Gene: creld1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.93 CRELD1 Sarah Leigh Publications for gene: CRELD1 were set to PMID 32437232
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Tag watchlist was removed from gene: ATP6V0C.
Tag Q3_23_promote_green tag was added to gene: ATP6V0C.
Tag Q3_23_NHS_review tag was added to gene: ATP6V0C.
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Classified gene: ATP6V0C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.92 ATP6V0C Achchuthan Shanmugasundram Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.91 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 24623842; 33190975; 35600075; 36074901; 37161035
Early onset or syndromic epilepsy v4.90 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.89 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.89 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465 to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.89 ATP6V0C Achchuthan Shanmugasundram Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465
Early onset or syndromic epilepsy v4.88 ATP6V0C Achchuthan Shanmugasundram Publications for gene: ATP6V0C were set to 33190975; 33090716
Early onset or syndromic epilepsy v4.87 ATP6V0C Achchuthan Shanmugasundram reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 24623842, 33190975, 35600075, 36074901, 37161035; Phenotypes: Epilepsy, early-onset, 3, with or without developmental delay, OMIM:620465; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.87 MAGI2 Zornitza Stark commented on gene: MAGI2: In addition, note the gene-disease relationship to epilepsy has been assessed as DISPUTED by ClinGen.
Early onset or syndromic epilepsy v4.87 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: {Epilepsy, juvenile myoclonic, susceptibility to, 6}, MIM# 607682, {Epilepsy, idiopathic generalized, susceptibility to, 9}, MIM#607682; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.87 CRELD1 Sarah Leigh Phenotypes for gene: CRELD1 were changed from Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate to Atrioventricular septal defect, partial, with heterotaxy syndrome, OMIM:606217; {Atrioventricular septal defect, susceptibility to, 2}, OMIM:606217; atrioventricular septal defect, susceptibility to, 2, MONDO:0011650
Early onset or syndromic epilepsy v4.86 PTCH1 Arina Puzriakova Phenotypes for gene: PTCH1 were changed from Basal cell nevus syndrome, 109400; Holoprosencephaly 7, 610828; Basal cell carcinoma, somatic, 605462 to Holoprosencephaly 7, OMIM:610828
Early onset or syndromic epilepsy v4.85 ATP6V0C Julia Baptista reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36074901; Phenotypes: Epilepsy, Intellectual Disability, Microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh edited their review of gene: PABPC1: Added comment: PABPC1 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35511136 reports four de novo PABPC1 variants in four unrelated cases with a phenotype of global DD, movement coordination disorders,
seizures, behavioral disorders and mild facial dysmorphisms. Intellectual disability ranged in the cases from profound (1/4), IQ: 61 (1/4) and IQ: 79 (2/4). Seizures were apparent in the all of the three cases where it was assessed.
Molecular modeling of the variants suggested that they would result in a reduced binding affinity to the messenger RNA metabolism-related protein - PAIP2. This predicted effect was seen in coimmunoprecipitation assays between variant PABPC1 and PAIP2 (PMID: 35511136). Further functional studies in PMID: 35511136, showed that the proliferation of neural progenitor cells in Pabpc1 knockdown mouse embryo brains were decreased, this effect was rescued by the wild-type Pabpc1, but not by the variants c.1691A>G (p.Glu564Gly) or c.1709T>C (p.Ile570Thr).
Other variants were identified in 3/4 cases in PMID: 35511136, two of these had a ACMG VUS classification (RBBP4: c.845A>G, p.(Asn282Ser), IGF2R: c.1850G>A p.Cys617Tyr), while the third variant was monoallelic, whereas bialleic variants in this gene are associated with disease (KDM5B: c.2265dupA, p.(Tyr755*))(PMID: 35511136, table 1).; Changed rating: GREEN
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: PABPC1.
Tag Q3_23_MOI tag was added to gene: PABPC1.
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Classified gene: PABPC1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.85 PABPC1 Sarah Leigh Gene: pabpc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.84 TMEM63B Annalisa Vetro reviewed gene: TMEM63B: Rating: ; Mode of pathogenicity: None; Publications: 37421948; Phenotypes: abnormal myelination, developmental and epileptic encephalopathy, hemolytic anemia, infantile spasms; Mode of inheritance: None
Early onset or syndromic epilepsy v4.84 AKT3 Arina Puzriakova Publications for gene: AKT3 were set to
Early onset or syndromic epilepsy v4.83 AKT3 Arina Puzriakova Phenotypes for gene: AKT3 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 615937 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, OMIM:615937
Early onset or syndromic epilepsy v4.82 KCNH5 Achchuthan Shanmugasundram Mode of pathogenicity for gene: KCNH5 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v4.81 KCNH5 Achchuthan Shanmugasundram Publications for gene: KCNH5 were set to 24133262; 23647072
Early onset or syndromic epilepsy v4.80 KCNH5 Achchuthan Shanmugasundram Phenotypes for gene: KCNH5 were changed from epilepsy to developmental and epileptic encephalopathy, MONDO:0100062; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.79 KCNH5 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.78 KCNH5 Achchuthan Shanmugasundram Classified gene: KCNH5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.78 KCNH5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence for the association of this gene to epilepsy. Hence, this gene can be promoted to green rating at the next GMS review.
Early onset or syndromic epilepsy v4.78 KCNH5 Achchuthan Shanmugasundram Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.77 KCNH5 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: KCNH5.
Early onset or syndromic epilepsy v4.77 KCNH5 Achchuthan Shanmugasundram reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23647072, 35874597, 36307226, 24133262; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100062, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.77 LETM1 Sarah Leigh changed review comment from: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).
Early onset or syndromic epilepsy v4.77 KCNH5 Dmitrijs Rots reviewed gene: KCNH5: 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: PMID: 36307226, 35874597; Phenotypes: NDD with seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.77 LETM1 Sarah Leigh Entity copied from Possible mitochondrial disorder - nuclear genes v3.41
Early onset or syndromic epilepsy v4.77 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Early onset or syndromic epilepsy. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Early onset or syndromic epilepsy v4.76 ATP5O Sarah Leigh Phenotypes for gene: ATP5O were changed from Mitochondrial complex V (ATP synthase) deficiency to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, OMIM:620359
Early onset or syndromic epilepsy v4.75 PIP5K1C Achchuthan Shanmugasundram Classified gene: PIP5K1C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.75 PIP5K1C Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated cases and supporting functional evidence) for promoting this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.75 PIP5K1C Achchuthan Shanmugasundram Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.74 PIP5K1C Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: PIP5K1C.
Early onset or syndromic epilepsy v4.74 PIP5K1C Achchuthan Shanmugasundram Phenotypes for gene: PIP5K1C were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.73 PIP5K1C Achchuthan Shanmugasundram edited their review of gene: PIP5K1C: Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.73 PIP5K1C Achchuthan Shanmugasundram gene: PIP5K1C was added
gene: PIP5K1C was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PIP5K1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIP5K1C were set to 37451268
Phenotypes for gene: PIP5K1C were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: PIP5K1C was set to GREEN
Added comment: Three de novo heterozygous missense variants in PIP5K1C (p.Glu146Lys, p.Tyr205Cys & p.Tyr221Cys) were identified in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. Intellectual disability was reported in all nine children and seizures were present in seven children, of which three had developmental and epileptic encephalopathy. In addition, there is functional evidence available, which includes an in vivo zebrafish model that recapitulates the human phenotype (developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities) (PMID:37451268).

This gene has been associated with another phenotype (Lethal congenital contractural syndrome 3, MIM #611369) in both OMIM and Gene2Phenotype, but not yet associated with this neurodevelopmental disorders in either databases.
Sources: Literature
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review; to: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram Classified gene: TMEM63B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review
Early onset or syndromic epilepsy v4.72 TMEM63B Achchuthan Shanmugasundram Gene: tmem63b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.71 TMEM63B Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: TMEM63B.
Early onset or syndromic epilepsy v4.71 TMEM63B Achchuthan Shanmugasundram changed review comment from: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.
Sources: Literature; to: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had early-onset drug-resistant epilepsy, whose onset ranged from birth to 3 years but occurred within the first year in 14/17 (82%) and in the first month of life in 6/17 (35%).
Sources: Literature
Early onset or syndromic epilepsy v4.71 TMEM63B Achchuthan Shanmugasundram gene: TMEM63B was added
gene: TMEM63B was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63B were set to 37421948
Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: TMEM63B was set to GREEN
Added comment: PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.
Sources: Literature
Early onset or syndromic epilepsy v4.70 CNOT9 Achchuthan Shanmugasundram Classified gene: CNOT9 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.70 CNOT9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (five unrelated cases) for this gene to be promoted to Green at the next major update.
Early onset or syndromic epilepsy v4.70 CNOT9 Achchuthan Shanmugasundram Gene: cnot9 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: CNOT9.
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Phenotypes for gene: CNOT9 were changed from epilepsy, MONDO:0005027 to epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Phenotypes for gene: CNOT9 were changed from epilepsy, MONDO:0005027 to epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.69 CNOT9 Achchuthan Shanmugasundram Phenotypes for gene: CNOT9 were changed from intellectual disability, MONDO:0001071 to epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.68 CNOT9 Achchuthan Shanmugasundram edited their review of gene: CNOT9: Changed phenotypes to: epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.68 CNOT9 Achchuthan Shanmugasundram gene: CNOT9 was added
gene: CNOT9 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT9 were set to 37092538
Phenotypes for gene: CNOT9 were set to intellectual disability, MONDO:0001071
Review for gene: CNOT9 was set to GREEN
Added comment: PMID:37092538 - Seven unrelated individuals with de novo variants in CNOT9 gene (one individual each with variants p.Arg46Gly, p.Pro131Leu and p.Arg227His and four individuals with p.Arg292Trp) were reported with a neurodevelopmental disorder. All affected persons have intellectual disability (three severe, three mild and one unclassified) and five of them have seizures.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh edited their review of gene: KDM6B: Added comment: KDM6B variants have been associated with relevant phenotype in OMIM and as strong Gen2Phen gene for KDM6B-related developmental disorder (monoallelic). PMID: 37196654 reports that in their cohort, 9/69 (13%) of individuals had seizures.; Changed rating: GREEN
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh Classified gene: KDM6B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.67 KDM6B Sarah Leigh Gene: kdm6b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.66 KDM6B Sarah Leigh Tag Q3_23_promote_green tag was added to gene: KDM6B.
Early onset or syndromic epilepsy v4.66 KDM6B Sarah Leigh Phenotypes for gene: KDM6B were changed from Global developmental delay; Intellectual disability; Hypotonia; Joint hypermobility; seizures; Overgrowth to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, OMIM:618505; neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, MONDO:0032790
Early onset or syndromic epilepsy v4.65 KDM6B Sarah Leigh Publications for gene: KDM6B were set to PMID: 37196654
Early onset or syndromic epilepsy v4.64 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.64 DALRD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as this is a good candidate gene but only a single family has been reported to date with variants. Additional evidence needed prior to adding the gene as diagnostic-grade.
Early onset or syndromic epilepsy v4.64 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.63 DALRD3 Arina Puzriakova Classified gene: DALRD3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.63 DALRD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as this is a good candidate gene but only a single family has been reported to date with variants. Additional evidence needed prior to adding the gene as diagnostic-grade.
Early onset or syndromic epilepsy v4.63 DALRD3 Arina Puzriakova Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.62 CPA6 John Taylor changed review comment from: The pathology of this gene is predicated on two publications: Salzmann et al. (2012) PubMed: 21922598 and Sapio et al. (2012) PubMed: 23105115. Both of these publications were issued prior to large population-based allele assessments and the evidence for pathogenicity is reliant on circumstantial evidence. None of the variants that form the foundation of this disease link would have sufficient evidence in support pathogenicity using current classification criteria. This gene should be recategorized as having a Red rating.

Evidence against pathogenicity for the reported variants:
Salzmann et al. (2012) proposed haploinsufficiency rather than gain of function; however, there is no obvious constraint score across the length of the gene. Previously reported pathogenic variants are, in some cases (see below), present in gnomAD at allele frequencies contrary to the incidence of the associated condition.

CPA6 p.(Ala270Val) rs114402678 has been reported has a homozygous variant in gnomADv3.1.2 in the non-neuro sub category (only samples that were not collected as part of a neurologic or psychiatric case/control study, or samples collected as part of a neurologic or psychiatric case/control study but designated as controls). The allele frequency and the observed number of homozygotes is not significantly different from the number of expected homozygote alleles based on the Hardy-Weinberg equilibrium.

CPA6(NM_020361.5):c.799G>A p.(Gly267Arg) rs61738009 was reported as a heterozygous pathogenic variant; however, this variant has been reported in >860 heterozygous individuals in gnomADv2.1.1 and v3.1.2.; to: The pathology of this gene is predicated on two publications: Salzmann et al. (2012) PubMed: 21922598 and Sapio et al. (2012) PubMed: 23105115. Both of these publications were issued prior to large population-based allele assessments and the evidence for pathogenicity is reliant on circumstantial evidence. None of the variants that form the foundation of this disease link would have sufficient evidence in support pathogenicity using current classification criteria. This gene should be recategorized as having a Red rating.

Evidence against pathogenicity for the reported variants:
Salzmann et al. (2012) proposed haploinsufficiency rather than gain of function; however, there is no obvious constraint score across the length of the gene. Previously reported pathogenic variants are, in some cases (see below), present in gnomAD at allele frequencies contrary to the incidence of the associated condition.

CPA6 p.(Ala270Val) rs114402678 has been reported has a homozygous variant in gnomADv3.1.2 in the non-neuro sub category (only samples that were not collected as part of a neurologic or psychiatric case/control study, or samples collected as part of a neurologic or psychiatric case/control study but designated as controls). The allele frequency and the observed number of homozygotes is not significantly different from the number of expected homozygote alleles based on the Hardy-Weinberg equilibrium.

CPA6(NM_020361.5):c.799G>A p.(Gly267Arg) rs61738009 was reported as a heterozygous pathogenic variant; however, this variant has been reported in >860 heterozygous individuals in gnomADv2.1.1 and v3.1.2.
Early onset or syndromic epilepsy v4.62 CPA6 John Taylor reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: Other; Publications: PMID:21922598, 23105115; Phenotypes: ; Mode of inheritance: Other
Early onset or syndromic epilepsy v4.62 KDM6B Hannah Robinson gene: KDM6B was added
gene: KDM6B was added to Early onset or syndromic epilepsy. Sources: NHS GMS
Mode of inheritance for gene: KDM6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM6B were set to PMID: 37196654
Phenotypes for gene: KDM6B were set to Global developmental delay; Intellectual disability; Hypotonia; Joint hypermobility; seizures; Overgrowth
Penetrance for gene: KDM6B were set to Incomplete
Review for gene: KDM6B was set to GREEN
gene: KDM6B was marked as current diagnostic
Added comment: Information from Rots et al. 2023 (PMID:37196654): According to OMIM, heterozygous variants in KDM6B cause “neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities.” Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.).

In this cohort, 9/69 (13%) of individuals had seizures.

The majority of individuals had de novo variants but 9/85 individuals inherited the variant (five maternal, four paternal) from a mildly affected (developmental delay [DD], learning problems, autism spectrum disorder [ASD]) or clinically unaffected parent.
Sources: NHS GMS
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Tag Q3_23_promote_green tag was added to gene: DNAJC6.
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Classified gene: DNAJC6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.62 DNAJC6 Sarah Leigh Gene: dnajc6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.61 DNAJC6 Sarah Leigh edited their review of gene: DNAJC6: Added comment: DNAJC6 variants are associated with Parkinson disease 19b, early-onset (OMIM:615528), but not with a phenotype in Gen2Phen. At least nine variants have been reported in unrelated families. Seizures were reported in 5/9 families and dystonia was reported in 4/9 families reported (data review in PMID: 34175496.; Changed rating: GREEN
Early onset or syndromic epilepsy v4.61 DNAJC6 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v4.61 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19b, early-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231 to Parkinson disease 19b, early-onset, OMIM:615528; Parkinson disease 19a juvenile-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Early onset or syndromic epilepsy v4.60 DNAJC6 Sarah Leigh Mode of inheritance for gene: DNAJC6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.59 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 22563501; 23211418; 26528954; 34175496; 26703368
Early onset or syndromic epilepsy v4.58 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to 23211418; 34175496
Early onset or syndromic epilepsy v4.57 DNAJC6 Sarah Leigh Publications for gene: DNAJC6 were set to
Early onset or syndromic epilepsy v4.56 DNAJC6 Sarah Leigh Added comment: Comment on phenotypes: OMIM:615528 also includes Parkinson disease 19a, juvenile-onset
Early onset or syndromic epilepsy v4.56 DNAJC6 Sarah Leigh Phenotypes for gene: DNAJC6 were changed from to Parkinson disease 19b, early-onset, OMIM:615528; juvenile onset Parkinson disease 19A, MONDO:0014231
Early onset or syndromic epilepsy v4.55 SAMD12 Sarah Leigh reviewed gene: SAMD12: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v4.55 SAMD12 Sarah Leigh Phenotypes for gene: SAMD12 were changed from Epilepsy, familial adult myoclonic, 1, MIM# 601068 to Epilepsy, familial adult myoclonic, 1, OMIM:601068; epilepsy, familial adult myoclonic, 1, MONDO:0010985
Early onset or syndromic epilepsy v4.54 SAMD12 Sarah Leigh Publications for gene: SAMD12 were set to 30194086; 29507423
Early onset or syndromic epilepsy v4.53 SAMD12 Sarah Leigh Classified gene: SAMD12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.53 SAMD12 Sarah Leigh Gene: samd12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.52 SAMD12 Sarah Leigh Tag STR tag was added to gene: SAMD12.
Early onset or syndromic epilepsy v4.52 EIF4A2 Sarah Leigh Classified gene: EIF4A2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.52 EIF4A2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rating Green at the major review.
Early onset or syndromic epilepsy v4.52 EIF4A2 Sarah Leigh Gene: eif4a2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.51 EIF4A2 Sarah Leigh gene: EIF4A2 was added
gene: EIF4A2 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_23_promote_green tags were added to gene: EIF4A2.
Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EIF4A2 were set to 36528028
Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder
Review for gene: EIF4A2 was set to GREEN
Added comment: EIF4A2 has not been associated with a phenotype in OMIM, Gen2Phen or Mondo at the time of reporting. PMID: 36528028 reports the findings of an international collaboration through Matchmaker Exchange, where EIF4A2 variants are found in cases with neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. A total of 15 EIF4A2 variants have been reported in PMID: 36528028, with 12 variants occurring as de novo monoallelic in 12 individuals and 3 as biallelic in two unrelated cases (one as homozygote and the other as compound heterozygous). Severe intellectual was seen in 6/10 unrelated cases where an assessment was made, epilepsy was evident in 10/14 unrelated cases and 13/14 cases had hyptonia. Functional studies were also presented and it would appear that both loss and gain functions maybe associated with EIF4A2 variants.
Sources: Literature
Early onset or syndromic epilepsy v4.50 PNPO Achchuthan Shanmugasundram Publications for gene: PNPO were set to 24658933; 28818555; 22196487; 21704546; 25296925; 26535729; 15772097; 24266778; 36106796
Early onset or syndromic epilepsy v4.49 PNPO Achchuthan Shanmugasundram Publications for gene: PNPO were set to 24658933; 28818555; 22196487; 21704546; 25296925; 26535729; 15772097; 24266778; 36106796
Early onset or syndromic epilepsy v4.49 PNPO Achchuthan Shanmugasundram Publications for gene: PNPO were set to 24658933; 28818555; 22196487; 21704546; 25296925; 26535729; 15772097; 24266778
Early onset or syndromic epilepsy v4.48 GRM7 Achchuthan Shanmugasundram changed review comment from: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising global developmental delay/ intellectual impairment, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).; to: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Early onset or syndromic epilepsy v4.48 GRM7 Achchuthan Shanmugasundram changed review comment from: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmentakl disorder comprising global developmental delay/ intellectual impairment, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).; to: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising global developmental delay/ intellectual impairment, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Early onset or syndromic epilepsy v4.48 GRM7 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: GRM7.
Early onset or syndromic epilepsy v4.48 GRM7 Achchuthan Shanmugasundram Classified gene: GRM7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.48 GRM7 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (6 unrelated cases and supporting mouse model) for this gene to be promoted to GREEN at the next major update.
Early onset or syndromic epilepsy v4.48 GRM7 Achchuthan Shanmugasundram Gene: grm7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.47 GRM7 Achchuthan Shanmugasundram Phenotypes for gene: GRM7 were changed from Epilepsy, microcephaly, developmental delay to Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities, OMIM:618922
Early onset or syndromic epilepsy v4.46 GRM7 Achchuthan Shanmugasundram reviewed gene: GRM7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32248644, 32286009; Phenotypes: Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities, OMIM:618922; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.46 TRA2B Achchuthan Shanmugasundram Classified gene: TRA2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.46 TRA2B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (7 unrelated cases) for rating this gene as GREEN in the next GMS review.
Early onset or syndromic epilepsy v4.46 TRA2B Achchuthan Shanmugasundram Gene: tra2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.45 TRA2B Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: TRA2B.
Early onset or syndromic epilepsy v4.45 TRA2B Achchuthan Shanmugasundram changed review comment from: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature; to: PMID:36549593 reported 12 individuals from 11 unrelated families identified with 11 different heterozygous variants in TRA2B gene. The variants arose de novo in 10 families, while the variant was inherited from father to son in one family. 6 variants were expected to disrupt the translation start site in exon 1 (start-loss variants), 3 were expected to disrupt the splicing process at the exon 2/3 boundary (splice-affecting variants), and the remaining 2 were expected to produce a premature stop codon (truncating variants).

These patients presented with a neurodevelopmental disorder comprising developmental delay/ intellectual disability (in all patients), axial or global hypotonia (10 patients), delayed motor milestones (all patients), behavioural issues (8 patients), speech impairment (9 patients), epilepsy (7 patients, initial presentation as infantile spasms in 6 and unclassified epileptic encephalopathy in 1), brain abnormalities (10 patients) and microcephaly (5 patients).

In addition, functional studies in mice showed that heterozygous knockout mice developed normal, while complete knockout mice cannot develop embryonically.

This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v4.45 TRA2B Achchuthan Shanmugasundram gene: TRA2B was added
gene: TRA2B was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: TRA2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRA2B were set to 36549593
Phenotypes for gene: TRA2B were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: TRA2B was set to GREEN
Added comment: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v4.44 CLDN5 Achchuthan Shanmugasundram changed review comment from: PMID:36477332 reported the identification of de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a number of clinical features including developmental delay including intellectual disability, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognisable pattern of pontine atrophy and brain calcifications. All 15 patients had seizures.

In addition, functional studies from zebrafish model also provided parallel evidence that CLDN5 variants cause a neurodevelopmental disorder involving disruption of the blood brain barrier and impaired neuronal function.

This gene has been associated with relevant phenotypes in Gene2Phenotype (CLDN5-related neurodevelopmental disorder with 'limited' rating in the DD panel), but not in OMIM.
Sources: Literature; to: PMID:36477332 reported the identification of de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a number of clinical features including developmental delay including intellectual disability, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognisable pattern of pontine atrophy and brain calcifications. All 15 patients had seizures.

In addition, functional studies from zebrafish model also provided parallel evidence that CLDN5 variants cause a neurodevelopmental disorder involving disruption of the blood brain barrier and impaired neuronal function.

This gene has been associated with relevant phenotypes in Gene2Phenotype (CLDN5-related neurodevelopmental disorder with 'limited' rating in the DD panel), but not in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v4.44 CLDN5 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: CLDN5.
Early onset or syndromic epilepsy v4.44 CLDN5 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.44 CLDN5 Achchuthan Shanmugasundram Classified gene: CLDN5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.44 CLDN5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated GREEN at the next GMS review.
Early onset or syndromic epilepsy v4.44 CLDN5 Achchuthan Shanmugasundram Gene: cldn5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.43 CLDN5 Achchuthan Shanmugasundram Classified gene: CLDN5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.43 CLDN5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated GREEN at the next GMS review.
Early onset or syndromic epilepsy v4.43 CLDN5 Achchuthan Shanmugasundram Gene: cldn5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.42 CLDN5 Achchuthan Shanmugasundram changed review comment from: PMID: 36477332 identified de novo heterozygous missense variants in CLDN5 in fifteen unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications.
Sources: Literature; to: PMID:36477332 reported the identification of de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a number of clinical features including developmental delay including intellectual disability, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognisable pattern of pontine atrophy and brain calcifications. All 15 patients had seizures.

In addition, functional studies from zebrafish model also provided parallel evidence that CLDN5 variants cause a neurodevelopmental disorder involving disruption of the blood brain barrier and impaired neuronal function.

This gene has been associated with relevant phenotypes in Gene2Phenotype (CLDN5-related neurodevelopmental disorder with 'limited' rating in the DD panel), but not in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v4.42 CLDN5 Achchuthan Shanmugasundram gene: CLDN5 was added
gene: CLDN5 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CLDN5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN5 were set to 36477332
Phenotypes for gene: CLDN5 were set to epilepsy, MONDO:0005027
Review for gene: CLDN5 was set to GREEN
Added comment: PMID: 36477332 identified de novo heterozygous missense variants in CLDN5 in fifteen unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications.
Sources: Literature
Early onset or syndromic epilepsy v4.41 RHEB Arina Puzriakova Tag Q2_23_promote_green tag was added to gene: RHEB.
Early onset or syndromic epilepsy v4.41 RHEB Arina Puzriakova changed review comment from: At least 2 additional cases reported (PMID: 33434304; 37015817) with a spectrum of cortical malformations and brain mosaic RHEB variants. This now meets the diagnostic-grade criteria and therefore this gene should be rated Green.; to: At least 2 additional cases reported (PMID: 33434304; 37015817) with seizures, a spectrum of cortical malformations and brain mosaic RHEB variants. This now meets the diagnostic-grade criteria and therefore this gene should be rated Green.
Early onset or syndromic epilepsy v4.41 RHEB Arina Puzriakova Classified gene: RHEB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.41 RHEB Arina Puzriakova Gene: rheb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.40 RHEB Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to support an association with epilepsy; however, it is worth noting that variants are brain-specific somatic. Still adding to this panel as other somatic mosaic genes (e.g. GNAQ, MTOR, TSC1, TSC2) are included.; to: Comment on list classification: There is sufficient evidence to support an association with epilepsy; however, it is worth noting that variants are brain-specific somatic. Still adding to this panel as other somatic mosaic genes are included (e.g. GNAQ, MTOR, TSC1, TSC2).
Early onset or syndromic epilepsy v4.40 RHEB Arina Puzriakova changed review comment from: Comment on list classification: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; to: Comment on list classification: There is sufficient evidence to support an association with epilepsy; however, it is worth noting that variants are brain-specific somatic. Still adding to this panel as other somatic mosaic genes (e.g. GNAQ, MTOR, TSC1, TSC2) are included.
Early onset or syndromic epilepsy v4.40 RHEB Arina Puzriakova Tag mosaicism tag was added to gene: RHEB.
Early onset or syndromic epilepsy v4.40 RHEB Arina Puzriakova Entity copied from Mosaic brain disorders - deep sequencing v0.116
Early onset or syndromic epilepsy v4.40 RHEB Arina Puzriakova gene: RHEB was added
gene: RHEB was added to Early onset or syndromic epilepsy. Sources: Expert Review Green,Expert list
somatic tags were added to gene: RHEB.
Mode of inheritance for gene: RHEB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RHEB were set to 29051493; 30414531; 33434304; 37015817
Phenotypes for gene: RHEB were set to Epilepsy and cortical dysplasia
Mode of pathogenicity for gene: RHEB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v4.39 CPA6 Eleanor Williams commented on gene: CPA6
Early onset or syndromic epilepsy v4.39 CPA6 Eleanor Williams Tag Q2_23_NHS_review tag was added to gene: CPA6.
Tag Q2_23_expert_review tag was added to gene: CPA6.
Early onset or syndromic epilepsy v4.39 CPA6 Eleanor Williams Tag to_be_confirmed_NHSE was removed from gene: CPA6.
Tag Q2_23_demote_red tag was added to gene: CPA6.
Early onset or syndromic epilepsy v4.39 NSF Achchuthan Shanmugasundram Phenotypes for gene: NSF were changed from Developmental and epileptic encephalopathy 96, OMIM:619340 to Developmental and epileptic encephalopathy 96, OMIM:619340
Early onset or syndromic epilepsy v4.39 NSF Achchuthan Shanmugasundram Phenotypes for gene: NSF were changed from Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 96, OMIM:619340
Early onset or syndromic epilepsy v4.38 NSF Achchuthan Shanmugasundram Publications for gene: NSF were set to 31675180; 36645181
Early onset or syndromic epilepsy v4.38 NSF Achchuthan Shanmugasundram Publications for gene: NSF were set to 31675180
Early onset or syndromic epilepsy v4.37 NSF Achchuthan Shanmugasundram edited their review of gene: NSF: Changed rating: AMBER
Early onset or syndromic epilepsy v4.37 NSF Achchuthan Shanmugasundram changed review comment from: PMID:36645181 describes the two previously reported cases from PMID:31675180. The third case reported had a very mild phenotype and did not present with epilepsy and had normal development. Hence, this gene should remain AMBER.; to: PMID:36645181 describes the two previously reported cases from PMID:31675180. The third case reported had a very mild phenotype and did not present with epilepsy and had normal development. Hence, this gene should remain AMBER.

This gene has now been associated with relevant phenotype in OMIM (MIM #619340), but not in Gene2Phenotype.
Early onset or syndromic epilepsy v4.37 NSF Achchuthan Shanmugasundram reviewed gene: NSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 36645181; Phenotypes: Developmental and epileptic encephalopathy 96, OMIM:619340; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.37 CPA6 Ian Berry reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.37 ENTPD1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: ENTPD1.
Early onset or syndromic epilepsy v4.37 ENTPD1 Achchuthan Shanmugasundram Classified gene: ENTPD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.37 ENTPD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, there are seven unrelated cases with epilepsy. Hence, this gene can be promoted to GREEN rating in the next major update.
Early onset or syndromic epilepsy v4.37 ENTPD1 Achchuthan Shanmugasundram Gene: entpd1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.36 ENTPD1 Achchuthan Shanmugasundram reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35471564; Phenotypes: Spastic paraplegia 64, autosomal recessive, OMIM:15683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.36 RNF13 Arina Puzriakova Phenotypes for gene: RNF13 were changed from Cortical visual impairment; Failure to thrive; Seizures; Congenital microcephaly; Epileptic encephalopathy, early infantile, 73; Abnormal muscle tone; Feeding difficulties; Intellectual disability; Global developmental delay; Sensorineural hearing impairment to Developmental and epileptic encephalopathy 73, OMIM:618379
Early onset or syndromic epilepsy v4.35 CHMP3 Arina Puzriakova Classified gene: CHMP3 as Red List (low evidence)
Early onset or syndromic epilepsy v4.35 CHMP3 Arina Puzriakova Added comment: Comment on list classification: Rating Red for now as only a single case has been reported to date.
Early onset or syndromic epilepsy v4.35 CHMP3 Arina Puzriakova Gene: chmp3 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.34 CHMP3 Arina Puzriakova gene: CHMP3 was added
gene: CHMP3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHMP3 were set to 35710109
Phenotypes for gene: CHMP3 were set to Complex spastic quadriplegia associated with developmental delay and seizures
Added comment: Cohen-Barak et al., 2022 (PMID: 35710109) reported on a consanguineous family, in which five individuals presented with intellectual and progressive motor disabilities, seizures and spastic quadriplegia, associated with a homozygous variant in CHMP3. Patient derived fibroblasts expressed ultrastructural and molecular features of impaired autophagy, partially rescued by ectopic expression of WT-CHMP3.
Sources: Literature
Early onset or syndromic epilepsy v4.33 RAC3 Arina Puzriakova Classified gene: RAC3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.33 RAC3 Arina Puzriakova Added comment: Comment on list classification: There are now at least 14 patients from 13 unrelated families with de novo heterozygous variants in this gene (PMIDs: 29276006; 30293988; 35851598; 35595279). Seizures reported in at least 8 individuals. Therefore, this gene can be promoted to Green at the next GMS panel update.
Early onset or syndromic epilepsy v4.33 RAC3 Arina Puzriakova Gene: rac3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.32 RAC3 Arina Puzriakova Tag Q2_23_promote_green tag was added to gene: RAC3.
Early onset or syndromic epilepsy v4.32 RAC3 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.114
Early onset or syndromic epilepsy v4.32 RAC3 Arina Puzriakova gene: RAC3 was added
gene: RAC3 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Green
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAC3 were set to 29276006; 30293988; 35851598; 35595279
Phenotypes for gene: RAC3 were set to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Penetrance for gene: RAC3 were set to unknown
Mode of pathogenicity for gene: RAC3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v4.31 GLRA2 Arina Puzriakova Phenotypes for gene: GLRA2 were changed from Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Microcephaly; Abnormality of eye movement to Intellectual developmental disorder, X-linked syndromic, Pilorge type, OMIM:301076
Early onset or syndromic epilepsy v4.30 GRIN2B Arina Puzriakova Publications for gene: GRIN2B were set to Endele et al (2010) Nature Genet 42(11): 1021-1028
Early onset or syndromic epilepsy v4.29 GRIN2B Arina Puzriakova Phenotypes for gene: GRIN2B were changed from Mental retardation, autosomal dominant 6; Epileptic encephalopathy, early infantile, 27; EPILEPTIC ENCEPHALOPATHY; AUTISM to Intellectual developmental disorder, autosomal dominant 6, with or without seizures, OMIM:613970; Developmental and epileptic encephalopathy 27, OMIM:616139
Early onset or syndromic epilepsy v4.28 UNC13B Achchuthan Shanmugasundram Phenotypes for gene: UNC13B were changed from partial epilepsy, MONDO:0005384 to partial epilepsy, MONDO:0005384
Early onset or syndromic epilepsy v4.28 UNC13B Achchuthan Shanmugasundram Phenotypes for gene: UNC13B were changed from Epilepsy to partial epilepsy, MONDO:0005384
Early onset or syndromic epilepsy v4.27 UNC13B Achchuthan Shanmugasundram Publications for gene: UNC13B were set to 33876820; 35380625
Early onset or syndromic epilepsy v4.27 UNC13B Achchuthan Shanmugasundram Publications for gene: UNC13B were set to 33876820; 35380625
Early onset or syndromic epilepsy v4.27 UNC13B Achchuthan Shanmugasundram Publications for gene: UNC13B were set to 33876820
Early onset or syndromic epilepsy v4.26 UNC13B Achchuthan Shanmugasundram Classified gene: UNC13B as Red List (low evidence)
Early onset or syndromic epilepsy v4.26 UNC13B Achchuthan Shanmugasundram Gene: unc13b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.26 UNC13B Achchuthan Shanmugasundram Classified gene: UNC13B as Red List (low evidence)
Early onset or syndromic epilepsy v4.26 UNC13B Achchuthan Shanmugasundram Gene: unc13b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.26 UNC13B Achchuthan Shanmugasundram Classified gene: UNC13B as Red List (low evidence)
Early onset or syndromic epilepsy v4.26 UNC13B Achchuthan Shanmugasundram Gene: unc13b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.25 UNC13B Achchuthan Shanmugasundram reviewed gene: UNC13B: Rating: RED; Mode of pathogenicity: None; Publications: 33876820, 35380625; Phenotypes: partial epilepsy, MONDO:0005384; Mode of inheritance: None
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Zornitza Stark (Australian Genomics), there are 8 unrelated cases with genetic epilepsy with febrile seizures plus and 4 unrelated cases with a neurodevelopmental disorder comprising intellectual disability and infantile-onset epilepsy and there are supporting functional evidence. Hence, this gene can be promoted to GREEN at the next GMS update.; to: Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Zornitza Stark (Australian Genomics), there are 8 unrelated cases with genetic epilepsy with febrile seizures plus and 4 unrelated cases with a neurodevelopmental disorder comprising intellectual disability and infantile-onset epilepsy and there are supporting functional evidence. Hence, this gene can be promoted to GREEN at the next GMS update.

Although this gene has not yet been associated with phenotypes in OMIM, it has been added to Gene2Phenotype with 'moderate' rating in the DD panel.
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Classified gene: SLC32A1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Zornitza Stark (Australian Genomics), there are 8 unrelated cases with genetic epilepsy with febrile seizures plus and 4 unrelated cases with a neurodevelopmental disorder comprising intellectual disability and infantile-onset epilepsy and there are supporting functional evidence. Hence, this gene can be promoted to GREEN at the next GMS update.
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Gene: slc32a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Classified gene: SLC32A1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Zornitza Stark (Australian Genomics), there are 8 unrelated cases with genetic epilepsy with febrile seizures plus and 4 unrelated cases with a neurodevelopmental disorder comprising intellectual disability and infantile-onset epilepsy and there are supporting functional evidence. Hence, this gene can be promoted to GREEN at the next GMS update.
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Gene: slc32a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Classified gene: SLC32A1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Zornitza Stark (Australian Genomics), there are 8 unrelated cases with genetic epilepsy with febrile seizures plus and 4 unrelated cases with a neurodevelopmental disorder comprising intellectual disability and infantile-onset epilepsy and there are supporting functional evidence. Hence, this gene can be promoted to GREEN at the next GMS update.
Early onset or syndromic epilepsy v4.25 SLC32A1 Achchuthan Shanmugasundram Gene: slc32a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.24 SLC32A1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: SLC32A1.
Early onset or syndromic epilepsy v4.24 SLC32A1 Achchuthan Shanmugasundram Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214 to developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214
Early onset or syndromic epilepsy v4.24 SLC32A1 Achchuthan Shanmugasundram Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214 to developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214
Early onset or syndromic epilepsy v4.24 SLC32A1 Achchuthan Shanmugasundram Phenotypes for gene: SLC32A1 were changed from Genetic epilepsy with febrile seizures plus to developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214
Early onset or syndromic epilepsy v4.23 SLC32A1 Achchuthan Shanmugasundram Publications for gene: SLC32A1 were set to 34038384; 36073542
Early onset or syndromic epilepsy v4.23 SLC32A1 Achchuthan Shanmugasundram Publications for gene: SLC32A1 were set to 34038384
Early onset or syndromic epilepsy v4.22 SLC32A1 Achchuthan Shanmugasundram reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34038384, 36073542; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100062, generalized epilepsy with febrile seizures plus, MONDO:0018214; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.22 PPFIBP1 Achchuthan Shanmugasundram Classified gene: PPFIBP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.22 PPFIBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Early onset or syndromic epilepsy v4.22 PPFIBP1 Achchuthan Shanmugasundram Gene: ppfibp1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.21 PPFIBP1 Achchuthan Shanmugasundram Phenotypes for gene: PPFIBP1 were changed from Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024 to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024
Early onset or syndromic epilepsy v4.21 PPFIBP1 Achchuthan Shanmugasundram Phenotypes for gene: PPFIBP1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024
Early onset or syndromic epilepsy v4.20 PPFIBP1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: PPFIBP1.
Early onset or syndromic epilepsy v4.20 PPFIBP1 Achchuthan Shanmugasundram reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35830857; Phenotypes: Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: PLXNA1.
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Deleted their comment
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Classified gene: PLXNA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (five unrelated cases) available for associating monoallelic variants in this gene with epilepsy/ seizures with a GREEN rating and hence this gene can be promoted at the next major review.
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Gene: plxna1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Classified gene: PLXNA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (five unrelated cases) available for associating monoallelic variants in this gene with epilepsy/ seizures with a GREEN rating and hence this gene can be promoted at the next major review.
Early onset or syndromic epilepsy v4.20 PLXNA1 Achchuthan Shanmugasundram Gene: plxna1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.19 PLXNA1 Achchuthan Shanmugasundram gene: PLXNA1 was added
gene: PLXNA1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLXNA1 were set to 28464511; 34054129
Phenotypes for gene: PLXNA1 were set to developmental and epileptic encephalopathy, MONDO:0100062
Review for gene: PLXNA1 was set to GREEN
Added comment: Monoallelic cases:

PMID:28464511 reported a male patient with a de novo variant in PLXNA1 and presenting with intractable infantile onset epilepsy, and intellectual disability with autism spectrum disorder. In addition, this patient also had features suggestive of Dubowitz syndrome, including growth failure, dermatologic symptoms, and characteristic dysmorphic facial features. It has also been reviewed in this publication that one of only two previously reported cases with missense PLXNA1 variants had epileptic encephalopathy.

PMID:34054129 reported ten cases from seven families with PLXNA1 variants. Of these cases, three unrelated cases had monoallelic de novo variants and presented with global developmental delay, seizures and craniofacial, brain and eye anomalies.


Biallelic cases:

Out of ten cases reported in PMID:34054129, seven cases from four unrelated families exhibited biallelic variants in PLXNA1 gene. They presented with global developmental delay and craniofacial, brain and eye anomalies. However, seizures are not reported in biallelic cases except one family (15 episodes of febrile and nonfebrile seizures reported in family A).

The biallelic variants in this gene has been associated with phenotypes in OMIM (MIM #619955). However, both monoalellic and biallelic variants in this gene has been associated with phenotypes in Gene2Phenotype (with 'limited' rating).

Functional studies:

Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Knockdown of plxna1a leads to cerebral anomalies and eye anomalies in zebrafish larvae.
Sources: Literature
Early onset or syndromic epilepsy v4.18 C2orf69 Arina Puzriakova Entity copied from Mitochondrial disorders v4.27
Early onset or syndromic epilepsy v4.18 C2orf69 Arina Puzriakova gene: C2orf69 was added
gene: C2orf69 was added to Early onset or syndromic epilepsy. Sources: Expert Review Amber,Literature
Q2_23_promote_green tags were added to gene: C2orf69.
Mode of inheritance for gene: C2orf69 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C2orf69 were set to 34038740; 33945503
Phenotypes for gene: C2orf69 were set to Combined oxidative phosphorylation deficiency 53, OMIM:619423
Early onset or syndromic epilepsy v4.17 PLK1 Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: PLK1.
Early onset or syndromic epilepsy v4.17 PLK1 Achchuthan Shanmugasundram Classified gene: PLK1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.17 PLK1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN at the next major review.
Early onset or syndromic epilepsy v4.17 PLK1 Achchuthan Shanmugasundram Gene: plk1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.16 PLK1 Achchuthan Shanmugasundram Publications for gene: PLK1 were set to 33875846
Early onset or syndromic epilepsy v4.15 PLK1 Achchuthan Shanmugasundram Publications for gene: PLK1 were set to
Early onset or syndromic epilepsy v4.14 PLK1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Dmitrijs Rots (RadboudUMC), PMID:33875846 reported five unrelated cases identified with homozygous variants in PLK1 gene and presenting with a neurodevelopmental disorder phenotype characterised with seizures, microcephaly and global developmental delay.; to: As reviewed by Dmitrijs Rots (RadboudUMC), PMID:33875846 reported five unrelated cases identified with homozygous variants in PLK1 gene and presenting with a neurodevelopmental disorder phenotype characterised with seizures, microcephaly and global developmental delay.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Early onset or syndromic epilepsy v4.14 PLK1 Achchuthan Shanmugasundram reviewed gene: PLK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100062; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.14 OTUD7A Achchuthan Shanmugasundram changed review comment from: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe).

PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11.

PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion.

This gene has been reported in the DD panel of Gene2Phenotype (with 'limited' rating), but has not yet been associated with phenotypes in OMIM.

OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.; to: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe).

PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11.

PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion.

OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.

This gene has been reported in the DD panel of Gene2Phenotype (with 'limited' rating), but has not yet been associated with phenotypes in OMIM.
Early onset or syndromic epilepsy v4.14 OTUD7A Achchuthan Shanmugasundram changed review comment from: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe).

PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11.

PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion.

OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.; to: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe).

PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11.

PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion.

This gene has been reported in the DD panel of Gene2Phenotype (with 'limited' rating), but has not yet been associated with phenotypes in OMIM.

OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.
Early onset or syndromic epilepsy v4.14 OTUD7A Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: OTUD7A.
Early onset or syndromic epilepsy v4.14 OTUD7A Achchuthan Shanmugasundram Classified gene: OTUD7A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.14 OTUD7A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.
Early onset or syndromic epilepsy v4.14 OTUD7A Achchuthan Shanmugasundram Gene: otud7a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.13 OTUD7A Achchuthan Shanmugasundram Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074; 33381903; 36180924
Early onset or syndromic epilepsy v4.13 OTUD7A Achchuthan Shanmugasundram Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Early onset or syndromic epilepsy v4.12 OTUD7A Achchuthan Shanmugasundram reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29395075, 31997314, 33381903, 36180924; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100062; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.12 CLCN4 Arina Puzriakova Phenotypes for gene: CLCN4 were changed from Raynaud-Claes syndrome 300114; Mental retardation, X-linked 49/15 to Raynaud-Claes syndrome, OMIM:300114
Early onset or syndromic epilepsy v4.11 PDHX Arina Puzriakova Phenotypes for gene: PDHX were changed from Lacticacidemia due to PDX1 deficiency 245349 to Lacticacidemia due to PDX1 deficiency, OMIM:245349
Early onset or syndromic epilepsy v4.10 NDUFS1 Arina Puzriakova Phenotypes for gene: NDUFS1 were changed from Mitochondrial complex I deficiency, 252010; LEIGH SYNDROME; MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226
Early onset or syndromic epilepsy v4.9 SUCLA2 Arina Puzriakova Phenotypes for gene: SUCLA2 were changed from Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), 612073 to Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria), OMIM:612073
Early onset or syndromic epilepsy v4.8 ATP5O Arina Puzriakova Entity copied from Mitochondrial disorder with complex V deficiency v2.5
Early onset or syndromic epilepsy v4.8 ATP5O Arina Puzriakova gene: ATP5O was added
gene: ATP5O was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber
new-gene-name, Q2_23_promote_green tags were added to gene: ATP5O.
Mode of inheritance for gene: ATP5O was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP5O were set to 34954817; 35621276
Phenotypes for gene: ATP5O were set to Mitochondrial complex V (ATP synthase) deficiency
Early onset or syndromic epilepsy v4.7 NAPB Arina Puzriakova Phenotypes for gene: NAPB were changed from Early infantile epileptic encephalopathy to Developmental and epileptic encephalopathy 107, OMIM:620033
Early onset or syndromic epilepsy v4.6 MED11 Sarah Leigh Classified gene: MED11 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.6 MED11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v4.6 MED11 Sarah Leigh Gene: med11 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.5 MED11 Sarah Leigh gene: MED11 was added
gene: MED11 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_23_promote_green tags were added to gene: MED11.
Mode of inheritance for gene: MED11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED11 were set to 36001086
Phenotypes for gene: MED11 were set to MED11-associated neurodevelopmental disorder
Review for gene: MED11 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, but is associated with MED11-associated neurodevelopmental disorder in Gen2Phen. PMID: 36001086 reports a single MED11 variant (NM_001001683.4: c.325C>T, p.Arg109*), that segregates with the condition in five unrelated families, however, there is homozygosity between two of these families, idicating that they may be related. Global delay was observed in three individuals from three unrelated familes and seizures were evident in four individuals from four unrelated families. Severe microcephaly was apparent in the two unrelated familes where this parameter was recorded. Overall, the MED11-associated neurodevelopmental disorder appeared to result in profound effects and proved fatal at birth and 10 days in two of the cases reported.
Sources: Literature
Early onset or syndromic epilepsy v4.4 UBAP2L Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Konstantinos Varvagiannis, 7 out of 12 unrelated cases from PMID:35977029 had seizures, while 3 of them had a formal diagnosis of epilepsy. This is sufficient evidence to promote this gene to GREEN at the next major review.

This gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate rating'.; to: Comment on list classification: As reviewed by Konstantinos Varvagiannis, 7 out of 12 unrelated cases from PMID:35977029 had seizures, while 3 of them had a formal diagnosis of epilepsy. This is sufficient evidence to promote this gene to GREEN at the next major review.

This gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate' rating.
Early onset or syndromic epilepsy v4.4 UBAP2L Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: UBAP2L.
Early onset or syndromic epilepsy v4.4 UBAP2L Achchuthan Shanmugasundram Classified gene: UBAP2L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.4 UBAP2L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Konstantinos Varvagiannis, 7 out of 12 unrelated cases from PMID:35977029 had seizures, while 3 of them had a formal diagnosis of epilepsy. This is sufficient evidence to promote this gene to GREEN at the next major review.

This gene has not yet been associated with relevant phenotypes in OMIM, but it has been reported in Gene2Phenotype with 'moderate rating'.
Early onset or syndromic epilepsy v4.4 UBAP2L Achchuthan Shanmugasundram Gene: ubap2l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.3 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Epileptic encephalopathy, early infantile, 5 to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Early onset or syndromic epilepsy v4.2 SPTAN1 Sarah Leigh Publications for gene: SPTAN1 were set to Saitsu et al (2010) Am J Hum Genet 86: 881_891
Early onset or syndromic epilepsy v4.1 Arina Puzriakova Panel version 4.0 has been signed off on 2023-03-22
Early onset or syndromic epilepsy v4.0 Arina Puzriakova promoted panel to version 4.0
Early onset or syndromic epilepsy v3.115 Sarah Leigh Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Early onset or syndromic epilepsy v3.114 Sarah Leigh Panel name changed from Genetic epilepsy syndromes to Early onset or syndromic epilepsy
List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; R59 to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; Genetic epilepsy syndromes; R59
Early onset or syndromic epilepsy v3.113 SATB2 Sarah Leigh edited their review of gene: SATB2: Added comment: Associated with Glass syndrome, OMIM:612313 and as definitive Gen2Phen gene for the same condition. Table 2 in PMID: 32446642 presents a clincal review of SATB2 variant carriers. Amongst the 35 cases carrying intragenic variants, 14 did not have clinical seizures, 19 had seizures (10 well controlled, 9 somewhat controlled) and the diagnosis was uncertain in two other cases.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.113 SATB2 Sarah Leigh Phenotypes for gene: SATB2 were changed from Glass syndrome, MIM# 612313 to Glass syndrome, OMIM:612313
Early onset or syndromic epilepsy v3.112 SATB2 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: SATB2.
Early onset or syndromic epilepsy v3.112 SATB2 Sarah Leigh Classified gene: SATB2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.112 SATB2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.112 SATB2 Sarah Leigh Gene: satb2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.111 KPTN Sarah Leigh Tag watchlist was removed from gene: KPTN.
Tag Q1_23_promote_green tag was added to gene: KPTN.
Early onset or syndromic epilepsy v3.111 KPTN Sarah Leigh edited their review of gene: KPTN: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least five KPTN variants have been reported in four unrelated cases of OMIM: 615637, seizures were evident in three unrelated cases (PMID: 24239382;25847626;32358097;32808430).; Changed rating: GREEN
Early onset or syndromic epilepsy v3.111 KPTN Sarah Leigh Classified gene: KPTN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.111 KPTN Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.111 KPTN Sarah Leigh Gene: kptn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.110 KPTN Sarah Leigh Phenotypes for gene: KPTN were changed from Mental retardation, autosomal recessive 4,1615637; seizures to Intellectual developmental disorder, autosomal recessive 41, OMIM:615637; macrocephaly-developmental delay syndrome, MONDO:0014289
Early onset or syndromic epilepsy v3.109 KPTN Sarah Leigh Publications for gene: KPTN were set to 24239382; 25847626
Early onset or syndromic epilepsy v3.108 GCSH Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: GCSH.
Early onset or syndromic epilepsy v3.108 GCSH Achchuthan Shanmugasundram changed review comment from: PMID:36190515 reported six unrelated individuals with biallelic variants in GCSH. They presented with a broad clinical spectrum with three cases with an early-onset severe fatal glycine encephalopathy and the other three cases displaying an attenuated phenotype of developmental delay, behavioural problems, epilepsy and variable movement problems and they had long-term survival. The three early-onset and fatal cases displayed compound heterozygous variants, while the cases with attenuated phenotype harboured homozygous variants.

All three individuals with the early-onset severe fatal glycine encephalopathy had epilepsy/ seizures as part of the presenting phenotypes. Only patient (patient 6) from the three cases with the attenuated phenotype had left-sided partial seizures, while other two had no seizures/ epilepsy.

Functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies demonstrated that most variants identified in this cohort produced a hypomorphic effect on both protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affected primarily one function only.

This gene has also been associated with Glycine encephalopathy in both OMIM and Gene2Phenotype.;; to: PMID:36190515 reported six unrelated individuals with biallelic variants in GCSH. They presented with a broad clinical spectrum with three cases with an early-onset severe fatal glycine encephalopathy and the other three cases displaying an attenuated phenotype of developmental delay, behavioural problems, epilepsy and variable movement problems and they had long-term survival. The three early-onset and fatal cases displayed compound heterozygous variants, while the cases with attenuated phenotype harboured homozygous variants.

All three individuals with the early-onset severe fatal glycine encephalopathy had epilepsy/ seizures as part of the presenting phenotypes. Only patient (patient 6) from the three cases with the attenuated phenotype had left-sided partial seizures, while other two had no seizures/ epilepsy.

Functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies demonstrated that most variants identified in this cohort produced a hypomorphic effect on both protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affected primarily one function only.

This gene has also been associated with Glycine encephalopathy in both OMIM and Gene2Phenotype.
Early onset or syndromic epilepsy v3.108 GCSH Achchuthan Shanmugasundram Classified gene: GCSH as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.108 GCSH Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are five unrelated cases identified with biallelic variants in GCSH and reported with seizures/ epilepsy as part of the phenotype. one case was reported in PMID:1671321 and four in PMID:36190515 (three with severe neonatal/ infantile phenotype and one with attenuated phenotype).
Early onset or syndromic epilepsy v3.108 GCSH Achchuthan Shanmugasundram Gene: gcsh has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.107 GCSH Achchuthan Shanmugasundram changed review comment from: PMID:36190515 reported six unrelated individuals with biallelic variants in GCSH. They presented with a broad clinical spectrum with three cases with an early-onset severe fatal glycine encephalopathy and the other three cases displaying an attenuated phenotype of developmental delay, behavioural problems, epilepsy and variable movement problems and they had long-term survival. The three early-onset and fatal cases displayed compound heterozygous variants, while the cases with attenuated phenotype harboured homozygous variants.

All three individuals with the early-onset severe fatal glycine encephalopathy had epilepsy/ seizures as part of the presenting phenotypes. Only patient (patient 6) from the three cases with the attenuated phenotype had left-sided partial seizures, while other two had no seizures/ epilepsy.

Functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies demonstrated that most variants identified in this cohort produced a hypomorphic effect on both protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affected primarily one function only.; to: PMID:36190515 reported six unrelated individuals with biallelic variants in GCSH. They presented with a broad clinical spectrum with three cases with an early-onset severe fatal glycine encephalopathy and the other three cases displaying an attenuated phenotype of developmental delay, behavioural problems, epilepsy and variable movement problems and they had long-term survival. The three early-onset and fatal cases displayed compound heterozygous variants, while the cases with attenuated phenotype harboured homozygous variants.

All three individuals with the early-onset severe fatal glycine encephalopathy had epilepsy/ seizures as part of the presenting phenotypes. Only patient (patient 6) from the three cases with the attenuated phenotype had left-sided partial seizures, while other two had no seizures/ epilepsy.

Functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies demonstrated that most variants identified in this cohort produced a hypomorphic effect on both protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affected primarily one function only.

This gene has also been associated with Glycine encephalopathy in both OMIM and Gene2Phenotype.;
Early onset or syndromic epilepsy v3.107 GCSH Achchuthan Shanmugasundram Phenotypes for gene: GCSH were changed from to ?Glycine encephalopathy, OMIM:605899; Neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v3.106 GCSH Achchuthan Shanmugasundram Publications for gene: GCSH were set to
Early onset or syndromic epilepsy v3.105 GCSH Achchuthan Shanmugasundram Mode of inheritance for gene: GCSH was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.105 GCSH Achchuthan Shanmugasundram Mode of inheritance for gene: GCSH was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.105 GCSH Achchuthan Shanmugasundram Mode of inheritance for gene: GCSH was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.104 GCSH Achchuthan Shanmugasundram reviewed gene: GCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 36190515; Phenotypes: ?Glycine encephalopathy, OMIM:605899, Neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.104 DEPDC5 Achchuthan Shanmugasundram commented on gene: DEPDC5: The MOI of this gene should be reviewed at the next NHS GMS review on whether it can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Early onset or syndromic epilepsy v3.104 DEPDC5 Achchuthan Shanmugasundram Tag Q1_23_MOI tag was added to gene: DEPDC5.
Early onset or syndromic epilepsy v3.104 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.104 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.104 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.104 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.104 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.103 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.103 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.103 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 32848577; 36067010
Early onset or syndromic epilepsy v3.103 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 36067010
Early onset or syndromic epilepsy v3.102 DEPDC5 Achchuthan Shanmugasundram reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32848577, 36067010; Phenotypes: Epilepsy, familial focal, with variable foci 1, OMIM:604364, epilepsy, MONDO:0005027, Macrocephaly, HP:0000256, polymicrogyria, MONDO:0000087, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.102 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 36067010
Early onset or syndromic epilepsy v3.102 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701; 36067010
Early onset or syndromic epilepsy v3.102 DEPDC5 Achchuthan Shanmugasundram Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701
Early onset or syndromic epilepsy v3.101 SARS Arina Puzriakova Publications for gene: SARS were set to 28236339; 34570399; 35790048
Early onset or syndromic epilepsy v3.100 SARS Arina Puzriakova edited their review of gene: SARS: Changed publications to: 35790048, 36041817
Early onset or syndromic epilepsy v3.100 SARS Arina Puzriakova changed review comment from: Comment on mode of inheritance: As only a single dominant case has been reported (details below), leaving MOI as biallelic for now with a watchlist_moi tag. Consider adding to other relevant panels if further cases are identified.

Single patient identified with de novo heterozygous splice site deletion (c.969_969+2delGGT) in the SARS1 gene. Phenotypes included complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Functional studies in both yeast strains and patient fibroblasts demonstrated a LoF, dominant negative effect.; to: Comment on mode of inheritance: As only a single dominant case has been reported (details below), leaving MOI as biallelic for now with a watchlist_moi tag. Consider adding to other relevant panels if further cases are identified.

PMID: 36041817 - Single patient identified with de novo heterozygous splice site deletion (c.969_969+2delGGT) in the SARS1 gene. Phenotypes included complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Functional studies in both yeast strains and patient fibroblasts demonstrated a LoF, dominant negative effect.
Early onset or syndromic epilepsy v3.100 SARS Arina Puzriakova changed review comment from: Comment on mode of inheritance: As only a single dominant case has been reported (details below), leaving MOI as biallelic for now with a watchlist_moi tag. Consider adding to other relevant panels if further cases are identified.

Single patient identified with de novo heterozygous splice site deletion (.969_969+2delGGT) in the SARS1 gene. Phenotypes included complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Functional studies in both yeast strains and patient fibroblasts demonstrated a LoF, dominant negative effect.; to: Comment on mode of inheritance: As only a single dominant case has been reported (details below), leaving MOI as biallelic for now with a watchlist_moi tag. Consider adding to other relevant panels if further cases are identified.

Single patient identified with de novo heterozygous splice site deletion (c.969_969+2delGGT) in the SARS1 gene. Phenotypes included complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Functional studies in both yeast strains and patient fibroblasts demonstrated a LoF, dominant negative effect.
Early onset or syndromic epilepsy v3.100 SARS Arina Puzriakova Added comment: Comment on mode of inheritance: As only a single dominant case has been reported (details below), leaving MOI as biallelic for now with a watchlist_moi tag. Consider adding to other relevant panels if further cases are identified.

Single patient identified with de novo heterozygous splice site deletion (.969_969+2delGGT) in the SARS1 gene. Phenotypes included complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Functional studies in both yeast strains and patient fibroblasts demonstrated a LoF, dominant negative effect.
Early onset or syndromic epilepsy v3.100 SARS Arina Puzriakova Mode of inheritance for gene: SARS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.99 SARS Arina Puzriakova Tag watchlist_moi tag was added to gene: SARS.
Early onset or syndromic epilepsy v3.99 SARS Arina Puzriakova Phenotypes for gene: SARS were changed from ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709 to Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Early onset or syndromic epilepsy v3.98 SARS Arina Puzriakova Publications for gene: SARS were set to 28236339; 34570399
Early onset or syndromic epilepsy v3.97 SARS Arina Puzriakova Classified gene: SARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.97 SARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least three unrelated cases with biallelic variants in this gene - seizures detected in all families.
Early onset or syndromic epilepsy v3.97 SARS Arina Puzriakova Gene: sars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.96 SARS Arina Puzriakova Tag watchlist was removed from gene: SARS.
Tag Q1_23_promote_green tag was added to gene: SARS.
Early onset or syndromic epilepsy v3.96 SARS Arina Puzriakova reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.96 SLC31A1 Achchuthan Shanmugasundram Classified gene: SLC31A1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.96 SLC31A1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated AMBER as it has been associated with neurodegeneration involving seizures in two unrelated cases.

This gene has been associated with phenotype in Gene2Phenotype, but not in OMIM.
Early onset or syndromic epilepsy v3.96 SLC31A1 Achchuthan Shanmugasundram Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.95 SLC31A1 Achchuthan Shanmugasundram Publications for gene: SLC31A1 were set to 35913762
Early onset or syndromic epilepsy v3.94 SLC31A1 Achchuthan Shanmugasundram edited their review of gene: SLC31A1: Added comment: PMID:36562171 reported a newborn infant of consanguineous parents with a homozygous pathogenic variant p.Leu79Pro in CTR1. This infant was born with pulmonary hypoplasia. At two weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at one month of age.; Changed rating: AMBER; Changed publications to: 35913762, 36562171
Early onset or syndromic epilepsy v3.94 SLC31A1 Achchuthan Shanmugasundram gene: SLC31A1 was added
gene: SLC31A1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to 35913762
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, MONDO:0700092; Epilepsy, MONDO:0005027
Review for gene: SLC31A1 was set to RED
Added comment: This gene has been associated with seizures in an identical twin male infants identified with homozygous novel missense variant p.Arg95His in CTR1. The twins had hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency.
Sources: Literature
Early onset or syndromic epilepsy v3.93 SEMA6B Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:35604360 reported new unrelated cases identified with heterozygous variants in SEMA6B. Out of 16 patients referred for ID clinic, 10 of them had epilepsy or myoclonus.

Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.
Early onset or syndromic epilepsy v3.93 SEMA6B Achchuthan Shanmugasundram Publications for gene: SEMA6B were set to 32169168; 35604360
Early onset or syndromic epilepsy v3.92 SEMA6B Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:35604360 reported new unrelated cases identified with heterozygous variants in SEMA6B. Out of 16 patients referred for ID clinic, 10 of them had epilepsy or myoclonus.

Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.
Early onset or syndromic epilepsy v3.92 SEMA6B Achchuthan Shanmugasundram Publications for gene: SEMA6B were set to 32169168; 35604360
Early onset or syndromic epilepsy v3.92 SEMA6B Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:35604360 reported new unrelated cases identified with heterozygous variants in SEMA6B. Out of 16 patients referred for ID clinic, 10 of them had epilepsy or myoclonus.

Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.
Early onset or syndromic epilepsy v3.92 SEMA6B Achchuthan Shanmugasundram Publications for gene: SEMA6B were set to 32169168
Early onset or syndromic epilepsy v3.91 GABRG2 Achchuthan Shanmugasundram Publications for gene: GABRG2 were set to 27066572; 11326275; 11326274; 34957497
Early onset or syndromic epilepsy v3.91 GABRG2 Achchuthan Shanmugasundram Publications for gene: GABRG2 were set to 27066572; 11326275; 11326274
Early onset or syndromic epilepsy v3.90 CPLX1 Sarah Leigh edited their review of gene: CPLX1: Added comment: Associated with Developmental and epileptic encephalopathy 63 (OMIM:617976), but not associated with a phenotype in Gen2Phen. Three CPLX1 variants have been reported in three unrelated cases, who all have intellectual disability and seizures (PMID:26539891; 28422131).; Changed rating: GREEN
Early onset or syndromic epilepsy v3.90 CPLX1 Sarah Leigh Classified gene: CPLX1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.90 CPLX1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.90 CPLX1 Sarah Leigh Gene: cplx1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.89 CPLX1 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: CPLX1.
Early onset or syndromic epilepsy v3.89 CPLX1 Sarah Leigh Phenotypes for gene: CPLX1 were changed from Epileptic encephalopathy, early infantile, 63, MIM# 617976 to Developmental and epileptic encephalopathy 63, OMIM:617976; developmental and epileptic encephalopathy, 63, MONDO:0033372
Early onset or syndromic epilepsy v3.88 CPLX1 Sarah Leigh Classified gene: CPLX1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.88 CPLX1 Sarah Leigh Gene: cplx1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.87 STXBP1 Sarah Leigh Publications for gene: STXBP1 were set to 31855252; 18469812; 19557857
Early onset or syndromic epilepsy v3.86 STXBP1 Sarah Leigh Added comment: Comment on mode of inheritance: Due to the report of biallelic STXBP1 variants in a family with encephalopathy, developmental delay, intellectual disability and epilepsy (PMID: 31855252), the mode of inheritance for this gene should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Early onset or syndromic epilepsy v3.86 STXBP1 Sarah Leigh Mode of inheritance for gene: STXBP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v3.85 STXBP1 Sarah Leigh reviewed gene: STXBP1: Rating: ; Mode of pathogenicity: None; Publications: 31855252, 35190816; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.85 STXBP1 Sarah Leigh Tag Q1_23_MOI tag was added to gene: STXBP1.
Early onset or syndromic epilepsy v3.85 STXBP1 Sarah Leigh Phenotypes for gene: STXBP1 were changed from Epileptic encephalopathy, early infantile, 4 to Developmental and epileptic encephalopathy 4, OMIM:612164; developmental and epileptic encephalopathy, 4, MONDO:0012812
Early onset or syndromic epilepsy v3.84 STXBP1 Sarah Leigh Publications for gene: STXBP1 were set to Saitsu et al (2008) Nature Genet 40 (6): 782-788
Early onset or syndromic epilepsy v3.83 EXT2 Sarah Leigh edited their review of gene: EXT2: Added comment: Associated Seizures, scoliosis, and macrocephaly syndrome in OMIM, but not associated with an equivalent phenotype in Gen2Phen. Six EXT2 variants have been reported four unrelated cases (PMID:26246518; 30288735; 30997052; 30075207).; Changed rating: GREEN
Early onset or syndromic epilepsy v3.83 EXT2 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: EXT2.
Early onset or syndromic epilepsy v3.83 EXT2 Sarah Leigh Classified gene: EXT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.83 EXT2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.83 EXT2 Sarah Leigh Gene: ext2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.82 EXT2 Sarah Leigh Phenotypes for gene: EXT2 were changed from Seizures, scoliosis, and macrocephaly syndrome, 616682 to Seizures, scoliosis, and macrocephaly syndrome, OMIM:616682; seizures-scoliosis-macrocephaly syndrome, MONDO:0014731
Early onset or syndromic epilepsy v3.81 EXT2 Sarah Leigh Publications for gene: EXT2 were set to 26246518; 30997052; 30288735; 30075207; 30806661
Early onset or syndromic epilepsy v3.80 EXT2 Sarah Leigh Publications for gene: EXT2 were set to 26246518; 30997052; 30288735; 30075207
Early onset or syndromic epilepsy v3.79 FOXRED1 Sarah Leigh Classified gene: FOXRED1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.79 FOXRED1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.79 FOXRED1 Sarah Leigh Gene: foxred1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.78 FOXRED1 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: FOXRED1.
Early onset or syndromic epilepsy v3.78 FOXRED1 Sarah Leigh edited their review of gene: FOXRED1: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least eleven variants have been reported in seven unrelated cases of Mitochondrial complex I deficiency, nuclear type 19, OMIM:618241 (20858599;20818383;27215383;31434271;30723688;33613441). Seizures were evident in six of these cases.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.78 FOXRED1 Sarah Leigh Publications for gene: FOXRED1 were set to 20858599; 20818383; 27215383; 31434271; 30723688
Early onset or syndromic epilepsy v3.77 FOXRED1 Sarah Leigh Publications for gene: FOXRED1 were set to 20858599; 20818383; 27215383; 31434271
Early onset or syndromic epilepsy v3.76 FOXRED1 Sarah Leigh Mode of inheritance for gene: FOXRED1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.75 FOXRED1 Sarah Leigh Publications for gene: FOXRED1 were set to 20858599, 20818383; 27215383; 31434271
Early onset or syndromic epilepsy v3.74 FOXRED1 Sarah Leigh Phenotypes for gene: FOXRED1 were changed from to Mitochondrial complex I deficiency, nuclear type 19, OMIM:618241; mitochondrial complex 1 deficiency, nuclear type 19, MONDO:0032624
Early onset or syndromic epilepsy v3.73 FOXRED1 Sarah Leigh Publications for gene: FOXRED1 were set to
Early onset or syndromic epilepsy v3.72 GRIA2 Sarah Leigh Classified gene: GRIA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.72 GRIA2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.72 GRIA2 Sarah Leigh Gene: gria2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.71 GRIA2 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: GRIA2.
Early onset or syndromic epilepsy v3.71 GRIA2 Sarah Leigh reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v3.71 GRIA2 Sarah Leigh Phenotypes for gene: GRIA2 were changed from Intellectual disability; Seizures; myoclonic seizures; status epilepticus; tonic-clonic seizures; focal seizures to Neurodevelopmental disorder with language impairment and behavioral abnormalities, OMIM:618917; neurodevelopmental disorder with language impairment and behavioral abnormalities, MONDO:0030060
Early onset or syndromic epilepsy v3.70 MAGI2 Sarah Leigh changed review comment from: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the next major review.; to: Comment on list classification: There is not enough evidence for this gene to be rated GREEN on this panel.
Early onset or syndromic epilepsy v3.70 MAGI2 Sarah Leigh Classified gene: MAGI2 as Green List (high evidence)
Early onset or syndromic epilepsy v3.70 MAGI2 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.70 MAGI2 Sarah Leigh Gene: magi2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v3.69 MAGI2 Sarah Leigh Tag Q1_23_demote_red tag was added to gene: MAGI2.
Early onset or syndromic epilepsy v3.69 MAGI2 Sarah Leigh edited their review of gene: MAGI2: Added comment: The association of MAGI2 deletions with epilepsy is disputed according to the ClinGen Epilepsy Gene Curation Expert Panel report (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7d622b88-9c77-47f8-93b1-808517da0cff-2018-06-19T160000.000Z?page=1&size=25&search= ). This expert panel outlines that although some of the deletions seen in epilepsy patients encompases MAGI2, other do not, suggesting the presence of another locus responsible for the epilepsy. Furthermore, no single-gene deletions or single nucleotide variants have been reported in MAGI2 in individuals with epilepsy.; Changed rating: RED
Early onset or syndromic epilepsy v3.69 MAGI2 Sarah Leigh Publications for gene: MAGI2 were set to 18565486; 27932480; 21694734
Early onset or syndromic epilepsy v3.68 MAGI2 Sarah Leigh Publications for gene: MAGI2 were set to 18565486; 27932480
Early onset or syndromic epilepsy v3.67 NUP214 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: NUP214.
Early onset or syndromic epilepsy v3.67 NUP214 Sarah Leigh edited their review of gene: NUP214: Added comment: Associated with Encephalopathy, acute, infection-induced, susceptibility to, 9, (OMIM:618426) and as strong Gen2Phen gene for Acute Febrile Encephalopathy. Four NUP214 variants have been reported in three unrelated families (PMID: 31178128; 30758658). Patient fibroblasts homozygous for rs1564175808 showed dysmorphic nuclei with an abnormal surface morphology and dramatic disruption of NUP214 localization from the nuclear rim similar to that observed in cells with knockdown of the NUP214 gene (PMID: 30758658). Developmental delay, epilespy and progressive severe microcephaly were reported in the three families reported above.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.67 NUP214 Sarah Leigh Phenotypes for gene: NUP214 were changed from Encephalopathy, acute, infection-induced, susceptibility to, 9, MIM# 618426; epileptic encephalopathy; developmental regression; microcephaly to Encephalopathy, acute, infection-induced, susceptibility to, 9, OMIM:618426; encephalopathy, acute, infection-induced, susceptibility to, 9, MONDO:0032742
Early onset or syndromic epilepsy v3.66 NUP214 Sarah Leigh Classified gene: NUP214 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.66 NUP214 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.66 NUP214 Sarah Leigh Gene: nup214 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.65 CAMLG Achchuthan Shanmugasundram gene: CAMLG was added
gene: CAMLG was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation, type IIz, OMIM:620201
Review for gene: CAMLG was set to RED
Added comment: Comment on classification of gene: This gene should be rated red as there is only one patient reported so far.

PMID:35262690 reported one patient with homozygous c.633 + 4A>G splice variant in CAMLG presented with a predominantly neurological phenotype with psychomotor disability, hypotonia, epilepsy and structural brain abnormalities.

This gene has already been associated with phenotype in OMIM (MIM #620201), but not in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v3.64 SLC39A8 Sarah Leigh edited their review of gene: SLC39A8: Added comment: Associated with Congenital disorder of glycosylation, type IIn (OMIM:616721) in OMIM and as definitive Gen2Phen gene for Intellectual Disability with Cerebellar Atrophy. At least five SLC39A8 variants have been reported in four unrelated cases of OMIM:616721 where seizures, infantile spasms or epilepsy have been reported (PMID: 26637978; 26637979). Haplotype analysis of the cases reported by PMID: 26637978, confirm that although the cases both were homozygous for the same variant (rs778210210), they were unrelated.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.64 SLC39A8 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: SLC39A8.
Early onset or syndromic epilepsy v3.64 SLC39A8 Sarah Leigh Classified gene: SLC39A8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.64 SLC39A8 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.64 SLC39A8 Sarah Leigh Gene: slc39a8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.63 SLC39A8 Sarah Leigh Phenotypes for gene: SLC39A8 were changed from Congenital disorder of glycosylation, type IIn , MIM#16721 to Congenital disorder of glycosylation, type IIn, OMIM:616721; SLC39A8-CDG, MONDO:0014746
Early onset or syndromic epilepsy v3.62 ST3GAL3 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: ST3GAL3.
Early onset or syndromic epilepsy v3.62 ST3GAL3 Sarah Leigh edited their review of gene: ST3GAL3: Added comment: Associated with Developmental and epileptic encephalopathy 15, OMIM:615006, but not associated with the same phenotype in Gen2Phen. At least two variants have been reported in two unrelated families (PMIDs: 23252400 & 31584066). Supportive functional studies are presented in PMID: 30089820.; Changed rating: GREEN; Changed publications to: 23252400, 30089820, 31584066
Early onset or syndromic epilepsy v3.62 ST3GAL3 Sarah Leigh Classified gene: ST3GAL3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.62 ST3GAL3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.62 ST3GAL3 Sarah Leigh Gene: st3gal3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.61 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066; 17120046; 25529582
Early onset or syndromic epilepsy v3.60 ST3GAL3 Sarah Leigh Mode of inheritance for gene: ST3GAL3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.59 ST3GAL3 Sarah Leigh Added comment: Comment on phenotypes: ST3GAL3 are also associated with: Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612, however, this phenotype does not include seizures.
Early onset or syndromic epilepsy v3.59 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003
Early onset or syndromic epilepsy v3.58 DOLK Sarah Leigh Tag Q1_23_promote_green tag was added to gene: DOLK.
Early onset or syndromic epilepsy v3.58 DOLK Sarah Leigh edited their review of gene: DOLK: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least five DOLK variants have been reported in four unrelated cases of Congenital disorder of glycosylation, type Im, OMIM:610768, where seizures were reported in the patients (PMID: 28816422 table 1)(PMID 24144945;23890587;17273964).; Changed rating: GREEN
Early onset or syndromic epilepsy v3.58 DOLK Sarah Leigh Phenotypes for gene: DOLK were changed from Congenital disorder of glycosylation, type Im, 610768 to Congenital disorder of glycosylation, type Im, OMIM:610768; DK1-congenital disorder of glycosylation, MONDO:0012556
Early onset or syndromic epilepsy v3.57 DOLK Sarah Leigh Classified gene: DOLK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.57 DOLK Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.57 DOLK Sarah Leigh Gene: dolk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.56 DOLK Sarah Leigh Publications for gene: DOLK were set to 23890587; 17273964; 24144945; 28816422
Early onset or syndromic epilepsy v3.55 FGFR3 Sarah Leigh edited their review of gene: FGFR3: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene for hypochondroplasia. The variant NM_000142.5(FGFR3):c.1620C>A (p.Asn540Lys) has been reported in at least six unrelated cases of hypochondroplasia (OMIM:146000), in which the patients also display epileptic seizures (PMIDs:12794698; 16222682;17621485 ;2463028; 23165795; 27485793). Biallelic FGFR3 variants have been also been reported in a novel phenotype of achondroplasia, which also includes seizures (PMID: 30160829). Migrating neonatal seizures were also reported in a case of Muenke syndrome (OMIM:602849), carrying the variant: NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)(PMID: 28551036).; Changed rating: GREEN
Early onset or syndromic epilepsy v3.55 FGFR3 Sarah Leigh Classified gene: FGFR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.55 FGFR3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.55 FGFR3 Sarah Leigh Gene: fgfr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.54 FGFR3 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: FGFR3.
Early onset or syndromic epilepsy v3.54 FGFR3 Sarah Leigh Publications for gene: FGFR3 were set to 30160829; 28551036; 27485793; 23649205; 24630288; 17621485; 16222682; 12794698; 23044018; 12794698; 18000976; http://doi.org/10.15844/pedneurbriefs-26-12-6; http://www.ashg.org/genetics/ashg07s/f20570.htm; https://jicna.org/index.php/journal/article/view/100
Early onset or syndromic epilepsy v3.53 FGFR3 Sarah Leigh Added comment: Comment on phenotypes: Isolated seizures have also been reported in cases with: Muenke syndrome, OMIM:602849;Muenke syndrome, MONDO:0011274;SADDAN, OMIM:616482;severe achondroplasia-developmental delay-acanthosis nigricans syndrome, MONDO:0014658
Early onset or syndromic epilepsy v3.53 FGFR3 Sarah Leigh Phenotypes for gene: FGFR3 were changed from Hypochondroplasia, OMIM:146000; hypochondroplasia, MONDO:0007793; Muenke syndrome, OMIM:602849; Muenke syndrome, MONDO:0011274; SADDAN, OMIM:616482; severe achondroplasia-developmental delay-acanthosis nigricans syndrome, MONDO:0014658 to Hypochondroplasia, OMIM:146000; hypochondroplasia, MONDO:0007793
Early onset or syndromic epilepsy v3.52 FGFR3 Sarah Leigh Publications for gene: FGFR3 were set to 28551036; 27485793; 23649205; 24630288; 17621485; 16222682; 12794698; 23044018; 12794698; 18000976; http://doi.org/10.15844/pedneurbriefs-26-12-6; http://www.ashg.org/genetics/ashg07s/f20570.htm; https://jicna.org/index.php/journal/article/view/100
Early onset or syndromic epilepsy v3.51 FGFR3 Sarah Leigh Phenotypes for gene: FGFR3 were changed from Hypochondroplasia, 146000; Focal Epilepsy; Muenke syndrome, 602849; Epilepsy to Hypochondroplasia, OMIM:146000; hypochondroplasia, MONDO:0007793; Muenke syndrome, OMIM:602849; Muenke syndrome, MONDO:0011274; SADDAN, OMIM:616482; severe achondroplasia-developmental delay-acanthosis nigricans syndrome, MONDO:0014658
Early onset or syndromic epilepsy v3.50 GABRB1 Sarah Leigh Tag Q1_23_promote_green tag was added to gene: GABRB1.
Early onset or syndromic epilepsy v3.50 GABRB1 Sarah Leigh edited their review of gene: GABRB1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least three variants have been reported in unrelated cases with epilepsy (PMID: 26950270, 27273810, 31618474).; Changed rating: GREEN
Early onset or syndromic epilepsy v3.50 GABRB1 Sarah Leigh Classified gene: GABRB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.50 GABRB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.50 GABRB1 Sarah Leigh Gene: gabrb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.49 GABRB1 Sarah Leigh Phenotypes for gene: GABRB1 were changed from Epileptic encephalopathy, early infantile, 45, 617153 to Epileptic encephalopathy, early infantile, 45, OMIM:617153; developmental and epileptic encephalopathy, 45, MONDO:0014942
Early onset or syndromic epilepsy v3.48 GABRB1 Sarah Leigh Publications for gene: GABRB1 were set to 26950270; 27273810
Early onset or syndromic epilepsy v3.47 NEDD4L Sarah Leigh Tag Q1_23_promote_green tag was added to gene: NEDD4L.
Early onset or syndromic epilepsy v3.47 NEDD4L Sarah Leigh edited their review of gene: NEDD4L: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least five variants have been reported in cases where seizures are reported (PMIDs:28515470, 27694961, 32117442).; Changed rating: GREEN; Changed publications to: 32117442
Early onset or syndromic epilepsy v3.47 NEDD4L Sarah Leigh Classified gene: NEDD4L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.47 NEDD4L Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v3.47 NEDD4L Sarah Leigh Gene: nedd4l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.46 CACNA1C Eleanor Williams Added comment: Comment on phenotypes: Adding back the phenotype of 'CACNA1C-related disorder' as this was specifically asked to be added by NHSE.
Early onset or syndromic epilepsy v3.46 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Timothy syndrome OMIM:601005 to Timothy syndrome OMIM:601005; CACNA1C-related disorder
Early onset or syndromic epilepsy v3.45 ARX Achchuthan Shanmugasundram Publications for gene: ARX were set to Tsurusaki et al (2002) Nature 30: 441-445; Kato et al (2004) Hum Mut 23: 147-159; Bienvenu et al (2002) Hum Mol Genet 11(8): 981-991; Partington et al (1998) Am J Med Genet 30: 251-262; 35094084
Early onset or syndromic epilepsy v3.44 ARX Achchuthan Shanmugasundram Publications for gene: ARX were set to Tsurusaki et al (2002) Nature 30: 441-445; Kato et al (2004) Hum Mut 23: 147-159; Bienvenu et al (2002) Hum Mol Genet 11(8): 981-991; Partington et al (1998) Am J Med Genet 30: 251-262
Early onset or syndromic epilepsy v3.43 NEDD4L Sarah Leigh Phenotypes for gene: NEDD4L were changed from Periventricular nodular heterotopia 7, 617201 to Periventricular nodular heterotopia 7, OMIM:617201; periventricular nodular heterotopia 7, MONDO:0014966
Early onset or syndromic epilepsy v3.42 NEDD4L Sarah Leigh Publications for gene: NEDD4L were set to 28515470; 23934111; 28212375; 27694961
Early onset or syndromic epilepsy v3.41 NEDD4L Sarah Leigh Publications for gene: NEDD4L were set to 27694961; 23934111
Early onset or syndromic epilepsy v3.40 NPRL2 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:34965576 describes conditional knockout mouse model of NPRL2-related epilepsy.
Early onset or syndromic epilepsy v3.40 NPRL2 Achchuthan Shanmugasundram Publications for gene: NPRL2 were set to 26505888; 27173016; 30093711
Early onset or syndromic epilepsy v3.39 NPRL3 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:34965576 describes conditional knockout mouse model of NPRL3-related epilepsy.
Early onset or syndromic epilepsy v3.39 NPRL3 Achchuthan Shanmugasundram Publications for gene: NPRL3 were set to 26505888; 26285051; 27173016; 34965576
Early onset or syndromic epilepsy v3.38 NPRL3 Achchuthan Shanmugasundram Publications for gene: NPRL3 were set to 26505888; 26285051; 27173016
Early onset or syndromic epilepsy v3.37 TRPM3 Eleanor Williams Tag gene-checked was removed from gene: TRPM3.
Early onset or syndromic epilepsy v3.37 TRPM3 Eleanor Williams Phenotypes for gene: TRPM3 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, OMIM:620224
Early onset or syndromic epilepsy v3.36 FAR1 Eleanor Williams Tag Q2_21_expert_review was removed from gene: FAR1.
Tag Q2_21_MOI was removed from gene: FAR1.
Tag Q3_22_NHS_review was removed from gene: FAR1.
Early onset or syndromic epilepsy v3.36 FAR1 Eleanor Williams commented on gene: FAR1
Early onset or syndromic epilepsy v3.36 FAR1 Eleanor Williams Classified gene: FAR1 as Green List (high evidence)
Early onset or syndromic epilepsy v3.36 FAR1 Eleanor Williams Gene: far1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v3.35 MED12 Eleanor Williams Tag Q3_21_MOI was removed from gene: MED12.
Tag Q3_21_expert_review was removed from gene: MED12.
Early onset or syndromic epilepsy v3.35 SPATA5L1 Eleanor Williams Tag gene-checked tag was added to gene: SPATA5L1.
Early onset or syndromic epilepsy v3.35 WNK3 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: WNK3.
Early onset or syndromic epilepsy v3.35 SCAMP5 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v3.35 RAB11A Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: RAB11A.
Early onset or syndromic epilepsy v3.35 DROSHA Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: DROSHA.
Early onset or syndromic epilepsy v3.35 BLOC1S1 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: BLOC1S1.
Early onset or syndromic epilepsy v3.35 PGM2L1 Achchuthan Shanmugasundram Phenotypes for gene: PGM2L1 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities, OMIM:620191
Early onset or syndromic epilepsy v3.34 PGM2L1 Achchuthan Shanmugasundram Tag gene-checked was removed from gene: PGM2L1.
Early onset or syndromic epilepsy v3.34 CAPRIN1 Achchuthan Shanmugasundram Tag Q1_23_promote_green tag was added to gene: CAPRIN1.
Early onset or syndromic epilepsy v3.34 CAPRIN1 Achchuthan Shanmugasundram Publications for gene: CAPRIN1 were set to 35979925; 35977029; 28135719; 31398340; https://doi.org/10.1101/2021.12.20.21267194
Early onset or syndromic epilepsy v3.33 CAPRIN1 Achchuthan Shanmugasundram Classified gene: CAPRIN1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.33 CAPRIN1 Achchuthan Shanmugasundram Gene: caprin1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.32 CAPRIN1 Achchuthan Shanmugasundram reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979925; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, Epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v3.32 ISCA-37429-Loss Arina Puzriakova Phenotypes for Region: ISCA-37429-Loss were changed from 194190; Wolf-Hirschhorn syndrome to Wolf-Hirschhorn syndrome, OMIM:194190
Early onset or syndromic epilepsy v3.31 ISCA-46297-Loss Arina Puzriakova reviewed Region: ISCA-46297-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v3.31 ISCA-46304-Gain Arina Puzriakova edited their review of Region: ISCA-46304-Gain: Changed rating: GREEN
Early onset or syndromic epilepsy v3.31 ISCA-46304-Gain Arina Puzriakova commented on Region: ISCA-46304-Gain
Early onset or syndromic epilepsy v3.31 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Following Genomics England clinical review and NHS Genomic Medicine Service approval, the genomic coordinates and triplosensitivity score (from 3 to 2) of this region were updated based on ClinGen Region Curation Results (version on 05 Aug 2022). Regardless of the change in triplosensitivity score, it was deemed appropriate for this regions to remain green as evidence to support pathogenicity remains.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.31 ISCA-46297-Loss Arina Puzriakova Region: ISCA-46297-Loss was added
Region: ISCA-46297-Loss was added to Genetic epilepsy syndromes. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46297-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46297-Loss were set to 31204719; 19888295; 20301607; 25719193; 30836598
Early onset or syndromic epilepsy v3.31 ISCA-46304-Gain Arina Puzriakova Region: ISCA-46304-Gain was added
Region: ISCA-46304-Gain was added to Genetic epilepsy syndromes. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46304-Gain 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 Region: ISCA-46304-Gain were set to 22679399; 29141583; 29618507; 32043567
Early onset or syndromic epilepsy v3.31 ISCA-37423-Gain Arina Puzriakova GRCh38 position for ISCA-37423-Gain was changed from 8261773-11908210 to 8242542-11908820.
Triplosensitivity Score for ISCA-37423-Gain was changed from 3 to 2.
Early onset or syndromic epilepsy v3.30 YIPF5 Arina Puzriakova Tag Q2_21_rating was removed from gene: YIPF5.
Early onset or syndromic epilepsy v3.30 TNPO2 Arina Puzriakova Tag Q3_21_rating was removed from gene: TNPO2.
Early onset or syndromic epilepsy v3.30 TMEM222 Arina Puzriakova Tag Q2_21_rating was removed from gene: TMEM222.
Early onset or syndromic epilepsy v3.30 SPATA5L1 Arina Puzriakova Tag Q1_22_rating was removed from gene: SPATA5L1.
Early onset or syndromic epilepsy v3.30 SPTBN1 Arina Puzriakova Tag Q3_21_rating was removed from gene: SPTBN1.
Early onset or syndromic epilepsy v3.30 SATB1 Arina Puzriakova Tag Q2_21_rating was removed from gene: SATB1.
Early onset or syndromic epilepsy v3.30 SCAMP5 Arina Puzriakova Tag watchlist was removed from gene: SCAMP5.
Tag Q2_21_rating was removed from gene: SCAMP5.
Early onset or syndromic epilepsy v3.30 PRPF8 Arina Puzriakova Tag Q2_22_rating was removed from gene: PRPF8.
Early onset or syndromic epilepsy v3.30 PMPCB Arina Puzriakova Tag Q2_21_rating was removed from gene: PMPCB.
Early onset or syndromic epilepsy v3.30 PIDD1 Arina Puzriakova Tag Q3_21_rating was removed from gene: PIDD1.
Early onset or syndromic epilepsy v3.30 PGM2L1 Arina Puzriakova Tag Q3_21_rating was removed from gene: PGM2L1.
Early onset or syndromic epilepsy v3.30 PCDHGC4 Arina Puzriakova Tag Q3_21_rating was removed from gene: PCDHGC4.
Early onset or syndromic epilepsy v3.30 NEUROD2 Arina Puzriakova Tag Q2_21_rating was removed from gene: NEUROD2.
Early onset or syndromic epilepsy v3.30 NAPB Arina Puzriakova Tag Q2_22_rating was removed from gene: NAPB.
Tag Q2_22_NHS_review was removed from gene: NAPB.
Early onset or syndromic epilepsy v3.30 MINPP1 Arina Puzriakova Tag Q2_21_rating was removed from gene: MINPP1.
Early onset or syndromic epilepsy v3.30 MED27 Arina Puzriakova Tag Q2_21_rating was removed from gene: MED27.
Early onset or syndromic epilepsy v3.30 KCND2 Arina Puzriakova Tag Q4_21_rating was removed from gene: KCND2.
Early onset or syndromic epilepsy v3.30 KCNH1 Arina Puzriakova Tag Q2_21_rating was removed from gene: KCNH1.
Early onset or syndromic epilepsy v3.30 KCNC2 Arina Puzriakova Tag Q2_22_rating was removed from gene: KCNC2.
Early onset or syndromic epilepsy v3.30 HID1 Arina Puzriakova Tag Q3_21_rating was removed from gene: HID1.
Early onset or syndromic epilepsy v3.30 GRIK2 Arina Puzriakova Tag Q4_21_rating was removed from gene: GRIK2.
Early onset or syndromic epilepsy v3.30 EMC10 Arina Puzriakova Tag Q2_21_rating was removed from gene: EMC10.
Early onset or syndromic epilepsy v3.30 DTYMK Arina Puzriakova Tag Q2_22_rating was removed from gene: DTYMK.
Early onset or syndromic epilepsy v3.30 DROSHA Arina Puzriakova Tag Q2_22_rating was removed from gene: DROSHA.
Early onset or syndromic epilepsy v3.30 DHDDS Arina Puzriakova Tag Q4_21_MOI was removed from gene: DHDDS.
Early onset or syndromic epilepsy v3.30 DEAF1 Arina Puzriakova Tag Q4_21_MOI was removed from gene: DEAF1.
Early onset or syndromic epilepsy v3.30 CLCN3 Arina Puzriakova Tag Q3_21_rating was removed from gene: CLCN3.
Early onset or syndromic epilepsy v3.30 CHD5 Arina Puzriakova Tag Q3_21_rating was removed from gene: CHD5.
Early onset or syndromic epilepsy v3.30 CELF2 Arina Puzriakova Tag Q2_22_rating was removed from gene: CELF2.
Tag Q2_22_NHS_review was removed from gene: CELF2.
Early onset or syndromic epilepsy v3.30 CACNA1I Arina Puzriakova Tag Q4_21_rating was removed from gene: CACNA1I.
Early onset or syndromic epilepsy v3.30 ARFGEF1 Arina Puzriakova Tag Q4_21_rating was removed from gene: ARFGEF1.
Early onset or syndromic epilepsy v3.30 ARF1 Arina Puzriakova Tag Q3_21_rating was removed from gene: ARF1.
Early onset or syndromic epilepsy v3.30 AP1G1 Arina Puzriakova Tag Q3_21_rating was removed from gene: AP1G1.
Early onset or syndromic epilepsy v3.30 ACOX1 Arina Puzriakova Tag Q3_21_MOI was removed from gene: ACOX1.
Early onset or syndromic epilepsy v3.30 CERS1 Arina Puzriakova Tag Q2_21_rating was removed from gene: CERS1.
Tag Q3_21_expert_review was removed from gene: CERS1.
Tag Q3_21_phenotype was removed from gene: CERS1.
Tag Q3_22_NHS_review was removed from gene: CERS1.
Early onset or syndromic epilepsy v3.30 WNK3 Arina Puzriakova Tag Q3_22_rating was removed from gene: WNK3.
Early onset or syndromic epilepsy v3.30 TIAM1 Arina Puzriakova Tag Q3_22_rating was removed from gene: TIAM1.
Tag Q3_22_MOI was removed from gene: TIAM1.
Early onset or syndromic epilepsy v3.30 TAF8 Arina Puzriakova Tag Q3_22_rating was removed from gene: TAF8.
Early onset or syndromic epilepsy v3.30 SNIP1 Arina Puzriakova Tag Q3_22_rating was removed from gene: SNIP1.
Tag Q3_22_expert_review was removed from gene: SNIP1.
Early onset or syndromic epilepsy v3.30 SLC38A3 Arina Puzriakova Tag Q3_22_rating was removed from gene: SLC38A3.
Early onset or syndromic epilepsy v3.30 OGDHL Arina Puzriakova Tag Q3_22_rating was removed from gene: OGDHL.
Early onset or syndromic epilepsy v3.30 NSRP1 Arina Puzriakova Tag Q3_22_rating was removed from gene: NSRP1.
Early onset or syndromic epilepsy v3.30 GLRA2 Arina Puzriakova Tag Q3_22_rating was removed from gene: GLRA2.
Tag Q3_22_MOI was removed from gene: GLRA2.
Early onset or syndromic epilepsy v3.30 FBXO28 Arina Puzriakova Tag Q3_22_rating was removed from gene: FBXO28.
Tag Q3_22_MOI was removed from gene: FBXO28.
Early onset or syndromic epilepsy v3.30 FASTKD2 Arina Puzriakova Tag Q3_22_rating was removed from gene: FASTKD2.
Early onset or syndromic epilepsy v3.30 CUL3 Arina Puzriakova Tag Q3_22_rating was removed from gene: CUL3.
Early onset or syndromic epilepsy v3.30 CLPB Arina Puzriakova Tag Q3_22_rating was removed from gene: CLPB.
Tag Q3_22_MOI was removed from gene: CLPB.
Tag Q3_22_expert_review was removed from gene: CLPB.
Early onset or syndromic epilepsy v3.30 CHKA Arina Puzriakova Tag Q3_22_rating was removed from gene: CHKA.
Tag Q3_22_MOI was removed from gene: CHKA.
Early onset or syndromic epilepsy v3.30 CACNA1A Arina Puzriakova Tag Q3_22_MOI was removed from gene: CACNA1A.
Tag Q3_22_NHS_review was removed from gene: CACNA1A.
Early onset or syndromic epilepsy v3.30 ATP6V0A1 Arina Puzriakova Tag watchlist_moi tag was added to gene: ATP6V0A1.
Early onset or syndromic epilepsy v3.30 ATP6V0A1 Arina Puzriakova Tag Q3_22_rating was removed from gene: ATP6V0A1.
Tag Q3_22_MOI was removed from gene: ATP6V0A1.
Early onset or syndromic epilepsy v3.30 ASH1L Arina Puzriakova Publications for gene: ASH1L were set to 34373061; 25961944
Early onset or syndromic epilepsy v3.29 ASH1L Arina Puzriakova Tag Q3_22_rating was removed from gene: ASH1L.
Tag Q3_22_expert_review was removed from gene: ASH1L.
Early onset or syndromic epilepsy v3.29 CACNA1C Arina Puzriakova reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 YIPF5 Arina Puzriakova edited their review of gene: YIPF5: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 TNPO2 Arina Puzriakova commented on gene: TNPO2: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 TMEM222 Arina Puzriakova reviewed gene: TMEM222: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 SPTBN1 Arina Puzriakova reviewed gene: SPTBN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 SPATA5L1 Arina Puzriakova reviewed gene: SPATA5L1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 SCAMP5 Arina Puzriakova reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 SATB1 Arina Puzriakova commented on gene: SATB1: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 PRPF8 Arina Puzriakova reviewed gene: PRPF8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 PMPCB Arina Puzriakova reviewed gene: PMPCB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 PIDD1 Arina Puzriakova edited their review of gene: PIDD1: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 PGM2L1 Arina Puzriakova edited their review of gene: PGM2L1: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 PCDHGC4 Arina Puzriakova reviewed gene: PCDHGC4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 NEUROD2 Arina Puzriakova commented on gene: NEUROD2: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 NAPB Arina Puzriakova edited their review of gene: NAPB: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 MINPP1 Arina Puzriakova edited their review of gene: MINPP1: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 MED27 Arina Puzriakova commented on gene: MED27: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 KCNH1 Arina Puzriakova commented on gene: KCNH1: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 KCND2 Arina Puzriakova reviewed gene: KCND2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 KCNC2 Arina Puzriakova reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 HID1 Arina Puzriakova commented on gene: HID1: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 GRIK2 Arina Puzriakova reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 EMC10 Arina Puzriakova commented on gene: EMC10: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 DTYMK Arina Puzriakova reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 DROSHA Arina Puzriakova reviewed gene: DROSHA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 DHDDS Arina Puzriakova commented on gene: DHDDS: The mode of inheritance of this gene has been updated to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 DEAF1 Arina Puzriakova commented on gene: DEAF1
Early onset or syndromic epilepsy v3.29 CLCN3 Arina Puzriakova edited their review of gene: CLCN3: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 CHD5 Arina Puzriakova reviewed gene: CHD5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 CELF2 Arina Puzriakova edited their review of gene: CELF2: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 CACNA1I Arina Puzriakova reviewed gene: CACNA1I: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 ARFGEF1 Arina Puzriakova reviewed gene: ARFGEF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 ARF1 Arina Puzriakova commented on gene: ARF1: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 AP1G1 Arina Puzriakova edited their review of gene: AP1G1: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 ACOX1 Arina Puzriakova commented on gene: ACOX1
Early onset or syndromic epilepsy v3.29 MED12 Arina Puzriakova commented on gene: MED12
Early onset or syndromic epilepsy v3.29 FAR1 Arina Puzriakova commented on gene: FAR1: The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 CERS1 Arina Puzriakova reviewed gene: CERS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 WNK3 Arina Puzriakova commented on gene: WNK3: The rating of this gene has been updated to Green and the mode of inheritance set to 'X-LINKED: hemizygous mutation in males, biallelic mutations in females' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 TIAM1 Arina Puzriakova reviewed gene: TIAM1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 TAF8 Arina Puzriakova edited their review of gene: TAF8: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 SNIP1 Arina Puzriakova reviewed gene: SNIP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 SLC38A3 Arina Puzriakova reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 OGDHL Arina Puzriakova edited their review of gene: OGDHL: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 NSRP1 Arina Puzriakova edited their review of gene: NSRP1: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 GLRA2 Arina Puzriakova reviewed gene: GLRA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 FBXO28 Arina Puzriakova reviewed gene: FBXO28: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 FASTKD2 Arina Puzriakova commented on gene: FASTKD2: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v3.29 CUL3 Arina Puzriakova edited their review of gene: CUL3: Added comment: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 CLPB Arina Puzriakova edited their review of gene: CLPB: Added comment: The rating of this gene has been updated to Green and the mode of inheritance updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Early onset or syndromic epilepsy v3.29 CHKA Arina Puzriakova reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 CACNA1A Arina Puzriakova commented on gene: CACNA1A
Early onset or syndromic epilepsy v3.29 ATP6V0A1 Arina Puzriakova reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.29 ASH1L Arina Puzriakova reviewed gene: ASH1L: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v3.28 YIPF5 Arina Puzriakova Source Expert Review Green was added to YIPF5.
Source NHS GMS was added to YIPF5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 WNK3 Arina Puzriakova Source Expert Review Green was added to WNK3.
Source NHS GMS was added to WNK3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 TNPO2 Arina Puzriakova Source Expert Review Green was added to TNPO2.
Source NHS GMS was added to TNPO2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 TMEM222 Arina Puzriakova Source Expert Review Green was added to TMEM222.
Source NHS GMS was added to TMEM222.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 TIAM1 Arina Puzriakova Source Expert Review Green was added to TIAM1.
Source NHS GMS was added to TIAM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 TAF8 Arina Puzriakova Source Expert Review Green was added to TAF8.
Source NHS GMS was added to TAF8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 SPTBN1 Arina Puzriakova Source Expert Review Green was added to SPTBN1.
Source NHS GMS was added to SPTBN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 SPATA5L1 Arina Puzriakova Source Expert Review Green was added to SPATA5L1.
Source NHS GMS was added to SPATA5L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 SNIP1 Arina Puzriakova Source Expert Review Green was added to SNIP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 SLC38A3 Arina Puzriakova Source Expert Review Green was added to SLC38A3.
Source NHS GMS was added to SLC38A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 SCAMP5 Arina Puzriakova Source Expert Review Green was added to SCAMP5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 SATB1 Arina Puzriakova Source Expert Review Green was added to SATB1.
Source NHS GMS was added to SATB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 PRPF8 Arina Puzriakova Source Expert Review Green was added to PRPF8.
Source NHS GMS was added to PRPF8.
Mode of inheritance for gene PRPF8 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 PMPCB Arina Puzriakova Source Expert Review Green was added to PMPCB.
Source NHS GMS was added to PMPCB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 PIDD1 Arina Puzriakova Source Expert Review Green was added to PIDD1.
Source NHS GMS was added to PIDD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 PGM2L1 Arina Puzriakova Source Expert Review Green was added to PGM2L1.
Source NHS GMS was added to PGM2L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 PCDHGC4 Arina Puzriakova Source Expert Review Green was added to PCDHGC4.
Source NHS GMS was added to PCDHGC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 OGDHL Arina Puzriakova Source Expert Review Green was added to OGDHL.
Source NHS GMS was added to OGDHL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 NSRP1 Arina Puzriakova Source Expert Review Green was added to NSRP1.
Source NHS GMS was added to NSRP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 NEUROD2 Arina Puzriakova Source Expert Review Green was added to NEUROD2.
Source NHS GMS was added to NEUROD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 NAPB Arina Puzriakova Source Expert Review Green was added to NAPB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 MINPP1 Arina Puzriakova Source Expert Review Green was added to MINPP1.
Source NHS GMS was added to MINPP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 MED27 Arina Puzriakova Source Expert Review Green was added to MED27.
Source NHS GMS was added to MED27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 KCNH1 Arina Puzriakova Source Expert Review Green was added to KCNH1.
Source NHS GMS was added to KCNH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 KCND2 Arina Puzriakova Source Expert Review Green was added to KCND2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 KCNC2 Arina Puzriakova Source Expert Review Green was added to KCNC2.
Source NHS GMS was added to KCNC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 HID1 Arina Puzriakova Source Expert Review Green was added to HID1.
Source NHS GMS was added to HID1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 GRIK2 Arina Puzriakova Source Expert Review Green was added to GRIK2.
Source NHS GMS was added to GRIK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 GLRA2 Arina Puzriakova Source Expert Review Green was added to GLRA2.
Source NHS GMS was added to GLRA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 FBXO28 Arina Puzriakova Source Expert Review Green was added to FBXO28.
Source NHS GMS was added to FBXO28.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 FASTKD2 Arina Puzriakova Source Expert Review Green was added to FASTKD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 FAR1 Arina Puzriakova Mode of inheritance for gene FAR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.28 EMC10 Arina Puzriakova Source Expert Review Green was added to EMC10.
Source NHS GMS was added to EMC10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 DTYMK Arina Puzriakova Source Expert Review Green was added to DTYMK.
Source NHS GMS was added to DTYMK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 DROSHA Arina Puzriakova Source Expert Review Green was added to DROSHA.
Source NHS GMS was added to DROSHA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 DHDDS Arina Puzriakova Mode of inheritance for gene DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v3.28 DEAF1 Arina Puzriakova Mode of inheritance for gene DEAF1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.28 CUL3 Arina Puzriakova Source Expert Review Green was added to CUL3.
Source NHS GMS was added to CUL3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CLPB Arina Puzriakova Source Expert Review Green was added to CLPB.
Source NHS GMS was added to CLPB.
Mode of inheritance for gene CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CLCN3 Arina Puzriakova Source Expert Review Green was added to CLCN3.
Source NHS GMS was added to CLCN3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CHKA Arina Puzriakova Source Expert Review Green was added to CHKA.
Source NHS GMS was added to CHKA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CHD5 Arina Puzriakova Source Expert Review Green was added to CHD5.
Source NHS GMS was added to CHD5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CERS1 Arina Puzriakova Source Expert Review Green was added to CERS1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CELF2 Arina Puzriakova Source Expert Review Green was added to CELF2.
Source NHS GMS was added to CELF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CACNA1I Arina Puzriakova Source Expert Review Green was added to CACNA1I.
Source NHS GMS was added to CACNA1I.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CACNA1C Arina Puzriakova Source Expert Review Green was added to CACNA1C.
Source NHS GMS was added to CACNA1C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 CACNA1A Arina Puzriakova Mode of inheritance for gene CACNA1A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.28 ATP6V0A1 Arina Puzriakova Source Expert Review Green was added to ATP6V0A1.
Source NHS GMS was added to ATP6V0A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 ASH1L Arina Puzriakova Source Expert Review Green was added to ASH1L.
Source NHS GMS was added to ASH1L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 ARFGEF1 Arina Puzriakova Source Expert Review Green was added to ARFGEF1.
Source NHS GMS was added to ARFGEF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 ARF1 Arina Puzriakova Source Expert Review Green was added to ARF1.
Source NHS GMS was added to ARF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 AP1G1 Arina Puzriakova Source Expert Review Green was added to AP1G1.
Source NHS GMS was added to AP1G1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v3.28 ACOX1 Arina Puzriakova Mode of inheritance for gene ACOX1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.27 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.26 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, OMIM:617159 to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.26 CHD4 Mafalda Gomes Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, MIM# 617159; Childhood idiopathic epilepsy and sinus arrhythmia to Sifrim-Hitz-Weiss syndrome, OMIM:617159
Early onset or syndromic epilepsy v3.25 CHD4 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: CHD4.
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.25 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome, OMIM:615115 to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.24 ASXL3 Mafalda Gomes Phenotypes for gene: ASXL3 were changed from Bainbridge-Ropers syndrome to Bainbridge-Ropers syndrome, OMIM:615115
Early onset or syndromic epilepsy v3.23 ASXL3 Mafalda Gomes Publications for gene: ASXL3 were set to 35172777; 27901041; 34436830; 33151654
Early onset or syndromic epilepsy v3.23 ASXL3 Mafalda Gomes Publications for gene: ASXL3 were set to 35172777; 27901041; 34436830
Early onset or syndromic epilepsy v3.22 ASXL3 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: ASXL3.
Early onset or syndromic epilepsy v3.22 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.22 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome, OMIM:619762 to Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.22 BAP1 Mafalda Gomes Phenotypes for gene: BAP1 were changed from to Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.21 BAP1 Mafalda Gomes Tag Q1_23_promote_green tag was added to gene: BAP1.
Early onset or syndromic epilepsy v3.21 CHD4 Mafalda Gomes reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: ; Publications: 34109749; Phenotypes: Sifrim-Hitz-Weiss syndrome, OMIM:617159; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v3.21 ASXL3 Mafalda Gomes reviewed gene: ASXL3: Rating: GREEN; Mode of pathogenicity: ; Publications: 34436830, 33151654; Phenotypes: Bainbridge-Ropers syndrome, OMIM:615115; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v3.21 BAP1 Mafalda Gomes commented on gene: BAP1: Kry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance.
Early onset or syndromic epilepsy v3.20 CHD4 Mafalda Gomes Source Expert Review Amber was added to CHD4.
Mode of inheritance for gene CHD4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.20 ASXL3 Mafalda Gomes Source Expert Review Amber was added to ASXL3.
Mode of inheritance for gene ASXL3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.20 BAP1 Mafalda Gomes Source Expert Review Amber was added to BAP1.
Rating Changed from No List (delete) to Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.19 CUX2 Sarah Leigh Tag Q1_23_MOI tag was added to gene: CUX2.
Tag Q1_23_NHS_review tag was added to gene: CUX2.
Early onset or syndromic epilepsy v3.19 CUX2 Sarah Leigh edited their review of gene: CUX2: Added comment: It is recommended that the mode of inheritance of CUX2 is changed from:
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, based on the review by Tracy Lester (Genetics laboratory, Oxford UK)(14 Nov 2022).; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v3.19 TUBB2B Arina Puzriakova Phenotypes for gene: TUBB2B were changed from Cortical dysplasia, complex, with other brain malformations 7, 610031 to Cortical dysplasia, complex, with other brain malformations 7, OMIM:610031
Early onset or syndromic epilepsy v3.18 PAFAH1B1 Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from Lissencephaly 1 607432 to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432
Early onset or syndromic epilepsy v3.17 NPRL2 Arina Puzriakova Phenotypes for gene: NPRL2 were changed from Epilepsy, familial focal, with variable foci 2, 617116 to Epilepsy, familial focal, with variable foci 2, OMIM:617116
Early onset or syndromic epilepsy v3.16 DCX Arina Puzriakova Phenotypes for gene: DCX were changed from Lissencephaly, X-linked 300067; Subcortical laminal heterotopia, X-linked 300067 to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067
Early onset or syndromic epilepsy v3.15 DDX3X Arina Puzriakova Phenotypes for gene: DDX3X were changed from Mental retardation, X-linked 102, 300958 to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Early onset or syndromic epilepsy v3.14 COX15 Arina Puzriakova Phenotypes for gene: COX15 were changed from Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 615119; Leigh syndrome 256000 to Mitochondrial complex IV deficiency, nuclear type 6, OMIM:615119
Early onset or syndromic epilepsy v3.13 COX10 Arina Puzriakova Phenotypes for gene: COX10 were changed from to Mitochondrial complex IV deficiency, nuclear type 3, OMIM:619046
Early onset or syndromic epilepsy v3.12 COX10 Arina Puzriakova Mode of inheritance for gene: COX10 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Classified gene: KLHL20 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
-----
Sleyp et al. 2022 (PMID: 36214804) reported on 14 patients with de novo missense variants who all presented with mild to severe ID, seizures, ASD, hyperactivity, and dysmorphic facial features. One variant (c.1069G>A, p.Gly357Arg) was recurrent in 11/14 cases but all variants clustered in the Kelch-type β-propeller domain (substrate binding surface) of the KLHL20 protein. No functional studies were performed but given the overlap in clinical presentation observed in patients with the same recurrent variant but also multiple different variants, its worth including as diagnostic-grade.
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Gene: klhl20 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.10 KLHL20 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: KLHL20.
Early onset or syndromic epilepsy v3.10 DNM1 Sarah Leigh Publications for gene: DNM1 were set to 25262651; 27066543; 33372033; 34172529
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Classified gene: FRMD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 5 unrelated cases with seizures plus supportive fly model.
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Gene: frmd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.8 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Genetic epilepsy syndromes. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Early onset or syndromic epilepsy v3.7 GPHN Achchuthan Shanmugasundram Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, OMIM:615501 to Molybdenum cofactor deficiency C, OMIM:615501; Developmental and epileptic encephalopathy, MONDO:0100062
Early onset or syndromic epilepsy v3.6 GPHN Achchuthan Shanmugasundram Publications for gene: GPHN were set to 26613940; 12684523; 11095995; 22040219; 24561070; 23393157
Early onset or syndromic epilepsy v3.5 GPHN Achchuthan Shanmugasundram reviewed gene: GPHN: Rating: GREEN; Mode of pathogenicity: None; Publications: 34617111; Phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062; Mode of inheritance: None
Early onset or syndromic epilepsy v3.5 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524; 34570759
Early onset or syndromic epilepsy v3.4 BET1 Achchuthan Shanmugasundram Phenotypes for gene: BET1 were changed from Epilepsy; congenical musculara dystrophy to Epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v3.3 BET1 Achchuthan Shanmugasundram Publications for gene: BET1 were set to PMID: 34779586
Early onset or syndromic epilepsy v3.2 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Red List (low evidence)
Early onset or syndromic epilepsy v3.2 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v3.1 BET1 Achchuthan Shanmugasundram reviewed gene: BET1: Rating: RED; Mode of pathogenicity: None; Publications: 34779586; Phenotypes: Epilepsy, MONDO:0005027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed phenotypes to: Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed rating: GREEN
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes gene: BAP1 was added
gene: BAP1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAP1 were set to 35051358
Added comment: Küry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance.
Sources: Literature
Early onset or syndromic epilepsy v3.1 KLHL20 Dmitrijs Rots gene: KLHL20 was added
gene: KLHL20 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to 36214804
Phenotypes for gene: KLHL20 were set to developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
Mode of pathogenicity for gene: KLHL20 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: KLHL20 was set to GREEN
Added comment: 14 cases with mostly recurrent missense variant in this gene is reported.
Sources: Literature
Early onset or syndromic epilepsy v3.1 Catherine Snow Panel version 3.0 has been signed off on 2022-11-30
Early onset or syndromic epilepsy v3.0 Catherine Snow promoted panel to version 3.0
Early onset or syndromic epilepsy v2.607 HNRNPR Eleanor Williams commented on gene: HNRNPR
Early onset or syndromic epilepsy v2.607 HNRNPR Eleanor Williams Phenotypes for gene: HNRNPR were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit; Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073
Early onset or syndromic epilepsy v2.606 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
Early onset or syndromic epilepsy v2.606 HID1 Eleanor Williams commented on gene: HID1
Early onset or syndromic epilepsy v2.606 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Early onset or syndromic epilepsy v2.605 HID1 Eleanor Williams Tag gene-checked was removed from gene: HID1.
Early onset or syndromic epilepsy v2.605 CACNA1I Eleanor Williams commented on gene: CACNA1I
Early onset or syndromic epilepsy v2.605 CACNA1I Eleanor Williams Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with speech impairment and with or without seizures, OMIM:620114
Early onset or syndromic epilepsy v2.604 CACNA1I Eleanor Williams Tag gene-checked was removed from gene: CACNA1I.
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams commented on gene: ARFGEF1
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams Tag gene-checked was removed from gene: ARFGEF1.
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams Phenotypes for gene: ARFGEF1 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027; Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, OMIM:619964
Early onset or syndromic epilepsy v2.603 CUX2 Tracy Lester edited their review of gene: CUX2: Added comment: Almost all cases reported to date have a de novo E590K variant, there is currently no evidence supporting this gene being imprinted or for LOF variants being pathogenic. I suggest the inheritance model should be updated to be monoallelic, NOT imprinted.; Changed mode of pathogenicity: Other; Changed publications to: 29795476, 29630738
Early onset or syndromic epilepsy v2.603 SNIP1 Helen Lord reviewed gene: SNIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34570759, 2279524, 31589614; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.603 CLPB Helen Lord reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 25597510, 25597511, 26916670; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.603 ASH1L Helen Lord reviewed gene: ASH1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 34373061, 25961944, 34782621, 32469098; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.603 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, 615501 to Molybdenum cofactor deficiency C, OMIM:615501
Early onset or syndromic epilepsy v2.602 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718 to Cerebral creatine deficiency syndrome 3, OMIM:612718
Early onset or syndromic epilepsy v2.601 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Early onset or syndromic epilepsy v2.600 ACOX1 Arina Puzriakova Publications for gene: ACOX1 were set to 18536048
Early onset or syndromic epilepsy v2.599 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960
Early onset or syndromic epilepsy v2.598 CLPB Eleanor Williams Tag Q3_21_MOI was removed from gene: CLPB.
Tag Q3_22_MOI tag was added to gene: CLPB.
Early onset or syndromic epilepsy v2.598 NRXN1 Arina Puzriakova Phenotypes for gene: NRXN1 were changed from Pitt-Hopkins-like syndrome 2, 614325 to Pitt-Hopkins-like syndrome 2, OMIM:614325 (AR); Complex neurodevelopmental disorder (AD)
Early onset or syndromic epilepsy v2.597 OTUD7A Dmitrijs Rots reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36180924, 31997314, 31997314; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.597 DPH5 Eleanor Williams Tag Q4_22_rating was removed from gene: DPH5.
Tag Q4_22_promote_green tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams Deleted their comment
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams commented on gene: SNIP1: Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams commented on gene: SNIP1
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams Tag Q4_21_expert_review was removed from gene: SNIP1.
Tag Q3_22_rating tag was added to gene: SNIP1.
Tag Q3_22_expert_review tag was added to gene: SNIP1.
Early onset or syndromic epilepsy v2.597 CLPB Eleanor Williams commented on gene: CLPB
Early onset or syndromic epilepsy v2.597 CLPB Eleanor Williams Tag Q4_21_expert_review was removed from gene: CLPB.
Tag Q3_21_MOI tag was added to gene: CLPB.
Tag Q3_22_rating tag was added to gene: CLPB.
Tag Q3_22_expert_review tag was added to gene: CLPB.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Tag Q4_22_rating tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Classified gene: DPH5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Gene: dph5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh edited their review of gene: DPH5: Added comment: Not associated with a phenotype in OMIM, but as moderate Gen2Phen gene for DPH5-related neurodevelopmental disorder. PMID: 35482014 reports four DPH5 variants in fives cases from three unrelated families. Biallelic NM_001077394.2:c.521dup (p.Asn174LysfsTer10) was identified in a consanguinous family (PMID: 35482014, family 3), the index case, an affected sibling and cousin all died in infancy. Affected members families 1 & 2 (PMID: 35482014) were seen in childhood, all had profound intellectual disability and seizures were seen in both families. A supportive mouse model was described, as were in vitro functonal studies (PMID: 35482014).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh Added comment: Comment on phenotypes: As described by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4902)
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh Phenotypes for gene: DPH5 were changed from Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck to DPH5-related neurodevelopmental disorder
Early onset or syndromic epilepsy v2.595 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Only two cases with epilepsy have been reported to date. Following consultation with Clinical team, decided to maintain Green rating as CNVs with variable penetrance are reported in clinical practice and can be relevant diagnostically; however, adding watchlist tag to monitor for clear evidence of particularly reduced penetrance at which stage the rating may be reviewed.; Changed publications to: 26097203
Early onset or syndromic epilepsy v2.595 ISCA-37423-Gain Arina Puzriakova Tag watchlist tag was added to Region: ISCA-37423-Gain.
Early onset or syndromic epilepsy v2.595 CACNA1A Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: CACNA1A.
Early onset or syndromic epilepsy v2.595 CAPRIN1 Konstantinos Varvagiannis edited their review of gene: CAPRIN1: Changed rating: GREEN
Early onset or syndromic epilepsy v2.595 CACNA1A Sarah Leigh Phenotypes for gene: CACNA1A were changed from Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Developmental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1A.
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh edited their review of gene: CACNA1A: Added comment: PMIDs: 36063114; 34267336; 33445191; 27250579 all report biallelic CACNA1A variants in cases of Developmental and epileptic encephalopathy 42 (OMIM:617106), therefore the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 36063114, 34267336, 33445191, 27250579; Changed phenotypes to: Developmental and epileptic encephalopathy 42, OMIM:617106; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh Publications for gene: CACNA1A were set to 29056246; 27476654; 11564488; 20071244; 15452324; 8898206
Early onset or syndromic epilepsy v2.593 DNAJC6 Dmitrijs Rots changed review comment from: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 cases had movement disorder and homozygous variant (nonsense, splice, frameshift and missense) and 3/6 cases had seizures reported.; to: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 studies had movement disorder and homozygous variant (nonsense, splice, frameshift and missense) and 3/6 studies had seizures reported.
Early onset or syndromic epilepsy v2.593 DNAJC6 Dmitrijs Rots reviewed gene: DNAJC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 34175496; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.593 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 21907012; 23252400; 31584066
Early onset or syndromic epilepsy v2.592 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Epileptic encephalopathy, early infantile, 15 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Early onset or syndromic epilepsy v2.591 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to
Early onset or syndromic epilepsy v2.590 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Early onset or syndromic epilepsy v2.590 XK Sarah Leigh edited their review of gene: XK: Added comment: After consultation with Helen Brittain (Clinical Fellow, Genomics England), the recommendation for XK has been changed to Amber. This is because there appear to be adult onset of neurological symptoms, including seizures. The scope of the Genetic epilepsy syndromes panel is targeting early onset severe or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v2.590 CACNA1A Hannah Robinson reviewed gene: CACNA1A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36063114, PMID: 34267336, PMID: 33445191, PMID: 27250579; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.590 CAPRIN1 Konstantinos Varvagiannis gene: CAPRIN1 was added
gene: CAPRIN1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPRIN1 were set to 35979925; 35977029; 28135719; 31398340; https://doi.org/10.1101/2021.12.20.21267194
Phenotypes for gene: CAPRIN1 were set to Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behavior; Seizures
Penetrance for gene: CAPRIN1 were set to Incomplete
Review for gene: CAPRIN1 was set to AMBER
Added comment: A cohort of 12 individuals harboring pathogenic CAPRIN1 variants is described in a recent report by Pavinato et al (2022 - PMID: 35979925).

DD, impaired speech/language development (100%), ID (83%), ASD (67%) and seizures (33%) are part of the phenotype (details below).

Enrichment for de novo LGD but also missense variants has also been demonstrated upon meta-analysis of different cohorts of 40,853 individuals with ID (N=31,625) or ASD (N=9,228) as discussed by Jia et al (2022 - PMID: 35977029).

Role of the gene:
Evidence supports among others, a role for CAPRIN1 in formation RNA-protein (stress) granules through interaction with other relevant proteins (e.g. G3BP1/2, FMRP) and regulation of gene expression (Pavinato et al - PMID: 35979925, Jia et al - PMID: 35977029).
Jia et al further demonstrated significant reduction of stress granule formation in CAPRIN1 KO HeLa lines.
Following generation of CAPRIN1+/- hiPSC line using CRISPR/Cas9 and differentiation into cortical neurons, Pavinato et al noted, altered neuronal structure, abnormal firing properties as well as increased neuronal degeneration possibly linked to presence of increased Ca+2 signals and increase in reactive oxygen species (ROS). Global de novo protein synthesis in neurons appeared to be impaired.

Variant type and inheritance :
All individuals reported by Paviato et al harbored pLoF (nonsense, frameshift, splicing and a synonymous variant resulting in abnormal splicing) variants. In most cases variants occurred de novo with the exception of 2 subjects having inherited pLoF variants from their affected/unaffected parent. Expressive variability, reduced penetrance and possibility of - a yet to be proven - sex bias are discussed (9M/3F).
Missense variants and enrichment for dn missense SNVs have also been shown in large cohorts. The impact of p.I373K has been studied.

Variant effect:
pLoF : Pavinato et al demonstrated reduced mRNA and protein levels for the truncating variants, and out-of frame exon skipping for a variant affecting splice donor site and a further SNV affecting the last nucleotide of ex8.
Missense SNVs : p.I373K abolished interaction with G3BP1/2 and disrupted stress granule formation in the study by Jia et al demonstrating a role of stress granules in pathogenesis of neurodevelopmental disorders.

Animal model:
As discussed by Pavinato et al abnormal neuronal structure and firing properties are observed in htz mouse models. Htz mice display features of ASD, difficulties in reversal learning (for ID), sporadic occurrence of seizures. Hearing impairment (as in 2-3 individuals described) due to reduced protection from noise exposure was reported in an ear-conditional ko model.

The report by Pavinato et al is summarized below.

For the study by Jia et al a summary can by found under the review of UBAP2L.

Reports of individuals in the context of larger cohorts were not here reviewed (eg. DDD study 2017, PMID: 28135719 || Ruzzo et al 2019, PMID: 31398340 || Fu et al 2021, https://doi.org/10.1101/2021.12.20.21267194).

----

Pavinato et al (2022 - PMID: 35979925) describe the phenotype associated with heterozygous CAPRIN1 pathogenic variants.

Overlapping features incl. impaired speech/language development (100%), ID (83%), ASD (67%), ADHD (82%), seizures (33% or 4/12 : absence seizures in 2, infantile spasms with absence epilepsy, secondary generalized epileptic seizures during sleep). Respiratory problems (50%), limb/skeletal anomalies (50%), feeding difficulties (33%), mild hearing hearing impairment (in 2 or 3). There was no evident dysmorphism, despite few recurrent features.

CAPRIN1 encodes cell cycle-associated protein 1. As the authors discuss, the gene is ubiquitously expressed with high expression in brain. The protein is known to interact with other RNA-binding proteins (eg. FMRP, G3BP1) for the formation of ribonucleoparticles / RNA granules. The gene localizes in neuronal RNA granules in dendrites. Previous studies have demonstrated a role in regulation of mRNA translation (acting as translational inhibitor with its overexpression leading to reduced protein synthesis). CAPRIN1 interacts with FMRP and CYFIP1, both also involved in regulation of mRNA translation.

One individual with microdeletion (~1.4 Mb spanning 8 genes with CAPRIN1 the only predicted to be haploinsufficient) as well as 11 additional subjects with nonsense/splicing variants were identified, following CMA, ES or GS. [The gene has a pHaplo of 0.98 and pLI of 0.97 (LOEUF 0.31)].

Variants were mostly de novo, although one individual had inherited a nonsense variant from his affected father while one further from her unaffected mother.

qRT-PCR showed reduced mRNA levels in patient fibroblasts and PBMCs while cycloheximide treatment in fibroblasts resulted in partial rescue in expression of mutant allele. Western blot in fibroblasts confirmed reduced protein levels.

cDNA analysis revealed that c.279+1G>T variant resulted in out-of-frame skipping of ex3, while c.879G>A (last base of ex8) resulted in out-of-frame skipping of ex8 and degradation by NMD, with cycloheximide restoring expression of mutant allele. [ NM_005898.5 ]

The authors generated a CAPRIN1+/- hiPSC line using CRISPR/Cas9 and hiPSCs were differentiated into cortical neurons. Htz immature neurons displayed altered neuronal structure, accompanied by reduced neurite length similar to previous observations in mice.

Increased neuronal degeneration was observed. Ca+2 signals (described in literature to trigger or contribute to neuronal death) were increased compared to controls. Increase in reactive oxygen species (ROS) following Ca+2 overload was also demonstrated, likely contributing to neuronal death.

Given the gene's role in regulation of mRNA translation, the authors assessed global de novo protein synthesis in neurons based on pyromicin incorporation (SUnSET assay) with findings supporting the impact of CAPRIN1 haploinsufficiency.

Heterozygous neurons were shown to display abnormal firing properties similar to a previously reported mouse model.

Mouse model : apart from the findings discussed above (abnormal neuronal structure and firing properties), heterozygous mice displayed similar features to the cohort described eg. reduced sociability and weaker preference for social novelty (as in ASD), difficulties in reversal learning (for ID), sporadic occurrence of seizures upon Morris water maze/contextual fearing tests and epileptic-like fEPSP after LTP. Breathing problems were noted in Carpin1-/- mice. Ear conditional ko was associated with early-onset progressive hearing loss and reduced protection from noise exposure which might be in line with few individuals with hearing impairment.
Sources: Literature
Early onset or syndromic epilepsy v2.590 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to AMBER
Added comment: Seizures have been reported in several individuals although a formal diagnosis of epilepsy was retained in ~30% in a small cohort discussed below. Consider inclusion with amber rating.

-----

Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

--------

Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that the number of unrelated families presenting the relevant phenotype meets the criteria for an Amber rating at this time.
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.589 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
Early onset or syndromic epilepsy v2.589 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Genetic epilepsy syndromes. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Early onset or syndromic epilepsy v2.588 FASTKD2 Arina Puzriakova Publications for gene: FASTKD2 were set to
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: FASTKD2.
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova reviewed gene: FASTKD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18771761, 28499982, 31944455, 35729327; Phenotypes: Combined oxidative phosphorylation deficiency 44, OMIM:618855; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Early onset or syndromic epilepsy v2.586 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.585 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Early onset or syndromic epilepsy v2.584 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Early onset or syndromic epilepsy v2.583 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22 616045; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Early onset or syndromic epilepsy v2.582 SLC32A1 Helen Lord reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34038384, Platzer et al, 2022 - not on pubmed curently; Phenotypes: developmental and epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.582 FBXO28 Sarah Leigh Mode of inheritance for gene: FBXO28 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.581 FBXO28 Sarah Leigh Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 100, OMIM:619777; developmental and epileptic encephalopathy 100, MONDO:0030695
Early onset or syndromic epilepsy v2.580 FBXO28 Sarah Leigh Publications for gene: FBXO28 were set to 33280099
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh edited their review of gene: FBXO28: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least six variants have been reported in at least six cases. In one of these cases the variant was inherited from the unanaffected mother, who was mosaic (PMID: 33280099), otherwise the variants were de novo heterozygotes (PMIDs: 30160831; 33280099).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Tag Q3_22_rating tag was added to gene: FBXO28.
Tag Q3_22_MOI tag was added to gene: FBXO28.
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Classified gene: FBXO28 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Gene: fbxo28 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Tag Q3_22_MOI tag was added to gene: GLRA2.
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Tag Q3_22_rating tag was added to gene: GLRA2.
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh edited their review of gene: GLRA2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35294868 reports eight GLRA2 variants in affected females (n=8) and males (n=5). The variants in the females were de novo and c.887C>T,
p.Thr296Met (NC_000023.10, chrX: g.14627284C>T) was present in six individuals (PMID: 35294868, table 2) and was found to have a gain-of-function effect, which is in contrast to c.754C>T, p.Arg252Cys and c.407A>G, p.Asn136Ser (PMID: 2637014). All of the 13 GLRA2 variant carriers in PMID: 35294868 had developmental delay/intellectual disability and epilepsy was evident in 7/13 of the cases (PMID: 35294868, table 2). Supportive functional studies were also presented.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Classified gene: GLRA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Gene: glra2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh edited their review of gene: TIAM1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35240055 reports six TIAM1 variants in four unrelated cases (5 cases in total) of Neurodevelopmental disorder with language delay and seizures, OMIM:619908. All of the cases displayed seizures and intellectual disability, where an assessment was made. The drospohila ortholog (still life) and funtional studies supported this gene disease association (PMID: 35240055).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TIAM1.
Tag Q3_22_MOI tag was added to gene: TIAM1.
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh Phenotypes for gene: TIAM1 were changed from Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology to Neurodevelopmental disorder with language delay and seizures, OMIM:619908
Early onset or syndromic epilepsy v2.576 TIAM1 Sarah Leigh Classified gene: TIAM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.576 TIAM1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.576 TIAM1 Sarah Leigh Gene: tiam1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh reviewed gene: CPSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh Classified gene: CPSF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh Gene: cpsf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.574 CPSF3 Sarah Leigh Phenotypes for gene: CPSF3 were changed from Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures to Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh edited their review of gene: CHKA: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35202461 reports five CHKA variants in five unrelated cases with a neurodevelopmental disorder, which includes intellectual disability, epileptic
encephalopathy and severe microcephaly (PMID: 35202461). Suportive functional studies are also presented in this article.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Classified gene: CHKA as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Gene: chka has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.572 CNKSR2 Eleanor Williams Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892; 25644381; 28098945; 34266427
Early onset or syndromic epilepsy v2.571 CNKSR2 Eleanor Williams commented on gene: CNKSR2
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant) in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported. ; to: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant) in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported.
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant)
in addition to developing severe ID.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.; to: Not associated with a phenotype in OMIM. Has a strong/probable association with 'Epilepsy and intellectual disability' in Gene2Phenotype.

PMID: 29100083 - Hamdan et al 2017 - performed WGS on 197 individuals with unexplained Developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. 2 patients reported with heterozygous missense variants in RAB11A, one of which had seizures (c.244C>T [p.Arg82Cys] variant) in addition to developing severe ID. 2 other individuals with missense variants in RAB11A and some phenotypic data from the DDD project are described but neither had seizures.

PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). Little patient information but the patient with the p. Asp127Gly variant is reported to have refractory epileptic spasms. Both had brain anomalies and intellectual disability reported.
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams Classified gene: RAB11A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 2 patients reported with seizures, 1 each in PMID: 29100083 and PMID: 33875846 but little clinical information.
Early onset or syndromic epilepsy v2.571 RAB11A Eleanor Williams Gene: rab11a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.570 RAB11A Eleanor Williams commented on gene: RAB11A
Early onset or syndromic epilepsy v2.570 RAB11A Eleanor Williams gene: RAB11A was added
gene: RAB11A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RAB11A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAB11A were set to 29100083; 33875846
Phenotypes for gene: RAB11A were set to Global developmental delay, HP:0001263; Intellectual disability, HP:0001249; seizures
Early onset or syndromic epilepsy v2.569 CERS1 Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: CERS1.
Early onset or syndromic epilepsy v2.569 FAR1 Sarah Leigh Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154; fatty acyl-CoA reductase 1 deficiency, MONDO:0014510
Early onset or syndromic epilepsy v2.568 FAR1 Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: FAR1.
Early onset or syndromic epilepsy v2.568 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621; 24782409
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554). Generalized seizures are reported in 20-40% cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842) according to OMIM.
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh Tag Q3_22_rating was removed from gene: XK.
Tag Q3_22_MOI was removed from gene: XK.
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.245
Early onset or syndromic epilepsy v2.567 XK Sarah Leigh gene: XK was added
gene: XK was added to Genetic epilepsy syndromes. Sources: Expert list,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: XK.
Mode of inheritance for gene: XK 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: XK were set to 11761473; 30128557; 8004674; 8619554
Phenotypes for gene: XK were set to McLeod syndrome with or without chronic granulomatous disease, OMIM:300842; McLeod neuroacanthocytosis syndrome, MONDO:0018945
Early onset or syndromic epilepsy v2.566 CNKSR2 Eleanor Williams Phenotypes for gene: CNKSR2 were changed from Mental retardation, X-linked, syndromic, Houge type 301008 to Intellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909
Early onset or syndromic epilepsy v2.565 CNKSR2 Eleanor Williams Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892; 25644381; 28098945
Early onset or syndromic epilepsy v2.564 ALKBH8 Arina Puzriakova Publications for gene: ALKBH8 were set to 31130284; 31079898
Early onset or syndromic epilepsy v2.563 ALKBH8 Arina Puzriakova reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079898, 33544954, 34757492, 35571055; Phenotypes: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.563 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from TFE3-related intellectual disability with pigmentary mosaicism to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
Early onset or syndromic epilepsy v2.562 PIGP Arina Puzriakova Phenotypes for gene: PIGP were changed from Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Developmental and epileptic encephalopathy 55, OMIM:617599
Early onset or syndromic epilepsy v2.561 PIGP Arina Puzriakova Tag watchlist was removed from gene: PIGP.
Early onset or syndromic epilepsy v2.561 KAT8 Arina Puzriakova Phenotypes for gene: KAT8 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism to Li-Ghorgani-Weisz-Hubshman syndrome, OMIM:618974; Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Early onset or syndromic epilepsy v2.560 KAT8 Arina Puzriakova Tag watchlist_moi tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.560 ASNS Arina Puzriakova Publications for gene: ASNS were set to 24139043; 25227173; 29375865; 24139043; 27469131
Early onset or syndromic epilepsy v2.559 TAF8 Arina Puzriakova Entity copied from Intellectual disability v3.1656
Early onset or syndromic epilepsy v2.559 TAF8 Arina Puzriakova gene: TAF8 was added
gene: TAF8 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: TAF8.
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to 29648665; 35759269
Phenotypes for gene: TAF8 were set to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Penetrance for gene: TAF8 were set to unknown
Early onset or syndromic epilepsy v2.558 CRELD1 Ivone Leong Added comment: Comment on phenotypes: Changed from "neurodevelopmental disorder;treatment resistant epileptic seizures;mild to severe developmental and cognitive delays;adrenal insufficiency;severe bilateral neural hearing loss;immature eye development;accuse respiratory distress and submucosal cleft palate" to "Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate" for Natalie Trump (Congenica) as the first option was entered by mistake.
Early onset or syndromic epilepsy v2.558 CRELD1 Ivone Leong Phenotypes for gene: CRELD1 were changed from neurodevelopmental disorder; treatment resistant epileptic seizures; mild to severe developmental and cognitive delays; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; accuse respiratory distress and submucosal cleft palate to Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate
Early onset or syndromic epilepsy v2.557 CRELD1 Ivone Leong Added comment: Comment on mode of inheritance: Changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" for Natalie Trump (Congenica) as the first option was entered by mistake.
Early onset or syndromic epilepsy v2.557 CRELD1 Ivone Leong Mode of inheritance for gene: CRELD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.556 SLC38A3 Catherine Snow Phenotypes for gene: SLC38A3 were changed from Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia to Developmental and epileptic encephalopathy 102, 619881
Early onset or syndromic epilepsy v2.555 SLC38A3 Catherine Snow Classified gene: SLC38A3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.555 SLC38A3 Catherine Snow Gene: slc38a3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.554 SLC38A3 Catherine Snow Tag Q3_22_rating tag was added to gene: SLC38A3.
Early onset or syndromic epilepsy v2.554 SLC38A3 Catherine Snow reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.554 CRELD1 Natalie Trump reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32437232; Phenotypes: Developmental epileptic encephalopathy, intractable seizures, global developmental delay and cognitive delay, treatment resistant epileptic seizures, adrenal insufficiency, severe bilateral neural hearing loss, immature eye development, acute respiratory distress, submucosal cleft palate; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.554 CRELD1 Natalie Trump Deleted their review
Early onset or syndromic epilepsy v2.554 CRELD1 Natalie Trump gene: CRELD1 was added
gene: CRELD1 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: CRELD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CRELD1 were set to PMID 32437232
Phenotypes for gene: CRELD1 were set to neurodevelopmental disorder; treatment resistant epileptic seizures; mild to severe developmental and cognitive delays; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; accuse respiratory distress and submucosal cleft palate
Penetrance for gene: CRELD1 were set to Incomplete
Mode of pathogenicity for gene: CRELD1 was set to Other
Review for gene: CRELD1 was set to GREEN
gene: CRELD1 was marked as current diagnostic
Added comment: Heterozygous variants in CRELD1 are known to be associated with susceptibility to atrioventricular septal defect (AVSD), AVSD2 and AVSD associated with heterotaxy syndrome. Unaffected carriers have been reported suggesting reduced penetrance for this phenotype (OMIM 606217) .

Unpublished data has recently identified 9 unrelated families (including 3 families with 2 affected siblings each) with biallelic CRELD1 variants.

The most common features in these children with biallelic CRELD1 variants is intractable seizures. Other features include global developmental delay and cognitive delay, treatment resistant epileptic seizures, adrenal insufficiency, severe bilateral neural hearing loss, immature eye development, accute respiratory distress and submucosal cleft palate.

All identified patients to-date are compound heterozygotes and each have one missense variant and one frameshift variant.
A recurrent missense variant (p.Cys192Tyr) has been identified in 8 individuals from 5 unrelated families. This missense change has been reported as a compound heterozygote with a frameshift variant a patient with seizures and global developmental delay (PMID: 32437232). This variant affects a cysteine residue that is predicted to form a disulphide bond in the protein which is important for protein folding and structural stability.
Two recurrent frameshift variants have also been identified:
- The p.Gln320ArgfsTer25 variant was found in 3 unrelated individuals (reported as compound heterozyogote in PMID: 32437232).
- The p.Ala377ThrfsTer7 variant was found in 5 individuals from 3 unrelated families.

CRELD1 encodes a member of a subfamily of epidermal growth factor-related proteins. CRELD1 plays a pivitol role in heart development and has also been shown to be an important gatekeeper of immune system homeostasis (PMID: 33169013).

There is one publication that reports a patient with seizures and global developmental delay with biallelic variants in CRELD1 (PMID: 32437232) but no other association between CRELD1 and brain function has been reported to date. Significantly, CRELD1 has high expression in human brain across different developmental stages.

There is no phenotype associated with biallelic CRELD1 variants in OMIM or G2P.
Sources: Expert Review
Early onset or syndromic epilepsy v2.554 CNNM2 Eleanor Williams Phenotypes for gene: CNNM2 were changed from Hypomagnesemia, seizures, and mental retardation 616418 to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631
Early onset or syndromic epilepsy v2.553 ATP2B1 Catherine Snow Phenotypes for gene: ATP2B1 were changed from Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck to Intellectual developmental disorder, autosomal dominant 66, 619910
Early onset or syndromic epilepsy v2.552 ATP2B1 Catherine Snow Classified gene: ATP2B1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.552 ATP2B1 Catherine Snow Gene: atp2b1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.551 ATP2B1 Catherine Snow Tag watchlist tag was added to gene: ATP2B1.
Early onset or syndromic epilepsy v2.551 ATP2B1 Catherine Snow reviewed gene: ATP2B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.551 ADD1 Catherine Snow Tag watchlist tag was added to gene: ADD1.
Early onset or syndromic epilepsy v2.551 ADD1 Catherine Snow Classified gene: ADD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.551 ADD1 Catherine Snow Gene: add1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.550 ADD1 Catherine Snow reviewed gene: ADD1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.550 OGDHL Arina Puzriakova Entity copied from Intellectual disability v3.1644
Early onset or syndromic epilepsy v2.550 OGDHL Arina Puzriakova gene: OGDHL was added
gene: OGDHL was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: OGDHL.
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 28017472; 34800363
Phenotypes for gene: OGDHL were set to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Early onset or syndromic epilepsy v2.549 NSRP1 Arina Puzriakova Entity copied from Intellectual disability v3.1641
Early onset or syndromic epilepsy v2.549 NSRP1 Arina Puzriakova gene: NSRP1 was added
gene: NSRP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: NSRP1.
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to NSRP1-associated developmental delay, epilepsy and microcephaly
Early onset or syndromic epilepsy v2.548 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 23603762; 29706637
Early onset or syndromic epilepsy v2.547 PPFIBP1 Konstantinos Varvagiannis gene: PPFIBP1 was added
gene: PPFIBP1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 30214071
Phenotypes for gene: PPFIBP1 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision
Penetrance for gene: PPFIBP1 were set to Complete
Review for gene: PPFIBP1 was set to GREEN
Added comment: Consider inclusion with green rating in the ID, epilepsy as well as other likely relevant gene panels (microcephaly, white matter disorders, corpus callosum abnormalities, intracerebral calficication disorders, malformations of cortical development, hereditary spastic paraplegia, growth failure in early childhood, etc) based on the summary below.

----

Rosenhahn et al (2022 - PMID: 35830857) describe the phenotype of 16 individuals - belonging to 12 unrelated families - with biallelic PPFIBP1 pathogenic variants. Most (14/16) were born to consanguineous parents. One of these families was previously reported by Shaheen et al (2019 - PMID: 30214071) who first identified PPFIBP1 as a candidate gene for congenital microcephaly. In the current study, Rosenhahn also identified a fetus homozygous for a missense variant and similar features.

All individuals presented global DD/ID (16/16 - in 15 cases profound/severe) and epilepsy (16/16 - onset 1d-4y / median 2m - focal seizures in 11/16, epileptic spams in 7/16, generalized onset in 7/16, myoclonic in 6/16 - drug-resistant : 13/16). Almost all (15/16) had microcephaly, commonly congenital (9/16) and progressive (11/16). Other neurological findings included hypertonia (10/16), spastic tetraplegia (6/16), hypotonia (5/16), dystonic movements (3/16) or nystagmus (4/16). Brain abnormalities were identified in all investigated with MRI and included leukoencephalopathy (11/14) mostly periventricular, abnormal cortex morphology (7/14 - polymicrogyria 1, increased cortical thickness 4, pachygyria 3), cortical atrophy, corpus callosum hypoplasia (7/14). Intracranial calcifications were identified in all (9/9) investigated with CT scan. Abnormal growth was reported for several (SGA in 9/16, FTT 8/16, short stature 7/16) often associated with feeding difficulties (7/16). Other features incl. abnormal hearing (4/16), congenital heart defects (7/16), ophthalmologic findings (8/16), undescended testes (3/10). There were no overlapping facial features.

The fetus displayed similar features incl. SGA, microcephaly, intracranial calcifications.

Investigations incl. exome/genome sequencing (singleton or trio) with Sanger for confirmation/segregation of variants where necessary. Variable previous investigations incl. metabolic screening, TORCH screening, chromosomal studies (CMA) are mentioned in the supplement and were non-diagnostic. Additional candidate variants were identified in few cases although cases with plausible dual diagnoses (e.g. ind14) were not included in the overall phenotypic description.

9 pLoF variants (nonsense, frameshift, 1 splicing) predicted to lead to NMD were identified. There were no functional studies performed.
The missense variant c.2177G>T / p.Gly726Val (NM_003622.4) was predicted deleterious by in silico tools while the AA change causing severe steric problems upon modelling.

PPFIBP1 encodes PPFIA-binding protein 1 also known as liprin-β1. As the authors discuss: The liprin family of proteins comprises liprins α1 to 4 and liprin β1 and β2 in mammals. Liprin β1 is known to homodimerize and heterodimerize with α-liprins. In fibroblast cultures liprins β1 and α1 colocalize to cell membrane and periphery of focal adhesions. Members of the liprin-α fam. are scaffold proteins playing a role in synapse formation/signaling and axonal transport.

A ko model of the PPFIBP1 ortholog in C.elegans displayed abnormal locomotion behavior. In Drosophila, null-allele mutants resulted in altered axon outgrowth and synapse formation of R7 photoreceptors and reduced neuromuscular junction size (Refs provided in article).

Using a PPFIBP1/hlb-1 ko C.elegans model the authors demonstrated defects in spontaneous and light-induced behavior. Sensitivity of the worms to an acetylcholinesterase inhibitor (aldicarb) was suggestive of a presynaptic defect.

----

There is currently no PPFIBP1 - associated phenotype in OMIM / G2P.
SysNDD lists PPFIBP1 among the ID genes (limited evidence based on the 3 sibs reported by Shaheen et al, 2019 - PMID: 30214071).
In PanelApp Australia the gene is listed with green rating for ID, epilepsy, microcephaly based on the medRxiv pre-print.
Sources: Literature
Early onset or syndromic epilepsy v2.547 SLC1A2 Sarah Leigh Phenotypes for gene: SLC1A2 were changed from Epileptic encephalopathy, early infantile, 41, 617105 to Epileptic encephalopathy, early infantile, 41, OMIM:617105; developmental and epileptic encephalopathy, 41, MONDO:0014916
Early onset or syndromic epilepsy v2.546 SLC1A2 Sarah Leigh Publications for gene: SLC1A2 were set to 27476654; 28777935; 23934111; 9180080; 28915517
Early onset or syndromic epilepsy v2.545 SLC1A2 Sarah Leigh changed review comment from: PMID:28915517 reports one case of homozygous c.1421+1G>C in a case of epileptic seizures with visual impairment. The nonconsanguineous German parents of the case, were heterozygous for c.1421+1G>C. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function. In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other.; to: PMID:28915517 reports one case of homozygous c.1421+1G>C in a case of epileptic seizures with visual impairment. The nonconsanguineous German parents of the case, were heterozygous for c.1421+1G>C. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function, possibly by abnormal channel conductance (PMID: 27445142). In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other. Clearly further functional studies will be required to clafiry the mechanisms by which SLC1A2 variants result in epilepsy and other phenotypic features.
Early onset or syndromic epilepsy v2.545 HECW2 Arina Puzriakova Publications for gene: HECW2 were set to 27389779; 27334371; 34321324
Early onset or syndromic epilepsy v2.544 HECW2 Arina Puzriakova Publications for gene: HECW2 were set to 27389779; 27334371
Early onset or syndromic epilepsy v2.543 DNM1 Arina Puzriakova Tag watchlist was removed from gene: DNM1.
Tag watchlist_moi tag was added to gene: DNM1.
Early onset or syndromic epilepsy v2.543 DNM1 Arina Puzriakova changed review comment from: Comment on list classification: Currently, there is only enough evidence for an Amber rating for the biallelic form and so I have kept the MOI as just 'Monoallelic' at this time. If this is a genuine association, biallelic cases would still be picked by the Genomics England pipeline under this MOI. Added watchlist tag in anticipation of further biallelic cases emerging.; to: Comment on list classification: Currently, there is only enough evidence for an Amber rating for the biallelic form and so I have kept the MOI as just 'Monoallelic' at this time. Added watchlist tag in anticipation of further biallelic cases emerging.
Early onset or syndromic epilepsy v2.543 CERS1 Helen Lord reviewed gene: CERS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33798445, 30800706, 27618929, 24782409; Phenotypes: progressive myoclonic epilepy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.543 FAR1 Helen Lord reviewed gene: FAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33239752, 25439727, 33586168, 28454995; Phenotypes: cataracts, spastic paraparesis and speech delay & peroxisomal fatty Acyl-CoA reductase I disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.543 WNK3 Arina Puzriakova changed review comment from: Comment on list classification: There is now enough evidence to promote this gene to Green at the next GMS review - at least 14 individuals from 6 unrelated families, all presenting with ID in association with variants in the WNK3 gene.; to: Comment on list classification: There is now enough evidence to promote this gene to Green at the next GMS review - at least 14 individuals from 6 unrelated families with variants in the WNK3 gene, of which at least 5 subjects (3 families) displayed seizures.
Early onset or syndromic epilepsy v2.543 WNK3 Arina Puzriakova Entity copied from Intellectual disability v3.1622
Early onset or syndromic epilepsy v2.543 WNK3 Arina Puzriakova gene: WNK3 was added
gene: WNK3 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber
Q3_22_rating tags were added to gene: WNK3.
Mode of inheritance for gene: WNK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WNK3 were set to 26350204; 35678782
Phenotypes for gene: WNK3 were set to X-linked intellectual disability, MONDO:0100284
Penetrance for gene: WNK3 were set to Complete
Early onset or syndromic epilepsy v2.542 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Early onset or syndromic epilepsy v2.542 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Early onset or syndromic epilepsy v2.542 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Early onset or syndromic epilepsy v2.542 KIAA1109 Sarah Leigh commented on gene: KIAA1109: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.
Early onset or syndromic epilepsy v2.542 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Early onset or syndromic epilepsy v2.542 GBA Sarah Leigh commented on gene: GBA
Early onset or syndromic epilepsy v2.542 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from Neurodevelopmental abnormality HP:0012759 to Neurodevelopmental disorder with poor growth and skeletal anomalies, OMIM:619880
Early onset or syndromic epilepsy v2.541 PCDHGC4 Sarah Leigh Tag gene-checked was removed from gene: PCDHGC4.
Early onset or syndromic epilepsy v2.541 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v2.540 NR4A2 Sarah Leigh Phenotypes for gene: NR4A2 were changed from Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, OMIM:619911
Early onset or syndromic epilepsy v2.539 NR4A2 Sarah Leigh Tag gene-checked was removed from gene: NR4A2.
Early onset or syndromic epilepsy v2.539 ATP6V0A1 Sarah Leigh Tag Q3_22_NHS_review was removed from gene: ATP6V0A1.
Early onset or syndromic epilepsy v2.539 ATP6V0A1 Sarah Leigh Entity copied from Intellectual disability v3.1614
Early onset or syndromic epilepsy v2.539 ATP6V0A1 Sarah Leigh gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI, Q3_22_NHS_review tags were added to gene: ATP6V0A1.
Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687; 33833240
Phenotypes for gene: ATP6V0A1 were set to ATP6V0A1-related developmental disorder (monoallelic)
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh changed review comment from: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMID 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature; to: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMID 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants. Decipher also reports four cases with seizures carrying ASH1L variants.
Sources: Literature
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh changed review comment from: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature; to: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMID 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Tag Q3_22_rating tag was added to gene: ASH1L.
Tag Q3_22_expert_review tag was added to gene: ASH1L.
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Classified gene: ASH1L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Added comment: Comment on list classification: The opinion of a GMS expert is required, to decide whether or not this gene can be rated as green on the Genetic epilepsy syndromes panel
Early onset or syndromic epilepsy v2.538 ASH1L Sarah Leigh Gene: ash1l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.537 ASH1L Sarah Leigh changed review comment from: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 & 25961944 have reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature; to: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature
Early onset or syndromic epilepsy v2.537 ASH1L Sarah Leigh gene: ASH1L was added
gene: ASH1L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ASH1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ASH1L were set to 34373061; 25961944
Phenotypes for gene: ASH1L were set to Intellectual developmental disorder, autosomal dominant 52, OMIM:617796
Review for gene: ASH1L was set to AMBER
Added comment: Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMIDs 34373061 & 25961944 have reported seizures in four unrelated cases with heterozygous ASH1L variants.
Sources: Literature
Early onset or syndromic epilepsy v2.536 ASXL3 Dmitrijs Rots gene: ASXL3 was added
gene: ASXL3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ASXL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ASXL3 were set to 35172777; 27901041; 34436830
Phenotypes for gene: ASXL3 were set to Bainbridge-Ropers syndrome
Penetrance for gene: ASXL3 were set to Complete
Review for gene: ASXL3 was set to GREEN
Added comment: In a review by Kuechler et al., seizures were reported in 3/15 cases. Additionally Khan et al., report a case with seizure onset since birth. In a description of novel 45 cases and review of previous 45 (n=90) by Schirwani et al., seizures were reported in 28/77 cases. Enough evidence for green rating also on this panel.
Sources: Literature
Early onset or syndromic epilepsy v2.536 ZMYM2 Sarah Leigh Phenotypes for gene: ZMYM2 were changed from Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh edited their review of gene: ZMYM2: Changed rating: AMBER
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 3 variants have been reported in cases with mild to unclassified intellectual disability in PMID: 32891193. The review from Tracy Lester (Genetics laboratory, Oxford UK) mentions several additional de novo variants reported by Decipher associated with intellectual / developmental disability.; to: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 2 variants have been reported in cases with seizures in PMID: 32891193.
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh Tag Q3_22_rating was removed from gene: ZMYM2.
Tag Q3_22_NHS_review was removed from gene: ZMYM2.
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh Entity copied from Intellectual disability v3.1600
Early onset or syndromic epilepsy v2.535 ZMYM2 Sarah Leigh gene: ZMYM2 was added
gene: ZMYM2 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_22_rating, Q3_22_NHS_review tags were added to gene: ZMYM2.
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Penetrance for gene: ZMYM2 were set to unknown
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.; to: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) in the Intellectual disabilty panel (https://panelapp.genomicsengland.co.uk/panels/285/gene/CUL3/#!review), all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh Tag Q3_22_rating tag was added to gene: CUL3.
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh Classified gene: CUL3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.534 CUL3 Sarah Leigh Gene: cul3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.533 CUL3 Sarah Leigh reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.533 CUL3 Sarah Leigh Publications for gene: CUL3 were set to 32341456
Early onset or syndromic epilepsy v2.532 CUL3 Sarah Leigh Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496 to Neurodevelopmental disorder with or without autism or seizures, OMIM:619239
Early onset or syndromic epilepsy v2.531 RYR2 Sarah Leigh edited their review of gene: RYR2: Added comment: PMID: 33897349 reports seven RYR2 variants in five unrelated cases of benign epilepsy of childhood with centrotemporal spikes (BECTS). Three of the affected individuals (cases 1,2 & 3) were heterozygous for a RYR2 variant, in one case (case 2) the variant was de novo and in the remaining cases RYR2 variant had been inherited from an unaffected parent. The remaining two individuals (cases 4 & 5) were compound heterozygous inheriting the RYR2 variants from each parent, who were unaffected apart form the father of case 5, who had arrhythmia.; Changed publications to: 33897349
Early onset or syndromic epilepsy v2.531 RYR2 Sarah Leigh Publications for gene: RYR2 were set to 18483626; 29667327; 11208676; 12093772; 11157710
Early onset or syndromic epilepsy v2.530 RYR2 Dmitrijs Rots reviewed gene: RYR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33897349; Phenotypes: Benign Epilepsy of Childhood With Centrotemporal Spikes; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.530 PRPF8 Sarah Leigh Entity copied from Intellectual disability v3.1587
Early onset or syndromic epilepsy v2.530 PRPF8 Sarah Leigh gene: PRPF8 was added
gene: PRPF8 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q2_22_rating tags were added to gene: PRPF8.
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRPF8 were set to 20811066; 23714367; 30420816; 31696658; 35543142
Phenotypes for gene: PRPF8 were set to PRPF8-related developmental disorder (monoallelic); Retinitis pigmentosa 13, OMIM:600059
Penetrance for gene: PRPF8 were set to unknown
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams changed review comment from: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases to promote to green. This gene has been proposed for inclusion on this panel through the NHS Test directory application group and therefore is not tagged for GMS review but will be promoted in the next cycle of updates.; to: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases to promote to green. This gene has been proposed for inclusion on this panel through the NHS Test directory application route and therefore is not tagged for GMS review but will be promoted in the next cycle of updates.
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams Classified gene: CACNA1C as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, but there are sufficient cases to promote to green. This gene has been proposed for inclusion on this panel through the NHS Test directory application group and therefore is not tagged for GMS review but will be promoted in the next cycle of updates.
Early onset or syndromic epilepsy v2.529 CACNA1C Eleanor Williams Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.528 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from to Timothy syndrome OMIM:601005
Early onset or syndromic epilepsy v2.527 CACNA1C Eleanor Williams Publications for gene: CACNA1C were set to
Early onset or syndromic epilepsy v2.526 CACNA1C Eleanor Williams reviewed gene: CACNA1C: Rating: ; Mode of pathogenicity: None; Publications: 15454078, 15863612, 28371864; Phenotypes: Timothy syndrome OMIM:601005; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh reviewed gene: DROSHA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Tag Q2_22_rating tag was added to gene: DROSHA.
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Tag locus-type-rna-micro tag was added to gene: DROSHA.
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Classified gene: DROSHA as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.526 DROSHA Sarah Leigh Gene: drosha has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.525 CACNA1C Eleanor Williams gene: CACNA1C was added
gene: CACNA1C was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: CACNA1C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.524 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA 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: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one).

Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ]

-----

Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants.

Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features.

Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq.

DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse.

As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided):
- in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity
- in Drosophila playing a role in the development of ovary, eye, nervous system etc.
- in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects.

Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes.

miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s.

Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs).

Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided).

Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly.

Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele.

The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction.

Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs.
Sources: Literature
Early onset or syndromic epilepsy v2.524 PRODH Sarah Leigh commented on gene: PRODH: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021 (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).
Early onset or syndromic epilepsy v2.524 PRODH Sarah Leigh Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I 239500 to Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400
Early onset or syndromic epilepsy v2.523 RALGAPB Arina Puzriakova Classified gene: RALGAPB as Red List (low evidence)
Early onset or syndromic epilepsy v2.523 RALGAPB Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Red as this currently represents a candidate gene and only a single individual has been reported with a relevant phenotype. Primary phenotype associated with this gene has been ASD which is not within the scope of this panel.
Early onset or syndromic epilepsy v2.523 RALGAPB Arina Puzriakova Gene: ralgapb has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.522 CELF2 Arina Puzriakova Classified gene: CELF2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.522 CELF2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 11 unrelated individuals harbouring heterozygous variants (10 de novo) in this gene. Seizures observed in 9/11 cases.
Early onset or syndromic epilepsy v2.522 CELF2 Arina Puzriakova Gene: celf2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.521 CELF2 Arina Puzriakova Tag Q2_22_rating tag was added to gene: CELF2.
Tag Q2_22_NHS_review tag was added to gene: CELF2.
Early onset or syndromic epilepsy v2.521 CELF2 Arina Puzriakova Publications for gene: CELF2 were set to 33131106
Early onset or syndromic epilepsy v2.520 CELF2 Arina Puzriakova Phenotypes for gene: CELF2 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 97, OMIM:619561
Early onset or syndromic epilepsy v2.519 PGM2L1 Arina Puzriakova Tag gene-checked tag was added to gene: PGM2L1.
Early onset or syndromic epilepsy v2.519 PCDHGC4 Arina Puzriakova Tag gene-checked tag was added to gene: PCDHGC4.
Early onset or syndromic epilepsy v2.519 NR4A2 Arina Puzriakova Tag gene-checked tag was added to gene: NR4A2.
Early onset or syndromic epilepsy v2.519 ADD1 Konstantinos Varvagiannis gene: ADD1 was added
gene: ADD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ADD1 were set to 34906466
Phenotypes for gene: ADD1 were set to Global developmental delay; Intellectual disability; Seizures; Ventriculomegaly; Abnormality of the corpus callosum
Penetrance for gene: ADD1 were set to unknown
Review for gene: ADD1 was set to AMBER
Added comment: A recent study suggests an ADD1-related phenotype (3 subjects with monoallelic de novo variants/1 with biallelic variants) with DD/ID and ventriculomegaly or corpus callosum dysgenesis and possibly seizures among the features.

There is currently no associated phenotype in other databases (OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the current panel with amber / green rating (3 subjects/variants/families, role of the gene and mouse models recapitulating ventriculomegaly/CC abnormalities, relevant expression, variant studies demonstrating abn. protein levels and/or disruption of adducin heterodimer formation || monoallelic vs bi-allelic variants).

Please consider inclusion in other possibly relevant gene panels (e.g. for corpus callosum / ventriculomegaly) [ Not added ].

--------

Qi et al (2022 - PMID: 34906466) describe the phenotype of 3 unrelated individuals with monoallelic de novo ADD1 pathogenic variants as well as of a fourth homozygous for a missense SNV.

Overall, the authors propose a common phenotype consisting of morphological brain abnormalities (incl. ventriculomegaly and corpus callosum dysgenesis) and neurological symptoms such as DD and/or ID and attention deficit.

All individuals were investigated with singleton/trio ES.

De novo variants - phenotype:
One individual investigated for hypotonia, DD & ID, partial ACC, well controlled seizures (on ketogenic diet) and proportional short stature harbored a de novo stopgain variant (NM_014189.3:c.1418G>A / p.Trp473*) absent from gnomAD.
Another affected subject with hypotonia, FTT/feeding difficulties, mild motor delays complete ACC, a seizure (2y11m), staring spells without EEG correlate, and fatigue (with low coenz. Q10, and complex I & IV deficiency in muscle biopsy) had a de novo fs variant (NM_001119:c.2029_2039del / p.Glu680Argfs*7 - gnomAD:0) and a VUS in a gene not associated with phenotype to date.
A 3rd subject investigated for seizures (onset:1y), speech delay, mild ID, ADHD, without MRI abnormalities harbored a de novo missense SNV (NM_001119:c.670C>T / p.His224Tyr - gnomAD:0) and with cmp htz for 2 missense SPTBN2 SNV not fitting the phenotype (no ataxia).

Biallelic variants - phenotype:
One individual with ID, and ACC, abnormal sulcation, enlarged lateral and 3rd ventricles, abnormal of white matter and hypoplastic vermis upon MRI was reported to harbor in homozygosity a missense SNV (NM_001119:c.169A>T / p.Arg57Trp). There was an additional variant in a gene without associated phenotype to date and not expressed in brain.

Role of the encoded protein:
ADD1 encodes adducin 1/alpha (similar to ADD2, ADD3 encoding other adducins). As the authors note, adducins are cytoskeleton proteins critical for osmotic rigidity and cell shape. In neurons they have been reported to form membrane associated periodic ring-like structures with actin and β-spectrin. Deletion of Add1 in mice results in increased MPS ring diameter and axonal degeneration (several refs provided).

ADD1/2/3 form heterodimers which in turn form heterotetramers. ADD1 is expressed in most tissues.

Mouse model:
Previous mouse models have demonstrated that Add1 null mice have also undetectable ADD2/3 (suggesting a role for stabilization of the latter) and exhibit growth delay, anemia and develop lethal hydrocephalus and ventriculomegaly with 50% penetrance (cited PMIDs: 27068466, 18723693). Here the authors demonstrated that surviving mice had ventriculomegaly and thinning of corpus callosum thus recapitulating the respective human phenotypes. Htz mice also presented thinner CC, though not to a statistically significant extent.

ADD1 expression and isoforms:
- Performing mRNA studies and W.Blot in (developing - GW15-17) human or mouse brain (E12.5-P40) the authors demonstrated dynamic expression of ADD1 with differentially expressed isoforms, notably alternative splicing of ex10 and ex15 with NM_176801 (extended ex10, inclusion of ex15) corresponding to a neuronal isoform and NM_001119 (shorter ex10, exclusion of ex15) corresponding to a neural progenitor cell (NPC) isoform.
- Variants here reported appear to affect both isoforms with the exception of NM_001119:c.2029_2039del / p.Glu680Argfs*7 affecting only the longer NPC one.
- PTBP1 is an RNA binding protein expressed in NPCs known to suppress neuronal exon insertion. The authors demonstrated in mouse Neuro2A cells, through shRNA targeting of Ptbp1, that the latter suppresses the neuronal Add1 isoform.

Variant studies demonstrated that effect of variants was mediated by decreased protein levels and/or disruption of adducin complex formation (ADD1-ADD2 dimer formation known to be mediated by N- and C- terminal ADD1 domains):
- Expression of Arg57Trp (found in hmz in one individual) NPC and neuronal isoforms in Neuro2a cells showed that while protein levels were not significantly affected, there were (also) truncated protein products for both isoforms suggesting that aberrant splicing or protein translation/cleavage may apply.
- The authors generated HEK293FT cells for the truncating variants demonstrating decreased protein levels (using N-/C- terminal antibodies).
- Reduced (HA-tagged)-ADD1-(V5-tagged)-ADD2 protein interaction was shown to apply for the Arg57Trp and Arg473* in HEK293FT cells. Similarly in Neuro2a cells, reduced ADD1-ADD2 interaction was shown for His224Tyr.
Sources: Literature
Early onset or syndromic epilepsy v2.519 CELF2 Julia Baptista reviewed gene: CELF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34107259, 33131106; Phenotypes: Developmental delay, epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.519 SCAF4 Eleanor Williams Tag gene-checked tag was added to gene: SCAF4.
Early onset or syndromic epilepsy v2.519 SNX27 Eleanor Williams Tag gene-checked tag was added to gene: SNX27.
Early onset or syndromic epilepsy v2.519 SYNCRIP Eleanor Williams Tag gene-checked tag was added to gene: SYNCRIP.
Early onset or syndromic epilepsy v2.519 TBC1D2B Eleanor Williams Tag gene-checked tag was added to gene: TBC1D2B.
Early onset or syndromic epilepsy v2.519 TMEM222 Eleanor Williams Tag gene-checked tag was added to gene: TMEM222.
Early onset or syndromic epilepsy v2.519 CACNA1I Eleanor Williams Tag gene-checked tag was added to gene: CACNA1I.
Early onset or syndromic epilepsy v2.519 ARFGEF1 Eleanor Williams Tag gene-checked tag was added to gene: ARFGEF1.
Early onset or syndromic epilepsy v2.519 TRPM3 Eleanor Williams Tag watchlist was removed from gene: TRPM3.
Tag gene-checked tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v2.519 LMBRD2 Eleanor Williams Tag gene-checked tag was added to gene: LMBRD2.
Early onset or syndromic epilepsy v2.519 WDR37 Eleanor Williams 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 to 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
Early onset or syndromic epilepsy v2.518 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
Early onset or syndromic epilepsy v2.518 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Early onset or syndromic epilepsy v2.518 CEP85L Eleanor Williams Tag gene-checked tag was added to gene: CEP85L.
Early onset or syndromic epilepsy v2.518 PABPC1 Konstantinos Varvagiannis gene: PABPC1 was added
gene: PABPC1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to 35511136
Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures
Penetrance for gene: PABPC1 were set to unknown
Review for gene: PABPC1 was set to AMBER
Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1.

Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible.

All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del).

Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date).

PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory.

To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes.

Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect.

While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence.

Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding.

In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules.

In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below).

Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype.

Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed.

Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194).

Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants).
Sources: Literature
Early onset or syndromic epilepsy v2.518 TUBGCP2 Catherine Snow Tag gene-checked tag was added to gene: TUBGCP2.
Early onset or syndromic epilepsy v2.518 KCND2 Arina Puzriakova Tag gene-checked tag was added to gene: KCND2.
Early onset or syndromic epilepsy v2.518 HID1 Arina Puzriakova Tag gene-checked tag was added to gene: HID1.
Early onset or syndromic epilepsy v2.518 KCTD3 Arina Puzriakova Tag gene-checked tag was added to gene: KCTD3.
Early onset or syndromic epilepsy v2.518 HNRNPR Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPR.
Early onset or syndromic epilepsy v2.518 CSNK1G1 Sarah Leigh Tag gene-checked tag was added to gene: CSNK1G1.
Early onset or syndromic epilepsy v2.518 DALRD3 Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, it's product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. Specifically, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS3).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lylsates, with severe reduction (/loss) of m3C modification specific to the specific arginine tRNAs, which was not the case for others (eg. tRNA-Ser-UGA). These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (among others cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature; to: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.

Sources: Literature
Early onset or syndromic epilepsy v2.518 DALRD3 Konstantinos Varvagiannis gene: DALRD3 was added
gene: DALRD3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DALRD3 were set to 32427860
Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910
Penetrance for gene: DALRD3 were set to Complete
Review for gene: DALRD3 was set to AMBER
Added comment: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, it's product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. Specifically, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS3).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lylsates, with severe reduction (/loss) of m3C modification specific to the specific arginine tRNAs, which was not the case for others (eg. tRNA-Ser-UGA). These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (among others cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature
Early onset or syndromic epilepsy v2.518 DPH5 Konstantinos Varvagiannis gene: DPH5 was added
gene: DPH5 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck
Penetrance for gene: DPH5 were set to unknown
Review for gene: DPH5 was set to AMBER
Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants.

As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date.

The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5).

WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser).

In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2.

In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression).

ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants.

Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice.

DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line.

The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653).

Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added).
Sources: Literature
Early onset or syndromic epilepsy v2.518 ENTPD1 Konstantinos Varvagiannis gene: ENTPD1 was added
gene: ENTPD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ENTPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENTPD1 were set to 35471564; 28742222
Phenotypes for gene: ENTPD1 were set to Spastic paraplegia 64, autosomal recessive, OMIM:615683
Penetrance for gene: ENTPD1 were set to Complete
Review for gene: ENTPD1 was set to AMBER
Added comment: Biallelic ENTPD1 pathogenic variants cause Spastic paraplegia 64, autosomal recessive (# 615683) with DD/ID being a universal feature as suggested by the study by Calame, Herman et al. Epilepsy was also reported in 7 unrelated individuals so far with supporting evidence also from mouse model.

Consider upgrade to green rating in the ID panel, inclusion in the epilepsy panel (amber/green). Also consider adding this gene in panels for white matter disorders (which does not appear to be the case so far).

-------

Calame, Herman et al (2022 - PMID:35471564) describe the phenotype of 27 individuals (from 17 unrelated families) with biallelic ENTPD1 pathogenic variants. The authors collected additional information from previously reported cases and summarize the core features of the disorder.

As they highlight, the disorder has a childhood onset, with DD/ID as a universal feature (27/27 or 36/36 considering cases from the literature), progressive spastic paraparesis (36/36) [On neurological examination, abnormal reflexes were common with hyperreflexia (8/36), hyporeflexia (5/36), areflexia (3/36) or both hyperreflexia and hypo/areflexia in 20, suggesting mixed upper and lower motor neuron dysfunction]. Other features included dysarthria (in 20/27 or 27/36 overall), white matter abnormalities on brain imaging (12/22 or 15/28, in 12-13 signal abnormalities in posterior limb of internal capsule), or dysmorphisms (13/27). Some individuals had evidence of neurocognitive regression (18/27 or 21/36). Epilepsy was reported in 7 unrelated individuals within the cohort (likely 7/25 as for 2 sibs from Fam11, this was NA). Previous studies had not reported this feature.

ENTPD1 encodes ectonucleoside triphosphate diphosphohydrolase 1, involved in hydrolysis of ATP to ADP (and ADP to AMP).

While previous studies identified 5 distinct variants (2 missense and 3 pLoF), the authors describe 12 novel variants 10 of which pLoF (stopgain, stoploss, splicing) and 2 missense (one SNV and one MNV).

In silico predictions were in favor of a deleterious effect. Almost all variants were ultrarare or absent from gnomAD, although 4 were recurrent ones [NM_001776.6]: c.1109T>A / p.(Leu370*) (possibly recurrent mutation found in 4 families from Persia/Poland), c.574-6_574-3del, c.770_771del / p.(Gly257Glufs*18) (possibly founder allele from the Iberian peninsula), c.1041del / p.(Ile348Phefs*19) (?founder allele in Persia).

Variant studies:
- c.574-6_574-3del : was shown to result to skipping (complete absence) of exon 6 (RNA extracted from a whole blood sample, followed by cDNA synthesis and Sanger seq using different primer sets).
- c.401T>G / p.Met134Arg : RT-qPCR of mRNA from patient lymphoblasts showed significantly reduced mRNA levels in individuals homozygous for this variant. Protein levels were also markedly decreased upon Western blot. ENTPD1 is essential for hydrolysis of ATP to ADP and ADP to AMP, with impairment of ATPase and ADPase activity (significantly decreased phosphate production) in patient lymphoblasts.
- c.185T>G / p.Leu62* : As ENTPD1 (also known as CD39) is highly expressed in lymphocytes and polymorphonuclear leukocytes, the authors used flow cytometry on whole blood from individuals hmz for this variant, carrier parents and controls, demonstrating complete absence of ENTPD1 positive cells in affected individuals. Immunohistochemistry for ENTPD1 using paraffin sections of sural nerve demonstrated complete absence of endo and epineural vascular staining (/lack of expression).

Untargeted metabolomic analyses were performed in plasma samples from 3 affected individuals. Consistent patterns of metabolic abnormalities with alterations in lipid, nucleotide and carbohydrate metabolism were observed. Some metabolite patterns or biomarkers were indicative of inflammatory state, liver disease, insulin resistance / metabolic syndrome.

The authors cite previous mouse models suggesting hepatocellular disfunction, impaired glucose homeostasis and intestinal inflammation in ectonucleotidase deficiency (probably not specific to Entpd1). Further, the authors cite a study by Lanser et al for Entpd1-/- mice exhibiting proepileptogenic activity (2017 - PMID: 28742222 / “Disruption of the ATP/adenosine balance in CD39(-/-) mice is associated with handling-induced seizures”).

In vitro studies using a cellular model of sympathetic neurons (nerve growth factor-differentiated PC12 cells) provided evidence that ENTPD1 expression levels modulate exocytic and ischemic neurotransmitter release (cited PMID: 21325440)

Overall, the authors propose accessible diagnostic biomarkers for the disorder (e.g. flow cytometry on periperal blood cells, immunochemistry of peripheral nerve biopsies, T2 hyperintense signal in posterior limb of internal capsule, diminished ATP/ADP breakdown in lymphoblast assays, alteration in metabolic pathways) and discuss potential future developments (ASOs for splicing variant, antagonism for purinergic receptor P2X7, etc).
Sources: Literature
Early onset or syndromic epilepsy v2.518 TFE3 Helen Lord reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v2.518 RNF13 Helen Lord changed review comment from: Agree there are 3 unrelated cases - so recladsify as green; to: Agree there are 3 unrelated cases - so reclassify as green
Early onset or syndromic epilepsy v2.518 RNF13 Helen Lord edited their review of gene: RNF13: Added comment: Agree there are 3 unrelated cases - so recladsify as green; Changed rating: GREEN
Early onset or syndromic epilepsy v2.518 PIGP Helen Lord edited their review of gene: PIGP: Added comment: Paper by Vetro et al 2020: 32042915 - Supports green rating; Changed rating: GREEN; Changed publications to: 28334793, 31139695, 32042915; Changed phenotypes to: developmental and epileptic encephalopathy 55
Early onset or syndromic epilepsy v2.518 KAT8 Helen Lord reviewed gene: KAT8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794431; Phenotypes: Li-Ghorgani-Weisz-Hubshman syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 KAT5 Helen Lord reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32822602; Phenotypes: Neurodevelopmental disorder with dysmorphic facies, sleep disturbance and brain abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 H3F3A Helen Lord reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Bryant-Li Bhoj neurodevelopmental syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 H3F3B Helen Lord reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Bryant-Li Bhoj neurodevelopmental syndrome 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.518 DMXL2 Helen Lord reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: developmental and epileptic encephalopathy 81; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.518 ASNS Helen Lord reviewed gene: ASNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24139043, 27469131, 29375865, 28776279, 29279279; Phenotypes: Asparagine Synthetase deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.518 ALKBH8 Helen Lord edited their review of gene: ALKBH8: Added comment: Saad et al, 2021: Third family of Egyptian descent harbouring a novel homozygous fs variant in the last exon of ALKBH8 - seen in two affected siblings, unaffected parents are het carriers. Parents are consanguineous. Variant likely to escape NMD.
Both proband and aff sister had global dev delay, autisitic features, - neither have epilepy or seizure-like episodes. Do have structural brain abnormalities including mild-mod cerebral volume loss, mild to mod cerebellar vermian hypoplasia, variable degrees of thinning of the corpus callosum and abnormal myelination for age on brain MRI.

Still would classify as amber...; Changed publications to: 33544954; Changed phenotypes to: Neurodevelopmental disorders
Early onset or syndromic epilepsy v2.518 CACNB4 Helen Lord edited their review of gene: CACNB4: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.518 GLRA2 Konstantinos Varvagiannis gene: GLRA2 was added
gene: GLRA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GLRA2 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: GLRA2 were set to 20531469; 20479760; 26370147; 28588452; 35294868
Phenotypes for gene: GLRA2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Microcephaly; Abnormality of eye movement
Penetrance for gene: GLRA2 were set to unknown
Mode of pathogenicity for gene: GLRA2 was set to Other
Review for gene: GLRA2 was set to AMBER
Added comment: Heterozygous or hemizygous pathogenic GLRA2 variants cause Intellectual developmental disorder, X-linked, syndromic, Pilorge type (# 301076) as summarized in a recent OMIM entry.

The phenotype is characterized by DD with variably impaired intellectual development, behavioral abnormalities (autistic features in some), variable ocular findings (nystagmus, strabismus, oculomotor apraxia) and seizures in some [ 6/13 in Ref4 ].

GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth.

Animal models support the role of the gene in CNS.

Studies have been performed for several of the variants reported to date (in all cases missense and a htz deletion of the last 2 exons).

As summarized by OMIM, most affected females carry de novo htz missense GoF variants, and most affected males inherited hemizygous LoF ones.

XCI has not been studied in most htz (affected/unaffected) females (with the exception of the del in Ref2, see also Ref3).

Details provided below.

(Note: Most articles refer to variants using HGVS nomenclature while few without incl. the signal peptide eg. p.Arg350Leu corresponding to Arg323Leu).

Consider inclusion in the current panel with amber/green rating.


[1]----
Piton et al (2011 - PMID: 20479760) sequenced 111 X-linked synaptic genes in a cohort of 142 individuals with ASD and identified a female (S00125) harboring Arg350Leu (NM_002063 chrX:14618871 G/T), inherited from her mother (no clinical information provided). Functional evaluation of the variant was performed in a later publication (Ref3), providing additional clinical details on the proband.

[2]----
Pilorge et al (2016 - PMID: 26370147) review the role of glycine receptors (GlyRs). These typically consist of pentameric combinations of alpha (α1-α4) and beta (β) subunits and form a pore that controls transmembrane flux of chloride. GlyRs can be formed either as homomers comprising five α subunits or as heteromers of α and β subunits (in 2:3 or 3:2 stoichiometry). Each subunit has an N-terminal extracellular domain with the ligand-binding site and 4 transmembrane domains. GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth. The authors discuss the role of glycine as inhibitory neurotransmitter in adult CNS and depolarizing/excitatory action in immature neurons, as well as the role of GlyR α2 in proliferation and neuronal migration during cortical development.

The authors previously (2010 - PMID: 20531469) identified a boy with ASD, language delay and low average IQ (verbal 93, performance 75, full-scale IQ 82) harboring a 142 kb microdeletion spanning the last 2 exons of GRLA2 (hg19 - chrX:14693216-14836199). This CNV was confirmed with qPCR and the breakpoints localized to intron 7 after sequencing. Reverse transcription of mRNA from blood revealed presence of a truncated transcript in the child suggestive of little or no NMD. In the mother, the non-truncated transcript was amplified. Further it was shown that the product leaded to incorporation of intron 7, with inclusion of 5 residues followed by a stop codon. The mother had a normal, non-skewed XCI. Previous testing had excluded an FMR1 expansion.

Screening of 400 males with ASD identified a further male with de novo missense SNV (NM_002063.3:c.458G>A / p.Arg153Gln). This child had non-syndromic autism, severe language delay, mild ID (fs IQ 63) and GTC seizures with onset at 18y. Previous testing incl. a normal karyotype, FMR1 analysis, and CMA. The boy had an older sister with ASD, not harboring the same GLRA2 variant (interpreted in the context of intrafamilial genetic heterogeneity for ASD).

The authors also studied a dn missense variant (NM_001118886.1:c.407A>G / p.Asn136Ser) previously reported in a proband with autism (11842.p2 - Iossifov et al, 2014 - PMID: 25363768).

In vitro studies demonstrated that the 3 aforementioned variants impaired GlyR2 α2 function:
- The authors generated constructs for wt, the deletion (of last 2 exons) and Arg153Gln and performed co-transfection with EGFP cDNA in Chinese hamster ovary (CHO) cells. While wt and Arg153Gln were observed at the plasma membrane of transfected cells, the del was undetectable at the cell surface and was mislocalized in the cytoplasm (as also expected by loss of the transmembrane domains).
- Upon isolation of biotinylated surface receptors and western blot, Arg153Gln was shown to result to 56% decreased surface expression compared to wt, while the intracellular fragment was also reduced by 32% suggesting impaired synthesis or degradation. Asn136Ser had 67% lower surface (and 15% lower intracellular) expression.
- Whole-cell patch clamp recordings of transfected CHO cells suggested that the minimum concentration of glycine to evoke whole-cell current was ~100 higher for Arg153Gln compared to wt. High concentrations of glycine were unable to evoke any current in the case of the deletion (due to loss of surface expression). Asn136Ser also reduced glycine sensitivity (14x increase in EC50).

Zebrafish studies for glra2 and the del or Arg153Gln variants:
Morpholino mediated knockdown of glra2 led to hyperbranching of spinal motor axons compared to ctrls. Co-injection of human wt mRNA with glra2 morpholino, rescued the aberrant branching phenotype which was not the case for the 2 variants.

Glra2 ko mouse model (also on chrX):
- Mutant mice (Glra2-/Y) had normal adult body, brain weight, were fertile and had a normal lifespan. They displayed no differences in locomotor activity, or social behavior compared to wt. They however exhibited impaired learning and memory in the novel object recognition task (spatial learning and memory in the novel location recognition task and Morris water maze were N).
- Long-term potentiation in prefrontal cortex after high frequency stimulation was significantly impaired in mutant mice compared to wt, overall supporting that impaired glycinergic signaling results in abnormal synaptic plasticity in this relevant for ASD region.

[3]----
Zhang et al (2017 - PMID: 28588452) determined the functional effects of Arg350Leu which was reported by Piton et al (Arg323Leu without the signal peptide).

The authors provide further clinical details on this female with autism, macrocephaly, loss of acquired words, seizures, mild motor delay and hypothyroidism. The mother of the, also carrier of the SNV, was reportedly unaffected.

The potency of glycine in activating recombinant homomeric α2 and heteromeric α2β receptors was examined by whole-cell patch-clamp recording (HEK293 cells).

In homo-/ and heteromeric receptors this variant resulted in small decrease in glycine sensitivity with peak currents not significantly different compared to wt (the latter suggestive of normal surface expression).

This variant resulted in prolonged inhibitory postsynaptic currents (IPSCs) with ~2-fold slower rise and decay times, while IPSC amplitude did not differ significantly. Overall, the slowed decay times, prolongation of active periods and small but significantly increased conductance of mutant channels suggested that this variant exerts a gain-of-function effect.

The authors briefly cite a study by Cotton et al (2015, PMID: 25381334) providing evidence that GLRA2 escapes XCI in the vast majority of tissues and brain.

[4]----
Marcogliese et al (2022 - PMID: 35294868) functionally tested the effects of missense DNM observed in individuals with ASD diagnosis in Drosophila. The authors generated TG4 (MiMIC cassette) fly mutants for candidate ASD genes (creating LoF alleles for the respective genes). Using a GAL4/UAS system with human cDNA constructs for reference/variants they performed the rescue/overexpression assays to study the functional consequences.

Flies expressing human ref GLRA2 cDNA failed to copulate but exhibited normal movement. Flies for Asn136Ser (a variant reported by Iossifov et al, 2014 - PMID: 25363768) copulated similar to the TG4 mutant providing evidence for a LoF effect of this variant.

Upon GAL4/UAS expression and co-staining with neuronal (Elav) and glial (Repo) nuclear markers, GLRA2 was shown to be expressed in CNS with expression in a subset of neurons and in some glia.

Upon ubiquitous overexpression of human reference or variant cDNA, Asn136Ser also behaved as a LoF allele.

Based on the evidence on this gene, and following re-analyses of exome data, GeneMatcher collaborations etc, the authors identified 13 additional unrelated subjects harboring GLRA2 variants (8 females/5 males). These had DD/ID of variable severity (13/13) w/wo autistic features (in 4 or 5), microcephaly (4-5/13 all females), epilepsy (6/13 - both sexes) and ocular manifestations (10/13 - incl. nystagmus, strabismus, etc). Hypotonia/incoordination was observed in 7/13.

All females had dn missense variants (8/8, NM_001118886.1:c.887C>T/p.Thr296Met in 6/8, others: c.140T>C/p.Phe47Ser, c.777C>G/p.Ile259Met), while all males had inherited missense SNVs from their unaffected mothers (p.Arg252Cys, p.Ala288Thr, p.Pro396Thr, p.Pro400Leu, p.Arg445Gln).

The authors studied an variant which was recurrent in females (Thr296Met) and another found in a male (Arg252Cys). Upon overexpression, the latter behaved - similarly to Asn136Ser - as LoF allele, while Thr296Met did not differ significantly from reference.

Structural modeling suggested that Thr296 is adjacent to a residue important for keeping the ion pore in closed conformation.

Upon pnr-GAL4 (over)expression in the dorsolateral stripe in the notum, Thr296Met caused lethality, which was not the case for the reference. When expressed at lower levels, Thr296Met formation of melanized nodules in thorax, a phenotype not previously observed upon overexpression of ref/other variants.

The authors performed ERGs in fly eyes. They first used a pan-neuronal driver (nSyb-GAL) leading to GLRA2 ref / variant expression in pre-synaptic photoreceptors and post-synaptic neurons. A significant increase of "OFF" transients was observed for Thr296Met, suggesting increase in synaptic transmission and a GoF effect. Expression limited to pre-synaptic photoreceptors (Rh1-GAL4 driver) did not lead to significant differences compared to ref allele, while Arg252Cys was associated with decreased amplitudes of "OFF" transients, suggestive of decreased synaptic transmission and confirming a LoF effect.

Marcogliese et al conclude that reduced GLRA2 activity can lead to disease in males but can be tolerated in htz females (as was the case for asymptomatic mothers), while GoF variants leading to overactivation of the channel could be overrepresented in affected females.
Sources: Literature
Early onset or syndromic epilepsy v2.518 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency, 606812; Seizures to Fumarase deficiency, OMIM:606812
Early onset or syndromic epilepsy v2.517 SLC1A2 Sarah Leigh changed review comment from: PMID 28915517 reports one case of hmz c.1421+1G>C in a case of epileptic seizures and visual impairment. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function. In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other.; to: PMID:28915517 reports one case of homozygous c.1421+1G>C in a case of epileptic seizures with visual impairment. The nonconsanguineous German parents of the case, were heterozygous for c.1421+1G>C. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function. In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other.
Early onset or syndromic epilepsy v2.517 SLC1A2 Sarah Leigh reviewed gene: SLC1A2: Rating: ; Mode of pathogenicity: None; Publications: 23934111, 27476654; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.517 CACNA2D1 Sarah Leigh reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.517 CACNA2D1 Sarah Leigh Classified gene: CACNA2D1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.517 CACNA2D1 Sarah Leigh Gene: cacna2d1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.516 CACNA2D1 Sarah Leigh Publications for gene: CACNA2D1 were set to 35293990
Early onset or syndromic epilepsy v2.515 KCNC2 Sarah Leigh Classified gene: KCNC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.515 KCNC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.515 KCNC2 Sarah Leigh Gene: kcnc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.514 KCNC2 Sarah Leigh Tag Q2_22_rating tag was added to gene: KCNC2.
Early onset or syndromic epilepsy v2.514 KCNC2 Sarah Leigh reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.514 KCNC2 Sarah Leigh Publications for gene: KCNC2 were set to 32392612; 31972370
Early onset or syndromic epilepsy v2.513 DTYMK Sarah Leigh Classified gene: DTYMK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.513 DTYMK Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be made green at the next major review.
Early onset or syndromic epilepsy v2.513 DTYMK Sarah Leigh Gene: dtymk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.512 DTYMK Sarah Leigh Tag Q2_22_rating tag was added to gene: DTYMK.
Early onset or syndromic epilepsy v2.512 DTYMK Sarah Leigh reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.512 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Early onset or syndromic epilepsy v2.511 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome, type 1 267750 to Knobloch syndrome, type 1, OMIM:267750
Early onset or syndromic epilepsy v2.510 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to 19160445; 28602933; 28950998
Early onset or syndromic epilepsy v2.509 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733; 21677750; 25660031; 31388108
Early onset or syndromic epilepsy v2.508 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures; KINSSHIP syndrome to KINSSHIP syndrome, OMIM:619297
Early onset or syndromic epilepsy v2.507 DTYMK Konstantinos Varvagiannis gene: DTYMK was added
gene: DTYMK was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to 31271740; 34918187; 35346037
Phenotypes for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Penetrance for gene: DTYMK were set to Complete
Review for gene: DTYMK was set to GREEN
Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported.

Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc].

Relevant studies are summarized below.
----
Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants.

The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y.

Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib.

There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway.

Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS).

Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood).

This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%.
----
Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem.

CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction).

WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu.

In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect.

Variants were both ultrarare without homozygotes in ExAC,.

The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells.

dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested.

In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase).

Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain.

Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage).

In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides).

Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks.

mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency.

Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents.

Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents.

Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction.

The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD.
------
In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed]
Sources: Literature
Early onset or syndromic epilepsy v2.507 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2A, 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Classified gene: NAPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. At least 3 unrelated families (4 affected individuals) with distinct homozygous variants in this gene, universally presenting seizures, profound ID and microcephaly. Pathogenicity is supported by a complimentary knockout mouse model demonstrating recurrent post-natal epileptic seizures which were lethal in some mice.
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Gene: napb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.505 NAPB Arina Puzriakova Tag Q2_22_rating tag was added to gene: NAPB.
Tag Q2_22_NHS_review tag was added to gene: NAPB.
Early onset or syndromic epilepsy v2.505 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from SLC5A6-related Neurodevelopmental Disorder to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Early onset or syndromic epilepsy v2.504 ATP2B1 Konstantinos Varvagiannis gene: ATP2B1 was added
gene: ATP2B1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B1 were set to 35358416; 33057194
Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck
Penetrance for gene: ATP2B1 were set to unknown
Review for gene: ATP2B1 was set to AMBER
Added comment: At least 12 individuals with NDD due to monoallelic missense/pLoF ATP2B1 variants have been reported to date. Seizures were observed in 5 of them.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with amber rating.
---
Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature
Early onset or syndromic epilepsy v2.504 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Early onset or syndromic epilepsy v2.504 ADAT3 Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36 615286 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286
Early onset or syndromic epilepsy v2.503 CACNA2D1 Konstantinos Varvagiannis reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35293990, 28097321; Phenotypes: Abnormal muscle tone, Feeding difficulties, Global developmental delay, Intellectual disability, Seizures, Microcephaly, Abnormality of the corpus callosum, Cerebral atrophy, Abnormality of movement, Cortical visual impairment, Pain insensitivity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.503 ACTL6B Arina Puzriakova Phenotypes for gene: ACTL6B were changed from Epileptic encephalopathy, early infantile, 76, 618468; Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy to Developmental and epileptic encephalopathy 76, OMIM:618468
Early onset or syndromic epilepsy v2.502 RELN Sarah Leigh Phenotypes for gene: RELN were changed from {Epilepsy, familial temporal lobe, 7} 616436 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; {Epilepsy, familial temporal lobe, 7}, OMIM:616436
Early onset or syndromic epilepsy v2.501 RELN Sarah Leigh Publications for gene: RELN were set to 26046367
Early onset or syndromic epilepsy v2.500 CACNA2D1 Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously providing a critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.500 CACNA2D1 Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin

Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.500 CACNA2D1 Helen Lord gene: CACNA2D1 was added
gene: CACNA2D1 was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990
Phenotypes for gene: CACNA2D1 were set to Early onset developmental epilepsy
Review for gene: CACNA2D1 was set to AMBER
Added comment: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin

Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.500 KCNC2 Helen Lord reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35314505; Phenotypes: epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.500 NAPB Tracy Lester gene: NAPB was added
gene: NAPB was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Review for gene: NAPB was set to GREEN
Added comment: Three cases reported with early infantile epileptic encepahlopathy and with homozygous LOF variants in this gene. Null mice also develop severe recurrent epileptic seizures from day 11, followed by ataxia. Sufficient evidence to be considered as green gene on the epilepsy and ID panels, autosomal recessive inheritance only.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.500 FAR1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline); to: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel.
Early onset or syndromic epilepsy v2.500 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37493-Loss Arina Puzriakova commented on Region: ISCA-37493-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37432-Gain Arina Puzriakova commented on Region: ISCA-37432-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37415-Loss Arina Puzriakova commented on Region: ISCA-37415-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37411-Loss Arina Puzriakova commented on Region: ISCA-37411-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Early onset or syndromic epilepsy v2.500 ISCA-46295-Loss Ivone Leong commented on Region: ISCA-46295-Loss
Early onset or syndromic epilepsy v2.500 ISCA-46290-Gain Ivone Leong commented on Region: ISCA-46290-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Early onset or syndromic epilepsy v2.500 ISCA-46290-Gain Arina Puzriakova GRCh38 position for ISCA-46290-Gain was changed from 48447780-52444265 to 48447780-52444264.
Haploinsufficiency Score for ISCA-46290-Gain was changed from None to .
Required Overlap Percentage for ISCA-46290-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37423-Gain Arina Puzriakova Haploinsufficiency Score for ISCA-37423-Gain was changed from None to .
Required Overlap Percentage for ISCA-37423-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37429-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37429-Loss was changed from None to .
Required Overlap Percentage for ISCA-37429-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37493-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37493-Loss was changed from None to .
Required Overlap Percentage for ISCA-37493-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37434-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37434-Loss was changed from None to .
Required Overlap Percentage for ISCA-37434-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37432-Gain Arina Puzriakova GRCh38 position for ISCA-37432-Gain was changed from 36458167-37854617 to 36458167-37854616.
Haploinsufficiency Score for ISCA-37432-Gain was changed from None to .
Required Overlap Percentage for ISCA-37432-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37430-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37430-Loss was changed from None to .
Required Overlap Percentage for ISCA-37430-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37415-Loss Arina Puzriakova GRCh38 position for ISCA-37415-Loss was changed from 15410597-16198411 to 15417854-16198408.
Triplosensitivity Score for ISCA-37415-Loss was changed from None to .
Required Overlap Percentage for ISCA-37415-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-46295-Loss Arina Puzriakova GRCh38 position for ISCA-46295-Loss was changed from 31727418-32153205 to 31727418-32153204.
Triplosensitivity Score for ISCA-46295-Loss was changed from None to .
Required Overlap Percentage for ISCA-46295-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37411-Loss Arina Puzriakova GRCh38 position for ISCA-37411-Loss was changed from 30844901-32153207 to 30900686-32153204.
Triplosensitivity Score for ISCA-37411-Loss was changed from None to .
Required Overlap Percentage for ISCA-37411-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Triplosensitivity Score for ISCA-37478-Loss was changed from None to .
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Haploinsufficiency Score for ISCA-37478-Gain was changed from None to .
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Triplosensitivity Score for ISCA-37404-Loss was changed from None to .
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.499 EEF1A2 Sarah Leigh Mode of pathogenicity for gene: EEF1A2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v2.498 CPA6 Sarah Leigh commented on gene: CPA6: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Early onset or syndromic epilepsy v2.498 SCN8A Sarah Leigh commented on gene: SCN8A: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Early onset or syndromic epilepsy v2.498 SLC5A6 Sarah Leigh commented on gene: SLC5A6: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Early onset or syndromic epilepsy v2.498 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Early onset or syndromic epilepsy v2.498 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Early onset or syndromic epilepsy v2.498 CPSF3 Konstantinos Varvagiannis gene: CPSF3 was added
gene: CPSF3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPSF3 were set to 35121750
Phenotypes for gene: CPSF3 were set to Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures
Penetrance for gene: CPSF3 were set to Complete
Review for gene: CPSF3 was set to AMBER
Added comment: Arnadottir (2022 - PMID: 35121750) describe the phenotype associated with biallelic CPSF3 pathogenic variants.

Based on WGS of 56,969 Icelanders and imputing the genotype of another 153,054 chip-genotyped Icelanders, the authors identified missense variants with a deficit of homozygous carriers to what would be expected based on AF. (For variants with MAF>0.4%, for which >=3 hmz carriers would be expected by H-W equilibrium, no identified hmz carriers within this cohort/dataset). A total of 114 such missense variants was identified.

5 of these SNVs, among which a CPSF3 one (NM_016207.3:c.1403G>A / p.Gly468Glu), were however observed in a series of 764 individuals investigated with clinical WGS at the National University Hospital.

The CPSF3 variant with a MAF of 0.41% (3 hmz expected but none observed in the population set) was found in homozygosity in 2 closely related individuals, both investigated for FTT, severe DD, ID, microcephaly, seizures but remaining unresolved following WGS with no other candidate variants.

Using genealogical information from the db of deCODE genetics, the authors identified 3 couples from the 153k genotyped Icelanders where both partners were htz carriers for this SNV. These 3 couples had 10 offspring, 4 of whom deceased but with the same phenotypic features as above (hypotonia 4/4, ID 4/4, seizures 3/4, microcephaly 2/4). Paraffin embedded samples of 2 of these children and WG & Sanger sequencing confirmed hmz for Gly468Glu in 2 sibs, without other candidate variants. Samples of the 2 other individuals were N/A.

Through GeneMatcher 2 additional first-cousin patients from Mexico were identified, being hmz for another CPSF3 variant (c.1061T>C/p.Ile354Thr) and having overlapping phenotype of abnormal muscle tone, ID, seizures and microcephaly. There were no other variants in WES analysis.

mRNA studies in WBCs from Gly468Glu htz carriers did not reveal reduced levels and W.Blot of lymphocytes from a hmz individual confirmed expression, overall suggesting that the variant does not affect the protein levels but presumably the function.

CPSF3 encodes cleavage and polyadenylation specificity factor 3, a 684 aa protein, subunit of the cleavage and polyadenylation specificity factor compex. As discussed, cleavage and polyadenylation of the 3' of pre-mRNAs is necessary before transport out of the nucleus with CPSF playing a crucial role in the process of cleavage.

CPSF3 ko mice exhibit embryonic lethality, while in yeast mutations in key residues of the CPSF3 homolog are lethal.

In gnomAD, CPSF3 has a pLI of 0, z-score of 3.61 with no homozygotes for pLoF variants in 141k individuals (or ~57k WGS Icelanders).

The 2 missense variants concern highly conserved residues (GERP ~5.8). Both are hypothesized to affect the ability of the protein to bind other factors involved in pre-mRNA cleavage.

Overall the authors speculate that not only complete loss of CPSF3 would result in drastic phenotypic effects - as in the murine model - but also variants altering its enzymatic function.

There is currently no CPSF3-related phenotype in OMIM, G2P, SysID, The gene is included with green rating in the ID, epilepsy and microcephaly panels in PanelApp Australia.

Consider inclusion probably with amber rating (Highly consistent phenotype, biological function, evidence from animal models. 2 identified variants, authors state that follow-up functional studies are needed). Also consider inclusion in other possibly relevant panels.
Sources: Literature
Early onset or syndromic epilepsy v2.498 TIAM1 Konstantinos Varvagiannis gene: TIAM1 was added
gene: TIAM1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIAM1 were set to 35240055; 33328293
Phenotypes for gene: TIAM1 were set to Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology
Penetrance for gene: TIAM1 were set to Complete
Review for gene: TIAM1 was set to AMBER
Added comment: Lu et al (2022 - PMID: 35240055) describe 5 individuals (from 4 families) with biallelic TIAM1 missense variants.

The phenotype overall corresponded to a neurodevelopmental disorder with DD (5/5), ID (4/4 individuals of relevant age - 3 families), speech delay (5/5), seizures (5/5 - onset: 2m-13y) and behavioral abnormalities (2/2, sibs with autism and ADHD). Several subjects had endocrine symptoms, namely hypothyroidism (N=3 - 2 families), Addison's disease (1) or hypomagnesemia (1). Non-consistent abnormalities were reported in (3/3) subjects who had a brain MRI.

Previous investigations were mentioned for 3 individuals (incl. 2 sibs) and included normal CMA and/or metabolic workup.

Singleton or trio exome sequencing (in one family) revealed biallelic missense TIAM1 variants.

6 different missense variants were reported, all ultra-rare or not present in gnomAD (also o/e:0.2, pLI:0.96), with CADD scores in favor of deleterious effect (NM_001353694.2): c.67C>T/p.Arg23Cys*, c.2584C>T/p.Leu862Phe*, c.983G>T/p.Gly328Val*, c.4640C>A/p.Ala1547Glu, c.1144G>C/p.Gly382Arg, c.4016C>T/p.Ala1339Val.

TIAM1 encodes a RAC1-specific guanine exchange factor (GEF), regulating RAC1 signaling pathways that in turn affect cell shape, migration, adhesion, growth, survival, and polarity, and influence actin cytoskeletal organization, endocytosis, and membrane trafficking. RAC1 signaling plays important role in control of neuronal morphogenesis and neurite outgrowth (based on the summary by Entrez and authors).

TIAM1 is highly expressed in human brain (GTEx).

The authors provide evidence that sif, the Drosophila ortholog, is expressed primarily in neurons of the fly CNS (but not in glia). Using different sif LoF mutant flies they demonstrate that loss of sif impairs viability. Surviving flies exhibited climbing defects and seizure-like behaviors, both significantly rescued upon UAS-sif expression. Neuronal specific sif knockdown resulted in similar phenotypes to ubiquitous knockdown, while glial knockdown did not result in climbing defects.

The semi-lethal phenotype could be fully rescued by expression of the fly sif cDNA, but only partially by human TIAM1 cDNA reference. Upon expression, 3 patient-variants (R23C, L862F, G328V) had variable rescue abilities similar to or lower (R23C) than TIAM1 Ref. TIAM1 Ref and variants could not rescue the neurological phenotypes though. Higher/ectopic expression of sif or TIAM1 Ref was toxic, which was also observed to a lesser extent for variants.

Overall, the evidence provided suggests that the 3 variants tested induce partial LoF.

In a recent study cited (PMID: 33328293), Tiam1 KO mice had simplified dendritic arbors, reduced spine density and diminished excitatory transmission in dentate gyrus. The authors comment that this mouse model presented only subtle behavioral abnormalities which they speculate may be secondary to GEF redundancy (eg. Tiam2).

There is no TIAM1-associated phenotype in OMIM/G2P/SysID. TIAM1 is included in PanelApp Australia in the ID and epilepsy panels with green rating.

Consider inclusion in the current panel with amber rating [As authors discuss: some phenotypic features differed in their small cohort and the contribution of other recessive conditions in 2 consanguineous families cannot be excluded. Also: in fig S1 only status of parents but not of affected/unaffected sibs is specified with the exception of Fam1].
Sources: Literature
Early onset or syndromic epilepsy v2.498 GABRD Ivone Leong Tag Q4_21_rating was removed from gene: GABRD.
Tag Q4_21_NHS_review was removed from gene: GABRD.
Early onset or syndromic epilepsy v2.498 HPDL Ivone Leong Tag Q2_21_rating was removed from gene: HPDL.
Early onset or syndromic epilepsy v2.498 UFSP2 Ivone Leong Tag Q2_21_rating was removed from gene: UFSP2.
Tag Q2_21_expert_review was removed from gene: UFSP2.
Tag Q2_21_NHS_review was removed from gene: UFSP2.
Early onset or syndromic epilepsy v2.498 UFSP2 Sarah Leigh commented on gene: UFSP2: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.
Early onset or syndromic epilepsy v2.498 HPDL Sarah Leigh commented on gene: HPDL
Early onset or syndromic epilepsy v2.498 GABRD Sarah Leigh commented on gene: GABRD: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.
Early onset or syndromic epilepsy v2.498 UFSP2 Ivone Leong Source Expert Review Green was added to UFSP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.498 HPDL Ivone Leong Source Expert Review Green was added to HPDL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.498 GABRD Ivone Leong Source Expert Review Green was added to GABRD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.497 CSTB_CCCCGCCCCGCG Arina Puzriakova Classified STR: CSTB_CCCCGCCCCGCG as Green List (high evidence)
Early onset or syndromic epilepsy v2.497 CSTB_CCCCGCCCCGCG Arina Puzriakova Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.496 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Green List (high evidence)
Early onset or syndromic epilepsy v2.496 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.493 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v2.493 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v2.492 NUS1 Arina Puzriakova Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa OMIM:617082; Mental retardation, autosomal dominant 55, with seizures OMIM:617831; Abnormality of extrapyramidal motor function to Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082
Early onset or syndromic epilepsy v2.491 ADAM22 Sarah Leigh Tag for-review was removed from gene: ADAM22.
Early onset or syndromic epilepsy v2.491 EEF1A2 Sarah Leigh Tag for-review was removed from gene: EEF1A2.
Early onset or syndromic epilepsy v2.491 CEP85L Sarah Leigh Tag for-review was removed from gene: CEP85L.
Early onset or syndromic epilepsy v2.491 SLC5A6 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: SLC5A6.
Early onset or syndromic epilepsy v2.491 SCN8A Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: SCN8A.
Early onset or syndromic epilepsy v2.491 CPA6 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: CPA6.
Early onset or syndromic epilepsy v2.491 APC2 Sarah Leigh Tag for-review was removed from gene: APC2.
Early onset or syndromic epilepsy v2.491 ASNS Sarah Leigh Tag for-review was removed from gene: ASNS.
Early onset or syndromic epilepsy v2.491 ANKRD11 Sarah Leigh Tag for-review was removed from gene: ANKRD11.
Early onset or syndromic epilepsy v2.491 CACNB4 Sarah Leigh Tag for-review was removed from gene: CACNB4.
Early onset or syndromic epilepsy v2.491 CDK19 Sarah Leigh Tag for-review was removed from gene: CDK19.
Early onset or syndromic epilepsy v2.491 GAD1 Sarah Leigh Tag for-review was removed from gene: GAD1.
Early onset or syndromic epilepsy v2.491 PIGK Sarah Leigh Tag for-review was removed from gene: PIGK.
Early onset or syndromic epilepsy v2.491 RALGAPA1 Sarah Leigh Tag for-review was removed from gene: RALGAPA1.
Early onset or syndromic epilepsy v2.491 PPIL1 Sarah Leigh Tag for-review was removed from gene: PPIL1.
Early onset or syndromic epilepsy v2.491 UBR7 Sarah Leigh Tag for-review was removed from gene: UBR7.
Early onset or syndromic epilepsy v2.491 FGF13 Sarah Leigh Tag for-review was removed from gene: FGF13.
Early onset or syndromic epilepsy v2.491 TIMM50 Sarah Leigh Tag for-review was removed from gene: TIMM50.
Early onset or syndromic epilepsy v2.491 TRPM3 Sarah Leigh Tag for-review was removed from gene: TRPM3.
Early onset or syndromic epilepsy v2.491 WDR45B Sarah Leigh Tag for-review was removed from gene: WDR45B.
Early onset or syndromic epilepsy v2.491 SETD5 Sarah Leigh Tag for-review was removed from gene: SETD5.
Early onset or syndromic epilepsy v2.491 SETD1B Sarah Leigh Tag for-review was removed from gene: SETD1B.
Early onset or syndromic epilepsy v2.491 RNF13 Sarah Leigh Tag for-review was removed from gene: RNF13.
Early onset or syndromic epilepsy v2.491 PIGP Sarah Leigh Tag for-review was removed from gene: PIGP.
Early onset or syndromic epilepsy v2.491 KAT5 Sarah Leigh Tag for-review was removed from gene: KAT5.
Early onset or syndromic epilepsy v2.491 PTEN Sarah Leigh Tag for-review was removed from gene: PTEN.
Early onset or syndromic epilepsy v2.491 ADARB1 Sarah Leigh Tag for-review was removed from gene: ADARB1.
Early onset or syndromic epilepsy v2.491 CARS2 Sarah Leigh Tag for-review was removed from gene: CARS2.
Early onset or syndromic epilepsy v2.491 HERC2 Sarah Leigh Tag for-review was removed from gene: HERC2.
Early onset or syndromic epilepsy v2.491 MADD Sarah Leigh Tag for-review was removed from gene: MADD.
Early onset or syndromic epilepsy v2.491 MTHFS Sarah Leigh Tag for-review was removed from gene: MTHFS.
Early onset or syndromic epilepsy v2.491 NR4A2 Sarah Leigh Tag for-review was removed from gene: NR4A2.
Early onset or syndromic epilepsy v2.491 NRROS Sarah Leigh Tag for-review was removed from gene: NRROS.
Early onset or syndromic epilepsy v2.491 OXR1 Sarah Leigh Tag for-review was removed from gene: OXR1.
Early onset or syndromic epilepsy v2.491 SCAF4 Sarah Leigh Tag for-review was removed from gene: SCAF4.
Early onset or syndromic epilepsy v2.491 TUBGCP2 Sarah Leigh Tag for-review was removed from gene: TUBGCP2.
Early onset or syndromic epilepsy v2.491 UGDH Sarah Leigh Tag for-review was removed from gene: UGDH.
Early onset or syndromic epilepsy v2.491 USP18 Sarah Leigh Tag for-review was removed from gene: USP18.
Early onset or syndromic epilepsy v2.491 TMX2 Sarah Leigh Tag for-review was removed from gene: TMX2.
Early onset or syndromic epilepsy v2.491 TRAPPC4 Sarah Leigh Tag for-review was removed from gene: TRAPPC4.
Early onset or syndromic epilepsy v2.491 UGP2 Sarah Leigh Tag for-review was removed from gene: UGP2.
Early onset or syndromic epilepsy v2.491 PCYT2 Sarah Leigh Tag for-review was removed from gene: PCYT2.
Early onset or syndromic epilepsy v2.491 SETD1A Sarah Leigh Tag for-review was removed from gene: SETD1A.
Early onset or syndromic epilepsy v2.491 SERPINI1 Sarah Leigh Tag for-review was removed from gene: SERPINI1.
Early onset or syndromic epilepsy v2.491 RNF113A Sarah Leigh Tag for-review was removed from gene: RNF113A.
Early onset or syndromic epilepsy v2.491 RARS Sarah Leigh Tag for-review was removed from gene: RARS.
Early onset or syndromic epilepsy v2.491 PUM1 Sarah Leigh Tag for-review was removed from gene: PUM1.
Early onset or syndromic epilepsy v2.491 PNPT1 Sarah Leigh Tag for-review was removed from gene: PNPT1.
Early onset or syndromic epilepsy v2.491 LARS Sarah Leigh Tag for-review was removed from gene: LARS.
Early onset or syndromic epilepsy v2.491 NARS Sarah Leigh Tag for-review was removed from gene: NARS.
Early onset or syndromic epilepsy v2.491 TFE3 Sarah Leigh Tag for-review was removed from gene: TFE3.
Early onset or syndromic epilepsy v2.491 H3F3A Sarah Leigh Tag for-review was removed from gene: H3F3A.
Early onset or syndromic epilepsy v2.491 H3F3B Sarah Leigh Tag for-review was removed from gene: H3F3B.
Early onset or syndromic epilepsy v2.491 GRN Sarah Leigh Tag for-review was removed from gene: GRN.
Early onset or syndromic epilepsy v2.491 TBC1D2B Sarah Leigh Tag for-review was removed from gene: TBC1D2B.
Early onset or syndromic epilepsy v2.491 ZNF335 Sarah Leigh Tag for-review was removed from gene: ZNF335.
Early onset or syndromic epilepsy v2.491 TRAPPC12 Sarah Leigh Tag for-review was removed from gene: TRAPPC12.
Early onset or syndromic epilepsy v2.491 DDC Sarah Leigh Tag for-review was removed from gene: DDC.
Early onset or syndromic epilepsy v2.491 ALG14 Sarah Leigh Tag for-review was removed from gene: ALG14.
Early onset or syndromic epilepsy v2.491 GALNT2 Sarah Leigh Tag for-review was removed from gene: GALNT2.
Early onset or syndromic epilepsy v2.491 SEMA6B Sarah Leigh Tag for-review was removed from gene: SEMA6B.
Early onset or syndromic epilepsy v2.491 ALKBH8 Sarah Leigh Tag for-review was removed from gene: ALKBH8.
Early onset or syndromic epilepsy v2.491 LMBRD2 Sarah Leigh Tag for-review was removed from gene: LMBRD2.
Early onset or syndromic epilepsy v2.491 KAT8 Sarah Leigh Tag for-review was removed from gene: KAT8.
Early onset or syndromic epilepsy v2.491 DMXL2 Sarah Leigh Tag for-review was removed from gene: DMXL2.
Early onset or syndromic epilepsy v2.491 DLL1 Sarah Leigh changed review comment from: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.; to: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 DLL1 Sarah Leigh Tag for-review was removed from gene: DLL1.
Early onset or syndromic epilepsy v2.491 ADAM22 Sarah Leigh commented on gene: ADAM22: NHSGenomic Medicine Service consideration - the amber rating is appropriate for this gene.
Early onset or syndromic epilepsy v2.491 EEF1A2 Sarah Leigh commented on gene: EEF1A2: NHS Genomic Medicine Service consideration - the phenotype is appropriate for this panel
Early onset or syndromic epilepsy v2.491 DLL1 Sarah Leigh commented on gene: DLL1
Early onset or syndromic epilepsy v2.491 SCAMP5 Sarah Leigh commented on gene: SCAMP5: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 DMXL2 Sarah Leigh commented on gene: DMXL2: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 KAT8 Sarah Leigh commented on gene: KAT8: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 TET3 Sarah Leigh commented on gene: TET3: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 LMBRD2 Sarah Leigh commented on gene: LMBRD2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 ALKBH8 Sarah Leigh commented on gene: ALKBH8
Early onset or syndromic epilepsy v2.491 SEMA6B Sarah Leigh commented on gene: SEMA6B
Early onset or syndromic epilepsy v2.491 GALNT2 Sarah Leigh commented on gene: GALNT2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 ALG14 Sarah Leigh commented on gene: ALG14: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 ADAM22 Sarah Leigh commented on gene: ADAM22: After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.
Early onset or syndromic epilepsy v2.491 DDC Sarah Leigh commented on gene: DDC: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 EEF1A2 Sarah Leigh commented on gene: EEF1A2: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Early onset or syndromic epilepsy v2.491 TRAPPC12 Sarah Leigh commented on gene: TRAPPC12
Early onset or syndromic epilepsy v2.491 ZNF335 Sarah Leigh commented on gene: ZNF335
Early onset or syndromic epilepsy v2.491 TBC1D2B Sarah Leigh commented on gene: TBC1D2B
Early onset or syndromic epilepsy v2.491 GRN Sarah Leigh commented on gene: GRN
Early onset or syndromic epilepsy v2.491 DMXL2 Sarah Leigh commented on gene: DMXL2
Early onset or syndromic epilepsy v2.491 H3F3B Sarah Leigh commented on gene: H3F3B: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 H3F3A Sarah Leigh commented on gene: H3F3A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 TFE3 Sarah Leigh commented on gene: TFE3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 NARS Sarah Leigh commented on gene: NARS
Early onset or syndromic epilepsy v2.491 LARS Sarah Leigh commented on gene: LARS
Early onset or syndromic epilepsy v2.491 PNPT1 Sarah Leigh commented on gene: PNPT1
Early onset or syndromic epilepsy v2.491 PUM1 Sarah Leigh commented on gene: PUM1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 RARS Sarah Leigh commented on gene: RARS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 RNF113A Sarah Leigh commented on gene: RNF113A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 SERPINI1 Sarah Leigh commented on gene: SERPINI1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 SETD1A Sarah Leigh commented on gene: SETD1A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 PCYT2 Sarah Leigh commented on gene: PCYT2
Early onset or syndromic epilepsy v2.491 UGP2 Sarah Leigh commented on gene: UGP2
Early onset or syndromic epilepsy v2.491 TRAPPC4 Sarah Leigh commented on gene: TRAPPC4
Early onset or syndromic epilepsy v2.491 KAT8 Sarah Leigh commented on gene: KAT8
Early onset or syndromic epilepsy v2.491 TMX2 Sarah Leigh commented on gene: TMX2
Early onset or syndromic epilepsy v2.491 USP18 Sarah Leigh commented on gene: USP18
Early onset or syndromic epilepsy v2.491 UGDH Sarah Leigh commented on gene: UGDH
Early onset or syndromic epilepsy v2.491 TUBGCP2 Sarah Leigh commented on gene: TUBGCP2
Early onset or syndromic epilepsy v2.491 SCAF4 Sarah Leigh commented on gene: SCAF4
Early onset or syndromic epilepsy v2.491 OXR1 Sarah Leigh commented on gene: OXR1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 NRROS Sarah Leigh commented on gene: NRROS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 NR4A2 Sarah Leigh commented on gene: NR4A2
Early onset or syndromic epilepsy v2.491 MTHFS Sarah Leigh commented on gene: MTHFS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 MADD Sarah Leigh commented on gene: MADD
Early onset or syndromic epilepsy v2.491 HERC2 Sarah Leigh commented on gene: HERC2
Early onset or syndromic epilepsy v2.491 CARS2 Sarah Leigh commented on gene: CARS2
Early onset or syndromic epilepsy v2.491 ADARB1 Sarah Leigh commented on gene: ADARB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 PTEN Sarah Leigh commented on gene: PTEN: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 KAT5 Sarah Leigh commented on gene: KAT5: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 PIGP Sarah Leigh commented on gene: PIGP: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 RNF13 Sarah Leigh commented on gene: RNF13: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 SETD1B Sarah Leigh commented on gene: SETD1B: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 SETD5 Sarah Leigh commented on gene: SETD5: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 WDR45B Sarah Leigh commented on gene: WDR45B: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 TRPM3 Sarah Leigh commented on gene: TRPM3
Early onset or syndromic epilepsy v2.491 TIMM50 Sarah Leigh commented on gene: TIMM50: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 FGF13 Sarah Leigh commented on gene: FGF13
Early onset or syndromic epilepsy v2.491 UBR7 Sarah Leigh commented on gene: UBR7
Early onset or syndromic epilepsy v2.491 PPIL1 Sarah Leigh commented on gene: PPIL1
Early onset or syndromic epilepsy v2.491 RALGAPA1 Sarah Leigh commented on gene: RALGAPA1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 PIGK Sarah Leigh commented on gene: PIGK: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 GAD1 Sarah Leigh commented on gene: GAD1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 CEP85L Sarah Leigh commented on gene: CEP85L
Early onset or syndromic epilepsy v2.491 CDK19 Sarah Leigh commented on gene: CDK19: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 CACNB4 Sarah Leigh commented on gene: CACNB4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 ANKRD11 Sarah Leigh commented on gene: ANKRD11: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 ASNS Sarah Leigh commented on gene: ASNS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.491 APC2 Sarah Leigh commented on gene: APC2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.490 DLL1 Sarah Leigh Source Expert Review Green was added to DLL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 SCAMP5 Sarah Leigh Source NHS GMS was added to SCAMP5.
Early onset or syndromic epilepsy v2.490 DMXL2 Sarah Leigh Source NHS GMS was added to DMXL2.
Early onset or syndromic epilepsy v2.490 KAT8 Sarah Leigh Source NHS GMS was added to KAT8.
Early onset or syndromic epilepsy v2.490 TET3 Sarah Leigh Source NHS GMS was added to TET3.
Early onset or syndromic epilepsy v2.490 LMBRD2 Sarah Leigh Source Expert Review Green was added to LMBRD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 ALKBH8 Sarah Leigh Source Expert Review Green was added to ALKBH8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 SEMA6B Sarah Leigh Source Expert Review Green was added to SEMA6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 GALNT2 Sarah Leigh Source Expert Review Green was added to GALNT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 ALG14 Sarah Leigh Source Expert Review Green was added to ALG14.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 DDC Sarah Leigh Source Expert Review Green was added to DDC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TRAPPC12 Sarah Leigh Source Expert Review Green was added to TRAPPC12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 ZNF335 Sarah Leigh Source Expert Review Green was added to ZNF335.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TBC1D2B Sarah Leigh Source Expert Review Green was added to TBC1D2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 GRN Sarah Leigh Source Expert Review Green was added to GRN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 DMXL2 Sarah Leigh Source Expert Review Green was added to DMXL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 H3F3B Sarah Leigh Source Expert Review Green was added to H3F3B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 H3F3A Sarah Leigh Source Expert Review Green was added to H3F3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TFE3 Sarah Leigh Source Expert Review Green was added to TFE3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 NARS Sarah Leigh Source Expert Review Green was added to NARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 LARS Sarah Leigh Source Expert Review Green was added to LARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 PNPT1 Sarah Leigh Source Expert Review Green was added to PNPT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 PUM1 Sarah Leigh Source Expert Review Green was added to PUM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 RARS Sarah Leigh Source Expert Review Green was added to RARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 RNF113A Sarah Leigh Source Expert Review Green was added to RNF113A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 SERPINI1 Sarah Leigh Source Expert Review Green was added to SERPINI1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 SETD1A Sarah Leigh Source Expert Review Green was added to SETD1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 PCYT2 Sarah Leigh Source Expert Review Green was added to PCYT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 UGP2 Sarah Leigh Source Expert Review Green was added to UGP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TRAPPC4 Sarah Leigh Source Expert Review Green was added to TRAPPC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 KAT8 Sarah Leigh Source Expert Review Green was added to KAT8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TMX2 Sarah Leigh Source Expert Review Green was added to TMX2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 USP18 Sarah Leigh Source Expert Review Green was added to USP18.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 UGDH Sarah Leigh Source Expert Review Green was added to UGDH.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TUBGCP2 Sarah Leigh Source Expert Review Green was added to TUBGCP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 SCAF4 Sarah Leigh Source Expert Review Green was added to SCAF4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 OXR1 Sarah Leigh Source Expert Review Green was added to OXR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 NRROS Sarah Leigh Source Expert Review Green was added to NRROS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 NR4A2 Sarah Leigh Source Expert Review Green was added to NR4A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 MTHFS Sarah Leigh Source Expert Review Green was added to MTHFS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 MADD Sarah Leigh Source Expert Review Green was added to MADD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 HERC2 Sarah Leigh Source Expert Review Green was added to HERC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 CARS2 Sarah Leigh Source Expert Review Green was added to CARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 ADARB1 Sarah Leigh Source Expert Review Green was added to ADARB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 PTEN Sarah Leigh Source Expert Review Green was added to PTEN.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 KAT5 Sarah Leigh Source Expert Review Green was added to KAT5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 PIGP Sarah Leigh Source Expert Review Green was added to PIGP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 RNF13 Sarah Leigh Source Expert Review Green was added to RNF13.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 SETD1B Sarah Leigh Source Expert Review Green was added to SETD1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 SETD5 Sarah Leigh Source Expert Review Green was added to SETD5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 WDR45B Sarah Leigh Source Expert Review Green was added to WDR45B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TRPM3 Sarah Leigh Source Expert Review Green was added to TRPM3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 TIMM50 Sarah Leigh Source Expert Review Green was added to TIMM50.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 FGF13 Sarah Leigh Source Expert Review Green was added to FGF13.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 UBR7 Sarah Leigh Source Expert Review Green was added to UBR7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 PPIL1 Sarah Leigh Source Expert Review Green was added to PPIL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 RALGAPA1 Sarah Leigh Source Expert Review Green was added to RALGAPA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 PIGK Sarah Leigh Source Expert Review Green was added to PIGK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 GAD1 Sarah Leigh Source Expert Review Green was added to GAD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 CEP85L Sarah Leigh Source Expert Review Green was added to CEP85L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 CDK19 Sarah Leigh Source Expert Review Green was added to CDK19.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 CACNB4 Sarah Leigh Source Expert Review Green was added to CACNB4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 ANKRD11 Sarah Leigh Source Expert Review Green was added to ANKRD11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 ASNS Sarah Leigh Source Expert Review Green was added to ASNS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.490 APC2 Sarah Leigh Source Expert Review Green was added to APC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.489 CHKA Konstantinos Varvagiannis gene: CHKA was added
gene: CHKA was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Review for gene: CHKA was set to GREEN
Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants.

Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6.

Eventual previous genetic testing was not discussed.

Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies.

Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype.

3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2):
- c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families],
- c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents],
- c.2T>C/p.(Met1?) [1 hmz individual born to related parents],
- c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual.

CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes.

CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP.

As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants].

Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc.

CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect.

In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine).

Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively).

NMD is thought to underly the deleterious effect of the frameshift one (not studied).

The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein.

Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714).

There is no associated phenotype in OMIM, Gene2Phenotype or SysID.

Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset).
Sources: Literature
Early onset or syndromic epilepsy v2.489 CSNK1G1 Sarah Leigh changed review comment from: Comment on list classification: NHS Genomic Medicine Service review of CSNK1G1 on the Intellectual disability panel, recommended that CSNK1G1 should be made amber on the Genetic epilepsy syndromes panel; as epilepsy was seen in 2/5 reported cases (PMID: 33009664).


Amber for epilepsy panel R59

review of on the Intellectual disability; to: Comment on list classification: NHS Genomic Medicine Service review of CSNK1G1 on the Intellectual disability panel, recommended that CSNK1G1 should be made amber on the Genetic epilepsy syndromes panel; as epilepsy was seen in 2/5 reported cases (PMID: 33009664).
Early onset or syndromic epilepsy v2.489 CSNK1G1 Sarah Leigh Publications for gene: CSNK1G1 were set to 24463883
Early onset or syndromic epilepsy v2.488 CSNK1G1 Sarah Leigh Classified gene: CSNK1G1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.488 CSNK1G1 Sarah Leigh Added comment: Comment on list classification: NHS Genomic Medicine Service review of CSNK1G1 on the Intellectual disability panel, recommended that CSNK1G1 should be made amber on the Genetic epilepsy syndromes panel; as epilepsy was seen in 2/5 reported cases (PMID: 33009664).


Amber for epilepsy panel R59

review of on the Intellectual disability
Early onset or syndromic epilepsy v2.488 CSNK1G1 Sarah Leigh Gene: csnk1g1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.487 CSNK2B Sarah Leigh Phenotypes for gene: CSNK2B were changed from Myoclonic epilepsy and intellectual disability to Poirier-Bienvenu neurodevelopmental syndrome, OMIM:618732; Poirier-Bienvenu neurodevelopmental syndrome, MONDO:0032889
Early onset or syndromic epilepsy v2.486 SPATA5L1 Ivone Leong Entity copied from Intellectual disability v3.1491
Early onset or syndromic epilepsy v2.486 SPATA5L1 Ivone Leong gene: SPATA5L1 was added
gene: SPATA5L1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: SPATA5L1.
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Neurodevelopmental disorder with hearing loss and spasticity, OMIM:619616
Early onset or syndromic epilepsy v2.485 SCN8A Sarah Leigh changed review comment from: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown from BOTH monoallelic and biallelic, autosomal or pseudoautosomal, while the strength of the evidence is reviewed.; to: Comment on mode of inheritance: The mode of inheritance has been reverted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown from BOTH monoallelic and biallelic, autosomal or pseudoautosomal, while the strength of the evidence is reviewed.
Early onset or syndromic epilepsy v2.485 SCN8A Sarah Leigh Added comment: Comment on mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown from BOTH monoallelic and biallelic, autosomal or pseudoautosomal, while the strength of the evidence is reviewed.
Early onset or syndromic epilepsy v2.485 SCN8A Sarah Leigh Mode of inheritance for gene: SCN8A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.484 SCN8A Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.484 PSMB8 Arina Puzriakova Phenotypes for gene: PSMB8 were changed from Autoinflammation, lipodystrophy, and dermatosis syndrome 256040 to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040
Early onset or syndromic epilepsy v2.483 SCN8A Helen Lord reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31625145; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.483 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800; seizures; myoclonic epilepsy to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Early onset or syndromic epilepsy v2.482 UFSP2 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams changed review comment from: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.; to: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.

PMID: 29581270 - Lin et al, 2018 - performed functional work that shows V404M enhances inactivation of channels that have not yet opened and dramatically impairs the inactivation of channels that have opened.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognative impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams Classified gene: KCND2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber with a recommendation for green rating following GMS review. 4 unrelated cases with a V404 missense variant and epilepsy.
Early onset or syndromic epilepsy v2.482 KCND2 Eleanor Williams Gene: kcnd2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.481 KCND2 Eleanor Williams Phenotypes for gene: KCND2 were changed from epilepsy; seizures to epilepsy, NBO:0000642; seizure, HP:0001250
Early onset or syndromic epilepsy v2.480 KCND2 Eleanor Williams Phenotypes for gene: KCND2 were changed from epilepsy; autism to epilepsy; seizures
Early onset or syndromic epilepsy v2.479 KCND2 Eleanor Williams Publications for gene: KCND2 were set to 24501278; 16934482; 29581270
Early onset or syndromic epilepsy v2.478 KCND2 Eleanor Williams Tag Q4_21_rating tag was added to gene: KCND2.
Early onset or syndromic epilepsy v2.478 KCND2 Eleanor Williams reviewed gene: KCND2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34245260; Phenotypes: seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.478 BET1 Dmitrijs Rots gene: BET1 was added
gene: BET1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: BET1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BET1 were set to PMID: 34779586
Phenotypes for gene: BET1 were set to Epilepsy; congenical musculara dystrophy
Penetrance for gene: BET1 were set to Complete
Review for gene: BET1 was set to GREEN
Added comment: 3 reported individuals from two families with biallelic variants and functional data supporting the role of the variants in the phenotype. Enough evidence for green rating.
Sources: Literature
Early onset or syndromic epilepsy v2.478 GNB5 Arina Puzriakova Phenotypes for gene: GNB5 were changed from Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; early infantile epileptic encephalopathy (EIEE) to Intellectual developmental disorder with cardiac arrhythmia, OMIM:617173
Early onset or syndromic epilepsy v2.477 KCNC2 Zornitza Stark gene: KCNC2 was added
gene: KCNC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KCNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNC2 were set to 32392612; 31972370
Phenotypes for gene: KCNC2 were set to epileptic encephalopathy; spastic tetraplegia; opisthotonus attacks; intellectual disability; West syndrome
Review for gene: KCNC2 was set to AMBER
Added comment: PMID: 31972370. De novo missense variant (p.Val471Leu) identified in a child with early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks.

PMID: 32392612. De novo missense variant (p.Asp167Tyr) identified in a neurofibromatosis type 1 related West syndrome patient. Functional analysis showed a significant reduction of the mean potassium current and a shift in the voltage dependence of steady-state activation. Maternally inherited NF1 variant (p.T1951Nfs*5) also identified, the mother was "clinically unremarkable".
Sources: Literature
Early onset or syndromic epilepsy v2.477 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181 to Aicardi-Goutieres syndrome 2, OMIM:610181
Early onset or syndromic epilepsy v2.476 RAB3GAP2 Arina Puzriakova Mode of inheritance for gene: RAB3GAP2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.475 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Early onset or syndromic epilepsy v2.474 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from Aicardi-Goutieres syndrome 7, 615846; seizures to Aicardi-Goutieres syndrome 7, OMIM:615846
Early onset or syndromic epilepsy v2.473 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from Pontocerebellar hypoplasia, type 1B, 614678 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Early onset or syndromic epilepsy v2.472 HPRT1 Arina Puzriakova Mode of inheritance for gene: HPRT1 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v2.471 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from to Lesch-Nyhan syndrome, OMIM:300322
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Tag Q4_21_rating tag was added to gene: GABRD.
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Classified gene: GABRD as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but this gene should now be promoted to Green at the next GMS panel update.

New evidence identified by Helen Lord (OUH NHS) highlights at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene (PMID: 34633442). All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID.
Early onset or syndromic epilepsy v2.470 GABRD Arina Puzriakova Gene: gabrd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.469 GABRD Arina Puzriakova Mode of pathogenicity for gene: GABRD was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v2.468 GABRD Arina Puzriakova Publications for gene: GABRD were set to 29785705
Early onset or syndromic epilepsy v2.467 GABRD Arina Puzriakova Phenotypes for gene: GABRD were changed from {Epilepsy, idiopathic generalized, 10} 613060; {Epilepsy, juvenile myoclonic, susceptibility to} 613060; {Epilepsy, generalized, with febrile seizures plus, type 5, susceptibility to} 613060 to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060; {Generalized epilepsy with febrile seizures plus, type 5, susceptibility to}, OMIM:613060
Early onset or syndromic epilepsy v2.466 GABRD Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: GABRD.
Early onset or syndromic epilepsy v2.466 CLPB Arina Puzriakova Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: CLPB.
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova reviewed gene: CLPB: Rating: ; Mode of pathogenicity: None; Publications: 25597510, 25597511, 26916670, 28687938, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.465 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Early onset or syndromic epilepsy v2.464 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678 to Developmental and epileptic encephalopathy 71, OMIM:618328
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is not enough evidence to support a gene-disease association as only 2 of 3 cases had seizures.
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong Tag Q4_21_rating was removed from gene: COLGALT1.
Tag watchlist tag was added to gene: COLGALT1.
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.216
Early onset or syndromic epilepsy v2.463 COLGALT1 Ivone Leong gene: COLGALT1 was added
gene: COLGALT1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: COLGALT1.
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3, OMIM:618360
Early onset or syndromic epilepsy v2.462 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset or syndromic epilepsy v2.461 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Early onset or syndromic epilepsy v2.460 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42, 617106; Epilepsy and migraine; Absence epilepsy; Migraine, familial hemiplegic, 1, 141500; Familial hemiplegic migraine 1 (FHM) to Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Early onset or syndromic epilepsy v2.459 ATN1_CAG Arina Puzriakova Phenotypes for STR: ATN1_CAG were changed from Dentatorubro-pallidoluysian atrophy 125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370
Early onset or syndromic epilepsy v2.458 ATN1 Arina Puzriakova Phenotypes for gene: ATN1 were changed from Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures; Generalized hypotonia to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Early onset or syndromic epilepsy v2.457 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from {Lipodystrophy, partial, acquired, susceptibility to}, 608709; ?Epilepsy, progressive myoclonic, 9, 616540 to ?Epilepsy, progressive myoclonic, 9, OMIM:616540
Early onset or syndromic epilepsy v2.456 GNB2 Eleanor Williams Entity copied from Mosaic skin disorders - deep sequencing v1.9
Early onset or syndromic epilepsy v2.456 GNB2 Eleanor Williams gene: GNB2 was added
gene: GNB2 was added to Genetic epilepsy syndromes. Sources: Literature
somatic tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 34124757
Phenotypes for gene: GNB2 were set to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Early onset or syndromic epilepsy v2.455 GNAQ Eleanor Williams Tag mosaicism tag was added to gene: GNAQ.
Tag somatic tag was added to gene: GNAQ.
Early onset or syndromic epilepsy v2.455 GNAQ Eleanor Williams Phenotypes for gene: GNAQ were changed from Sturge-Weber syndrome, somatic, mosaic, 185300 to Sturge-Weber syndrome, somatic, mosaic, OMIM:185300
Early onset or syndromic epilepsy v2.454 GNAQ Eleanor Williams Publications for gene: GNAQ were set to 25374402; 23656586; 28126187
Early onset or syndromic epilepsy v2.453 GNAQ Eleanor Williams reviewed gene: GNAQ: Rating: ; Mode of pathogenicity: None; Publications: 34124757; Phenotypes: Sturge-Weber syndrome, somatic, mosaic, OMIM:185300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.453 LMNB1 Arina Puzriakova Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Early onset or syndromic epilepsy v2.452 GABRD Helen Lord changed review comment from: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onse epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4.
From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher.
The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic.
The T291I variant was detected in an aff mother and her aff twin boys.
The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients.
All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD.
The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits.
Functional analysis suggests:
P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaeed propensity to desensitise - LOF trait.
The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait.
No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis.

The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~).
The patient with the LOF variant has ASD, normal intelligence and no seizure history.

In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder.
One GOF variant was identifed (de novo) in a patient with ASD but no seizures.
Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.; to: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onset epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4.
From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher.
The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic.
The T291I variant was detected in an aff mother and her aff twin boys.
The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients.
All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD.
The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits.
Functional analysis suggests:
P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaesed propensity to desensitise - LOF trait.
The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait.
No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis.

The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~).
The patient with the LOF variant has ASD, normal intelligence and no seizure history.

In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder.
One GOF variant was identifed (de novo) in a patient with ASD but no seizures.
Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.
Early onset or syndromic epilepsy v2.452 GABRD Helen Lord reviewed gene: GABRD: Rating: GREEN; Mode of pathogenicity: None; Publications: 34633442; Phenotypes: Neurodevelopmental disorders, generalised epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.452 PLK1 Dmitrijs Rots gene: PLK1 was added
gene: PLK1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: >5 cases with epileptic encephalopathy with homozygous variants in PMID: 33875846
Sources: Literature
Early onset or syndromic epilepsy v2.452 SNIP1 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SNIP1.
Early onset or syndromic epilepsy v2.452 SNIP1 Sarah Leigh commented on gene: SNIP1: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, to decide whether this gene could be green, as the disease association has only been associated with a the founder variant.
Early onset or syndromic epilepsy v2.452 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to 27343064; 29100083
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Tag Q4_21_MOI tag was added to gene: DHDDS.
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Monoallelic' at the next GMS panel update. Monoallelic variants are associated with a neurodevelopmental disorder comprising DD/ID, epilepsy and a variable movement disorder phenotype - >3 unrelated individuals reported in literature. To date, only one individual with biallelic variants and epilepsy has been reported (PMID: 27343064). This patient presented with glycosylation defects but no corroborating cases have been reported since.
As only one patient has been described with biallelic inheritance and this phenotype, MOI should be set to 'Monoallelic' until evidence of additional cases emerges - biallelic variants would still be picked up by the Genomics England pipeline under this MOI.
Early onset or syndromic epilepsy v2.451 DHDDS Arina Puzriakova Mode of inheritance for gene: DHDDS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.450 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836; developmental and epileptic encephalopathy (DEE); ?Congenital disorder of glycosylation, type 1bb,613861 to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Early onset or syndromic epilepsy v2.449 DEAF1 Ivone Leong Tag Q4_21_MOI tag was added to gene: DEAF1.
Early onset or syndromic epilepsy v2.449 DEAF1 Ivone Leong reviewed gene: DEAF1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.449 CELF2 Dmitrijs Rots reviewed gene: CELF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: DEE; Mode of inheritance: None
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong Entity copied from Intellectual disability v3.1376
Early onset or syndromic epilepsy v2.449 ARFGEF1 Ivone Leong gene: ARFGEF1 was added
gene: ARFGEF1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: ARFGEF1.
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v2.448 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628
Early onset or syndromic epilepsy v2.447 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Monoallelic' only. Seizures have been linked with monoallelic variants (MIM# 607628) although there is debate regarding this gene-disease relationship, hence the current Red rating on this panel. Autosomal recessive pathogenic variants are also associated with Leukoencephalopathy (MIM# 615651) which does not include epilepsy.
Early onset or syndromic epilepsy v2.447 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.446 SARS Ivone Leong Entity copied from Intellectual disability v3.1356
Early onset or syndromic epilepsy v2.446 SARS Ivone Leong gene: SARS was added
gene: SARS was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
watchlist, new-gene-name tags were added to gene: SARS.
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Early onset or syndromic epilepsy v2.445 ATP6V0C Ivone Leong Entity copied from Intellectual disability v3.1354
Early onset or syndromic epilepsy v2.445 ATP6V0C Ivone Leong gene: ATP6V0C was added
gene: ATP6V0C was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: ATP6V0C.
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh edited their review of gene: SNIP1: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.; Changed rating: AMBER
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh Tag founder-effect tag was added to gene: SNIP1.
Early onset or syndromic epilepsy v2.444 SNIP1 Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism 614501 to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787
Early onset or syndromic epilepsy v2.443 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524
Early onset or syndromic epilepsy v2.442 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant to Mental retardation, autosomal recessive, 6, OMIM:611092; non-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Early onset or syndromic epilepsy v2.441 GRIK2 Ivone Leong Mode of inheritance for gene: GRIK2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.440 GRIK2 Ivone Leong Classified gene: GRIK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.440 GRIK2 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Amber as this gene has not been approved to be on this panel yet. It should be noted that not all patients with variants in this gene develop seizures.
Early onset or syndromic epilepsy v2.440 GRIK2 Ivone Leong Gene: grik2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.439 GRIK2 Ivone Leong Tag Q4_21_MOI was removed from gene: GRIK2.
Tag Q4_21_rating tag was added to gene: GRIK2.
Early onset or syndromic epilepsy v2.439 GRIK2 Ivone Leong Entity copied from Intellectual disability v3.1341
Early onset or syndromic epilepsy v2.439 GRIK2 Ivone Leong gene: GRIK2 was added
gene: GRIK2 was added to Genetic epilepsy syndromes. Sources: Radboud University Medical Center, Nijmegen,Expert Review Green,Victorian Clinical Genetics Services
Q4_21_MOI tags were added to gene: GRIK2.
Mode of inheritance for gene: GRIK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRIK2 were set to 34375587; 17847003; 25039795
Phenotypes for gene: GRIK2 were set to Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Penetrance for gene: GRIK2 were set to Complete
Early onset or syndromic epilepsy v2.438 CACNA1I Ivone Leong Entity copied from Intellectual disability v3.1339
Early onset or syndromic epilepsy v2.438 CACNA1I Ivone Leong gene: CACNA1I was added
gene: CACNA1I was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: CACNA1I.
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Early onset or syndromic epilepsy v2.437 CHRM1 Ivone Leong Classified gene: CHRM1 as Red List (low evidence)
Early onset or syndromic epilepsy v2.437 CHRM1 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red to match my review.
Early onset or syndromic epilepsy v2.437 CHRM1 Ivone Leong Gene: chrm1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong Tag watchlist was removed from gene: CHRM1.
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently only 1 case with epilepsy this gene has been given a Red rating.
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong Entity copied from Intellectual disability v3.1338
Early onset or syndromic epilepsy v2.436 CHRM1 Ivone Leong gene: CHRM1 was added
gene: CHRM1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: CHRM1.
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability, MONDO:0001071; autism
Early onset or syndromic epilepsy v2.435 UNC13B Zornitza Stark gene: UNC13B was added
gene: UNC13B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UNC13B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC13B were set to 33876820
Phenotypes for gene: UNC13B were set to Epilepsy
Review for gene: UNC13B was set to RED
Added comment: No OMIM human disease association. Gene encodes a presynaptic protein Munc13-2 highly expressed in the brain (predominantly cerebral cortex).

Variant interpretation data in human epilepsy cohort somewhat conflicting and restricted to a single study. Wang et al, Brain, 2021 - trio-based whole-exome sequencing identified UNC13B in 12 individuals affected by partial epilepsy and/or febrile seizures from 8 unrelated families. Identified:
x1 de novo nonsense variant, absent in gnomad, damaging in silicos
x1 de novo splice site, absent in gnomad, damaging in silicos
x1 splice site variant present in unaffected mother (low frequency in gnomad)
x2 compound het in one individual - more severe phenotype postulated (x1 variant present in contro cohortl, the other variant present in low frequency in gnomad)
x1 missense variant - in Han Chinese major depressive disorders study, not in gnomad
x1 missense variant - highly conserved residue, not in gnomad
x2 other missense variant - highly conserved residue, low frequency in gnomad
Latter 4 missense variants cosegregated with affected individuals in the families

In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila

De novo UNC13B variants previously reported in bipolar disorder and autism spectrum disorder
Sources: Literature
Early onset or syndromic epilepsy v2.435 CHD4 Zornitza Stark gene: CHD4 was added
gene: CHD4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CHD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD4 were set to 27479907; 27616479; 34109749
Phenotypes for gene: CHD4 were set to Sifrim-Hitz-Weiss syndrome, MIM# 617159; Childhood idiopathic epilepsy and sinus arrhythmia
Review for gene: CHD4 was set to GREEN
Added comment: PMID 34109749: 8 individuals from 4 families with childhood idiopathic epilepsy and sinus arrhythmia. This may be a distinct gene-disease association as the variants were located outside of the typical domains associated with SHW syndrome (central regions from SNF2-like region to DUF1087 domain).

SHW syndrome: seizures are also reported, though not as a common feature.
Sources: Literature
Early onset or syndromic epilepsy v2.435 JAKMIP1 Ivone Leong Entity copied from Intellectual disability v3.1334
Early onset or syndromic epilepsy v2.435 JAKMIP1 Ivone Leong gene: JAKMIP1 was added
gene: JAKMIP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: JAKMIP1.
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability, MONDO:0001071; seizures
Early onset or syndromic epilepsy v2.434 MED12 Eleanor Williams Tag Q3_21_MOI tag was added to gene: MED12.
Tag Q3_21_expert_review tag was added to gene: MED12.
Early onset or syndromic epilepsy v2.434 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct although consideration should be given to the carrier implications for the predominantly male-only phenotypes associated with this gene.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Early onset or syndromic epilepsy v2.434 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Tag watchlist tag was added to gene: VPS50.
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Classified gene: VPS50 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Early onset or syndromic epilepsy v2.434 VPS50 Ivone Leong Gene: vps50 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.433 ARF3 Ivone Leong Classified gene: ARF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.433 ARF3 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia. Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.
Early onset or syndromic epilepsy v2.433 ARF3 Ivone Leong Gene: arf3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.432 ARF3 Ivone Leong Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Global developmental delay; Intellectual disability, MONDO:0001071; Seizures; Morphological abnormality of the central nervous system; microcephaly, MONDO:0001149
Early onset or syndromic epilepsy v2.431 ARF3 Ivone Leong Tag watchlist tag was added to gene: ARF3.
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases seizures with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases seizures with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.; to: Review of mode of inheritance shows that although in some families only males were affected, females were also reported in 5 cases with MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

Reports of males only affected:
PMID: 17369503 - Schwartz et al 2007 - report 2 kindreds with males (7 total) affected with Lujan-Fryns syndrome and variants in MED12. Seizures were noted in 1 individual from 1 kindred.

PMID: 23395478 - Vulto-van Silfhout et al 2013 - report 3 unrelated cases with males affected by Ohdo syndrome MKB type. In 2 families 2 males were affected, in the third 1 male. In all, missense changes in MED12 were detected. In family 2 a second segregating missense variant in the ATRX gene (linked to ATRX syndrome) but further investigation did not support a ATRX syndrome diagnosis. Intellectual disability was noted (1 mild, 1 moderate, 2 severe, 1 severity not noted) in all 5 individuals. Seizures were noted in 1.

PMID: 32715471 - Rubin et al 2020 - report 1 family with three male siblings of with intellectual disability and characteristic facial and distal extremity anomalies with a novel missense variant in MED12. The diagnosis most closely matched Ohdo syndrome. Seizures are not reported.

PMID: 17334363 - Risheg et al 2007 - report 6 families in with Opitz-Kaveggia syndrome (also known as FG syndrome) in with the same 2881C>T variant identified in MED12. Two of the families are stated to be from different ethnic groups. In all families only males were affected. Intellectual disability was present in all affected males (4 families) who survived long enough for developmental or cognitive assessment. Seizures were noted in 3 of the families (4/7 individuals). Marked skewed X inactivation was noted in female carriers in 3 families, moderate skewing in 1 family and absence of skewing in two families.

Reports with females affected:

PMID: 33244165 - Polla et al 2021 - report on assembled clinical and genetic data of 18 females with de novo variants in MED12. 11/18 have severe intellectual disability. Seizures were noted in 5.
Analysis of X-inactivation status showed extreme skewing (>95%) in 10 indivduals, skewing (85%) in 1 individual and it was random XCI in 6 (3 with protein truncating variants, 3 with missense). The androgen receptor alleles were non-informative for 1 person.

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Early onset or syndromic epilepsy v2.431 MED12 Eleanor Williams commented on gene: MED12
Early onset or syndromic epilepsy v2.431 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from ?Trichothiodystrophy 5, nonphotosensitive, 300953 to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Early onset or syndromic epilepsy v2.430 CERS1 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
However, the Q3_21_expert_review and Q3_21_phenotype tags have been added to this gene for an NHS review, because the phenotype associated with variants CERS1 includues progessive cognitive impairment and dementia.
Early onset or syndromic epilepsy v2.430 CERS1 Sarah Leigh Tag Q3_21_expert_review tag was added to gene: CERS1.
Tag Q3_21_phenotype tag was added to gene: CERS1.
Early onset or syndromic epilepsy v2.430 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from neurodevelopmental syndrome to Neurodevelopmental abnormality HP:0012759
Early onset or syndromic epilepsy v2.429 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.429 TNPO2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting were a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.429 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.428 TNPO2 Arina Puzriakova gene: TNPO2 was added
gene: TNPO2 was added to Genetic epilepsy syndromes. Sources: Literature
Q3_21_rating tags were added to gene: TNPO2.
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Review for gene: TNPO2 was set to GREEN
Added comment: Goodman et al., 2021 (PMID: 34314705) reported on 15 unrelated individuals with different variants in this gene (14 de novo, 1 mosaic in mother; 12 SNVs, 3 in-frame deletions, 1 deletion-insertion). All had GDD and all those who were assessed also had ID (9/9), ranging from mild to severe. ID also suspected but not investigated in another 3 cases. 6 had seizures starting between 1 and 2.5 years of age. 5 individuals had microcephaly (HC ranging -2.77 to -4.53 SD). Other less common features were also observed such as variable brain, gastrointestinal and ophthalmologic abnormalities.

Notably 6 individuals had additional SNVs/CNVs of uncertain significance, some of which include known ID genes (e.g. SETBP1, CUX2, ARMC9, PDE4D), but were discounted due to lack of explanation of the overall patient phenotype.

Some functional studies conducted in Drosophila demonstrated that patient-associated variants caused neurodevelopmental defects that were dosage and location (of variant within protein) dependent.
Sources: Literature
Early onset or syndromic epilepsy v2.427 CLCN3 Arina Puzriakova Entity copied from Intellectual disability v3.1299
Early onset or syndromic epilepsy v2.427 CLCN3 Arina Puzriakova gene: CLCN3 was added
gene: CLCN3 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: CLCN3.
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Mode of pathogenicity for gene: CLCN3 was set to Other
Early onset or syndromic epilepsy v2.426 AP1G1 Arina Puzriakova Entity copied from Intellectual disability v3.1293
Early onset or syndromic epilepsy v2.426 AP1G1 Arina Puzriakova gene: AP1G1 was added
gene: AP1G1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q3_21_rating tags were added to gene: AP1G1.
Mode of inheritance for gene: AP1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Early onset or syndromic epilepsy v2.425 SYNCRIP Arina Puzriakova Classified gene: SYNCRIP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.425 SYNCRIP Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as only two individuals with seizures have been reported to date (MAE type)
Early onset or syndromic epilepsy v2.425 SYNCRIP Arina Puzriakova Gene: syncrip has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.424 MED17 Ivone Leong Tag watchlist tag was added to gene: MED17.
Early onset or syndromic epilepsy v2.424 MED17 Ivone Leong Phenotypes for gene: MED17 were changed from Microcephaly, postnatal progressive, with seizures and brain atrophy 613668 to Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668
Early onset or syndromic epilepsy v2.423 MED17 Ivone Leong Publications for gene: MED17 were set to 26004231; 20950787
Early onset or syndromic epilepsy v2.422 MED17 Ivone Leong reviewed gene: MED17: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.422 HID1 Arina Puzriakova Entity copied from Intellectual disability v3.1274
Early onset or syndromic epilepsy v2.422 HID1 Arina Puzriakova gene: HID1 was added
gene: HID1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: HID1.
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Early onset or syndromic epilepsy v2.421 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Early onset or syndromic epilepsy v2.421 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from None to Other
Early onset or syndromic epilepsy v2.420 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Mental retardation, autosomal dominant 8; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; early onset epileptic encephalopathies; involuntary movements; severe developmental delay; intellectual disability; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Early onset or syndromic epilepsy v2.419 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, 616973; seizures to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Early onset or syndromic epilepsy v2.418 MYO1H Sarah Leigh Entity copied from Familial dysautonomia v1.15
Early onset or syndromic epilepsy v2.418 MYO1H Sarah Leigh gene: MYO1H was added
gene: MYO1H was added to Genetic epilepsy syndromes. Sources: Expert Review Red,Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to ?Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction OMIM:619482
Early onset or syndromic epilepsy v2.417 PARP6 Arina Puzriakova Entity copied from Intellectual disability v3.1263
Early onset or syndromic epilepsy v2.417 PARP6 Arina Puzriakova gene: PARP6 was added
gene: PARP6 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: PARP6.
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to 34067418
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Early onset or syndromic epilepsy v2.416 SLC32A1 Zornitza Stark gene: SLC32A1 was added
gene: SLC32A1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC32A1 were set to 34038384
Phenotypes for gene: SLC32A1 were set to Genetic epilepsy with febrile seizures plus
Review for gene: SLC32A1 was set to GREEN
Added comment: 8 unrelated families reported, including segregation evidence in two large pedigrees. Variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition.
Sources: Literature
Early onset or syndromic epilepsy v2.416 EML1 Arina Puzriakova Phenotypes for gene: EML1 were changed from Band heterotopia, 600348 to Band heterotopia, OMIM:600348
Early onset or syndromic epilepsy v2.415 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1 604364 to Epilepsy, familial focal, with variable foci 1, OMIM:604364
Early onset or syndromic epilepsy v2.414 CTNNA2 Arina Puzriakova Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 4, 618174, seizures to Cortical dysplasia, complex, with other brain malformations 9, OMIM:618174
Early onset or syndromic epilepsy v2.413 CSNK2A1 Arina Puzriakova Phenotypes for gene: CSNK2A1 were changed from Neurodevelopmental abnormalities and dysmorphic features; seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Early onset or syndromic epilepsy v2.412 PIDD1 Arina Puzriakova Classified gene: PIDD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.412 PIDD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Overall there are sufficient unrelated cases (>3) with a relevant phenotype and biallelic variants in this gene to rate as Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.412 PIDD1 Arina Puzriakova Gene: pidd1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.411 PIDD1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: PIDD1.
Early onset or syndromic epilepsy v2.411 ARF1 Arina Puzriakova edited their review of gene: ARF1: Added comment: Added to this panel as seizures have been reported in 3/5 cases. Epilepsy is likely to arise in these cases prior to detection of cortical malformations and may prompt earlier genetic investigation. Inclusion on this panel could increase the likelihood of detecting cases and therefore a Green rating is warranted.; Changed rating: GREEN; Changed publications to: 28868155, 34353862; Changed phenotypes to: Periventricular nodular heterotopia 8, OMIM:618185; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.411 ARF1 Arina Puzriakova Entity copied from Malformations of cortical development v2.62
Early onset or syndromic epilepsy v2.411 ARF1 Arina Puzriakova gene: ARF1 was added
gene: ARF1 was added to Genetic epilepsy syndromes. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: ARF1.
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155; 34353862
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, OMIM:618185
Early onset or syndromic epilepsy v2.410 KMT2E Arina Puzriakova Publications for gene: KMT2E were set to 31079897
Early onset or syndromic epilepsy v2.409 GALC Arina Puzriakova Phenotypes for gene: GALC were changed from Krabbe disease, 245200; seizures; CALC deficiency; Galactosylceramide beta-galactosidase deficiency to Krabbe disease, OMIM:245200
Early onset or syndromic epilepsy v2.408 SLC16A2 Arina Puzriakova Phenotypes for gene: SLC16A2 were changed from Allan-Herndon-Dudley syndrome, 300523; AHDS to Allan-Herndon-Dudley syndrome, OMIM:300523
Early onset or syndromic epilepsy v2.407 WDR45B Arina Puzriakova Phenotypes for gene: WDR45B were changed from Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977; profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, OMIM:617977
Early onset or syndromic epilepsy v2.406 HACE1 Arina Puzriakova Publications for gene: HACE1 were set to 26437029; 26424145
Early onset or syndromic epilepsy v2.405 ARG1 Arina Puzriakova Phenotypes for gene: ARG1 were changed from Argininemia 207800 to Argininemia, OMIM:207800
Early onset or syndromic epilepsy v2.404 AIMP1 Arina Puzriakova Phenotypes for gene: AIMP1 were changed from Leukodystrophy, hypomyelinating 3 260600 to Leukodystrophy, hypomyelinating, 3, OMIM:260600
Early onset or syndromic epilepsy v2.403 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: ARF3 were set to unknown
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu.

Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both.

ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively.

Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons.

There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185).

In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val).

This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia.

Evidence to support the effect of each variant include:

Arg99Leu:
Had identical Golgi localization to that of wt
Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF)
In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF).
In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu)

Asp67Val:
Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant)
Displayed decreased protein stability
In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF)
In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye.

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Early onset or syndromic epilepsy v2.403 VPS50 Konstantinos Varvagiannis gene: VPS50 was added
gene: VPS50 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature
Early onset or syndromic epilepsy v2.403 PGM2L1 Arina Puzriakova Entity copied from Intellectual disability v3.1218
Early onset or syndromic epilepsy v2.403 PGM2L1 Arina Puzriakova gene: PGM2L1 was added
gene: PGM2L1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: PGM2L1.
Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGM2L1 were set to 33979636
Phenotypes for gene: PGM2L1 were set to Neurodevelopmental disorder
Early onset or syndromic epilepsy v2.402 PIDD1 Konstantinos Varvagiannis changed review comment from: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-relared NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other; to: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other
Early onset or syndromic epilepsy v2.402 PIDD1 Konstantinos Varvagiannis gene: PIDD1 was added
gene: PIDD1 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Penetrance for gene: PIDD1 were set to Complete
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested.

The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families].

Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants.

Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder.

PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage.

There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation.

Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants.

Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26

Evidence so far provided includes:
- Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern.
- Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability.
- Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp]
- Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain.
- Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD.

Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects.

There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-relared NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes.

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other
Early onset or syndromic epilepsy v2.402 KIF1A Arina Puzriakova Phenotypes for gene: KIF1A were changed from Mental retardation, autosomal dominant 9 614255 to NESCAV syndrome, OMIM:614255
Early onset or syndromic epilepsy v2.401 COQ2 Ivone Leong Phenotypes for gene: COQ2 were changed from Coenzyme Q10 deficiency, primary, 1 607426 to Coenzyme Q10 deficiency, primary, 1, OMIM:607426
Early onset or syndromic epilepsy v2.400 COG4 Arina Puzriakova Phenotypes for gene: COG4 were changed from to Congenital disorder of glycosylation, type IIj, OMIM:613489
Early onset or syndromic epilepsy v2.399 COG4 Arina Puzriakova Mode of inheritance for gene: COG4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.398 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Intractable epilepsy and neurological regression; Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Encephalopathy, progressive, with or without lipodystrophy, OMIM:615924
Early onset or syndromic epilepsy v2.397 DLL1 Arina Puzriakova Tag Q3_21_rating was removed from gene: DLL1.
Tag for-review tag was added to gene: DLL1.
Early onset or syndromic epilepsy v2.397 DLL1 Arina Puzriakova Phenotypes for gene: DLL1 were changed from Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis to Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, OMIM:618709
Early onset or syndromic epilepsy v2.396 DLL1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: DLL1.
Early onset or syndromic epilepsy v2.396 SYNCRIP Konstantinos Varvagiannis gene: SYNCRIP was added
gene: SYNCRIP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to AMBER
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.

The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.

Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.

Overall the variants reported to date include [NM_006372.5]:
1 - c.858_859del p.(Gly287Leufs*5)
2 - c.854dupA p.(Asn285Lysfs*8)
3 - c.734T>C p.(Leu245Pro)
4 - chr6:85605276-85683190 deletion (GRCh38)
5 - c.629T>C p.(Phe210Ser)
6 - c.1573_1574delinsTT p.(Gln525Leu)
7 - c.1247_1250del p.(Arg416Lysfs*145)
8 - c.1518_1519insC p.(Ala507Argfs*14)

[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]

SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.

Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.

The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.

There are no additional studies performed.

Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]

Animal models are not discussed.

There is no associated phenotype in OMIM or PanelApp AUS.
This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Early onset or syndromic epilepsy v2.396 ZDHHC9 Ivone Leong Phenotypes for gene: ZDHHC9 were changed from epilepsy; intellectual disability; Mental retardation, X-linked syndromic, Raymond type, 300799 to epilepsy; intellectual disability; Mental retardation, X-linked syndromic, Raymond type, OMIM:300799
Early onset or syndromic epilepsy v2.395 CHD5 Ivone Leong Tag Q3_21_rating tag was added to gene: CHD5.
Early onset or syndromic epilepsy v2.395 CHD5 Ivone Leong Entity copied from Intellectual disability v3.1197
Early onset or syndromic epilepsy v2.395 CHD5 Ivone Leong gene: CHD5 was added
gene: CHD5 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v2.394 CEP85L Rachel Challis reviewed gene: CEP85L: Rating: GREEN; Mode of pathogenicity: None; Publications: 32097629, 32097630; Phenotypes: Intellectual disability, epilepsy, lissencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.394 PCDHGC4 Sarah Leigh Classified gene: PCDHGC4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.394 PCDHGC4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.394 PCDHGC4 Sarah Leigh Gene: pcdhgc4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.393 PCDHGC4 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (15/7/2021). At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Early onset or syndromic epilepsy v2.393 PCDHGC4 Sarah Leigh gene: PCDHGC4 was added
gene: PCDHGC4 was added to Genetic epilepsy syndromes. Sources: Literature
Q3_21_rating tags were added to gene: PCDHGC4.
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to neurodevelopmental syndrome
Review for gene: PCDHGC4 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Early onset or syndromic epilepsy v2.392 HEATR5B Ivone Leong Entity copied from Intellectual disability v3.1190
Early onset or syndromic epilepsy v2.392 HEATR5B Ivone Leong gene: HEATR5B was added
gene: HEATR5B was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: HEATR5B.
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia, MONDO:0020135; intellectual disability, MONDO:0001071; seizures
Early onset or syndromic epilepsy v2.391 SPTBN1 Sarah Leigh Classified gene: SPTBN1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.391 SPTBN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.391 SPTBN1 Sarah Leigh Gene: sptbn1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.390 SPTBN1 Sarah Leigh gene: SPTBN1 was added
gene: SPTBN1 was added to Genetic epilepsy syndromes. Sources: Literature
Q3_21_rating tags were added to gene: SPTBN1.
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to 34211179
Phenotypes for gene: SPTBN1 were set to autosomal dominant neurodevelopmental syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (as of 13/07/2021). At least 27 monoallelic variants reported in 29 individuals with neurodevelopmental abnormalities. Developmental delay was reported in 28/28 tested cases. Intellectual disabilty was reported in 21/24 tested cases (including severe in 5 cases, moderate to severe in 2 cases and moderate in 4 cases) and epilepsy/seizures was reported in 9/24 tested cases (including febrile seizures in 2 cases). Extensive supportive functional evidence was also reported (PMID 34211179).
Sources: Literature
Early onset or syndromic epilepsy v2.389 RNF2 Eleanor Williams Classified gene: RNF2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.389 RNF2 Eleanor Williams Added comment: Comment on list classification: Promoting to amber as there are 2 cases reported
Early onset or syndromic epilepsy v2.389 RNF2 Eleanor Williams Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.388 RNF2 Eleanor Williams gene: RNF2 was added
gene: RNF2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNF2 were set to 33864376
Phenotypes for gene: RNF2 were set to epilepsy; intellectual disability; intrauterine growth retardation
Review for gene: RNF2 was set to AMBER
Added comment: Not associated with any phenotype in OMIM.

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 v2.387 DNM1 Arina Puzriakova Publications for gene: DNM1 were set to EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11; 25262651; 27066543
Early onset or syndromic epilepsy v2.386 DNM1 Arina Puzriakova Tag watchlist tag was added to gene: DNM1.
Early onset or syndromic epilepsy v2.386 DNM1 Arina Puzriakova Classified gene: DNM1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.386 DNM1 Arina Puzriakova Added comment: Comment on list classification: Currently, there is only enough evidence for an Amber rating for the biallelic form and so I have kept the MOI as just 'Monoallelic' at this time. If this is a genuine association, biallelic cases would still be picked by the Genomics England pipeline under this MOI. Added watchlist tag in anticipation of further biallelic cases emerging.
Early onset or syndromic epilepsy v2.386 DNM1 Arina Puzriakova Gene: dnm1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.385 DNM1 Arina Puzriakova reviewed gene: DNM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34172529; Phenotypes: Developmental and epileptic encephalopathy 31, OMIM:616346; Mode of inheritance: None
Early onset or syndromic epilepsy v2.385 DNM1 Arina Puzriakova Phenotypes for gene: DNM1 were changed from Epileptic encephalopathy, early infantile, 31, 616346 to Developmental and epileptic encephalopathy 31, OMIM:616346
Early onset or syndromic epilepsy v2.384 ACOX1 Ivone Leong edited their review of gene: ACOX1: Changed phenotypes to: Mitchell syndrome, OMIM:618960
Early onset or syndromic epilepsy v2.384 ACOX1 Ivone Leong reviewed gene: ACOX1: Rating: ; Mode of pathogenicity: None; Publications: 32169171; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.384 ACOX1 Ivone Leong Tag Q3_21_MOI tag was added to gene: ACOX1.
Early onset or syndromic epilepsy v2.384 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Early onset or syndromic epilepsy v2.383 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to 18536048
Early onset or syndromic epilepsy v2.382 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to 18536048
Early onset or syndromic epilepsy v2.382 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Tag Q3_21_MOI was removed from gene: ACOX1.
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Deleted their review
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Deleted their comment
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Tag Q3_21_MOI tag was added to gene: ACOX1.
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong reviewed gene: ACOX1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.381 ARHGEF9 Arina Puzriakova Phenotypes for gene: ARHGEF9 were changed from Epileptic encephalopathy, early infantile, 8 300607 to Developmental and epileptic encephalopathy 8, OMIM:300607
Early onset or syndromic epilepsy v2.380 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie, 608799 to Congenital disorder of glycosylation, type Ie, OMIM:608799
Early onset or syndromic epilepsy v2.379 UFSP2 Sarah Leigh changed review comment from: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; to: The Q2_21_expert_review tag has been added to consider the evidence for the founder variant rs142500730, which appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.
Early onset or syndromic epilepsy v2.379 UFSP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.379 FAR1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, the rating was set to Amber for this allelic requirement. However, there is now also evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline); to: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline)
Early onset or syndromic epilepsy v2.379 FAR1 Arina Puzriakova Added comment: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, the rating was set to Amber for this allelic requirement. However, there is now also evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline)
Early onset or syndromic epilepsy v2.379 FAR1 Arina Puzriakova Mode of inheritance for gene: FAR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.378 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 25439727
Early onset or syndromic epilepsy v2.377 FAR1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: FAR1.
Tag Q2_21_MOI tag was added to gene: FAR1.
Early onset or syndromic epilepsy v2.377 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: ; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.377 PIGB Arina Puzriakova Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Developmental and epileptic encephalopathy 80, OMIM:618580
Early onset or syndromic epilepsy v2.376 ALKBH8 Arina Puzriakova Phenotypes for gene: ALKBH8 were changed from Intellectual developmental disorder, autosomal recessive 71, 618504; Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Early onset or syndromic epilepsy v2.375 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080 to Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364
Early onset or syndromic epilepsy v2.374 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: RED; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.374 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from ?Spinocerebellar ataxia, autosomal recessive 15 615705 to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Early onset or syndromic epilepsy v2.373 RORB Arina Puzriakova Phenotypes for gene: RORB were changed from generalized epilepsies with predominant absence seizures to {Epilepsy, idiopathic generalized, susceptibility to, 15}, OMIM:618357
Early onset or syndromic epilepsy v2.372 PHACTR1 Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures to Developmental and epileptic encephalopathy 70, OMIM:618298
Early onset or syndromic epilepsy v2.371 EIF3F Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295
Early onset or syndromic epilepsy v2.370 CUX2 Arina Puzriakova Phenotypes for gene: CUX2 were changed from Seizures; Epileptic encephalopathy, early infantile, 67, 618141; Infantile onset myoclonic epileptic encephalopathy to Developmental and epileptic encephalopathy 67, OMIM:618141; Infantile onset myoclonic epileptic encephalopathy
Early onset or syndromic epilepsy v2.369 EMC10 Arina Puzriakova Entity copied from Intellectual disability v3.1124
Early onset or syndromic epilepsy v2.369 EMC10 Arina Puzriakova gene: EMC10 was added
gene: EMC10 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: EMC10.
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858; 33531666
Phenotypes for gene: EMC10 were set to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Early onset or syndromic epilepsy v2.368 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to PMID: 21441262
Early onset or syndromic epilepsy v2.367 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant to Rett syndrome, congenital variantRett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Early onset or syndromic epilepsy v2.366 SLC6A1 Arina Puzriakova Publications for gene: SLC6A1 were set to 25865495; Carvill et al (2015) Am J Hum Genet 96(5): 808-15
Early onset or syndromic epilepsy v2.365 SLC6A1 Arina Puzriakova Phenotypes for gene: SLC6A1 were changed from Myoclonic-atonic epilepsy, 616421 to Myoclonic-atonic epilepsy, OMIM:616421
Early onset or syndromic epilepsy v2.364 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.364 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from ?Ribose 5-phosphate isomerase deficiency 608611 to Ribose 5-phosphate isomerase deficiency, OMIM:608611
Early onset or syndromic epilepsy v2.363 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, 617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Early onset or syndromic epilepsy v2.362 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Epilepsy, progressive myoclonic 1B 612437 to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh edited their review of gene: UFSP2: Added comment: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.361 UFSP2 Konstantinos Varvagiannis reviewed gene: UFSP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33473208; Phenotypes: Abnormal muscle tone, Seizures, Global developmental delay, Delayed speech and language development, Intellectual disability, Strabismus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.361 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Early onset or syndromic epilepsy v2.361 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Early onset or syndromic epilepsy v2.360 UNC80 Arina Puzriakova Publications for gene: UNC80 were set to 26545877; 26708753; 26708751
Early onset or syndromic epilepsy v2.359 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Early onset or syndromic epilepsy v2.358 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy, early infantile, 83, 618744; seizures to Developmental and epileptic encephalopathy 83, OMIM:618744
Early onset or syndromic epilepsy v2.357 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 20956791; 7854532; 26701950; 20952379
Early onset or syndromic epilepsy v2.356 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 4, 225753; Pontocerebellar hypoplasia type 2A, 277470; ?Pontocerebellar hypoplasia type 5, 610204 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Early onset or syndromic epilepsy v2.355 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F, 617026; seizures to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Early onset or syndromic epilepsy v2.354 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Early onset or syndromic epilepsy v2.353 TRAPPC6B Arina Puzriakova Publications for gene: TRAPPC6B were set to 28626029; 28397838; DOI 10.1055/s-0039-1693664
Early onset or syndromic epilepsy v2.352 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Early onset or syndromic epilepsy v2.352 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Tag Q2_21_rating tag was added to gene: CERS1.
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh edited their review of gene: CERS1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least two missense variants reported in two unrelated cases, together with supportive functional evidence.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Classified gene: CERS1 as Amber List (moderate evidence)