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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.
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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).

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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.

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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.

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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.

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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.

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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 ]

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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.
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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%.
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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.
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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.
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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)
Early onset or syndromic epilepsy v2.351 CERS1 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 v2.351 CERS1 Sarah Leigh Gene: cers1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.350 CERS1 Sarah Leigh Phenotypes for gene: CERS1 were changed from ?Epilepsy, progressive myoclonic, 8, 616230 to ?Epilepsy, progressive myoclonic, 8 OMIM:616230; progressive myoclonic epilepsy type 8 MONDO:0014545
Early onset or syndromic epilepsy v2.349 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Early onset or syndromic epilepsy v2.348 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Early onset or syndromic epilepsy v2.347 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Classified gene: NSF as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Gene: nsf has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.345 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Tag Q2_21_rating tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh edited their review of gene: PMPCB: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Neurodegeneration in Early Childhood. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Classified gene: PMPCB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.345 PMPCB 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 v2.345 PMPCB Sarah Leigh Gene: pmpcb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.344 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Early onset or syndromic epilepsy v2.343 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Tag Q2_21_rating tag was added to gene: TMEM222.
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Seizures were evident in six individuals from six families.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Classified gene: TMEM222 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.342 TMEM222 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 v2.342 TMEM222 Sarah Leigh Gene: tmem222 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.341 TMEM222 Sarah Leigh Publications for gene: TMEM222 were set to 33824500
Early onset or syndromic epilepsy v2.340 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to AMBER
Added comment: Seizures have been reported in 7 individuals (from 6 families). Consider inclusion with amber/green rating. From the ID panel :

Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Early onset or syndromic epilepsy v2.340 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability; Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Tag Q2_21_rating was removed from gene: UFSP2.
Tag founder-effect tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208; 28892125; 26428751; 32755715
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Classified gene: UFSP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Added comment: 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).
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208
Early onset or syndromic epilepsy v2.334 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 (MIM 615516) to Mental retardation, autosomal recessive 38, OMIM:615516
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova changed review comment from: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.; to: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline if this gene is upgraded to Green on this panel in the future.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Classified gene: NCDN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Added comment: Comment on list classification: Rating Amber with monoallelic MOI, awaiting further cases with seizures (2/3 de novo cases with epilepsy - PMID: 33711248). Currently 'Red' evidence level for biallelic form.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Gene: ncdn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Mode of inheritance for gene: NCDN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.331 NCDN Arina Puzriakova gene: NCDN was added
gene: NCDN was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NCDN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to AMBER
Added comment: NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. All 3 sibs had generalised seizures (fever induced in 2), while 2/3 individuals with heterozygous variants developed epileptic spasms presenting several times per day prior to treatment. Supportive functional data included.
Sources: Literature
Early onset or syndromic epilepsy v2.330 UFSP2 Tracy Lester gene: UFSP2 was added
gene: UFSP2 was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Penetrance for gene: UFSP2 were set to Complete
Mode of pathogenicity for gene: UFSP2 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: UFSP2 was set to GREEN
Added comment: This is a founder variant that has been reported homozygously in several individuals with an epileptic encephalopathy like phenotype. Three additional cases have been identified in the GEL 100K database by the MSK GeCIP. Recessive LOF variants in this gene cause a skeletal dysplasia phenotype. Functional studies support a gain of function for this variant.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.330 PIGC Arina Puzriakova Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16, 617816 to Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816
Early onset or syndromic epilepsy v2.329 PIGC Arina Puzriakova Publications for gene: PIGC were set to
Early onset or syndromic epilepsy v2.328 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both dominant negative variants that result in LOF effect (RCV000170511, rs786205231) and GOF variants (rs786205231, rs786205232) have been associated with Developmental and epileptic encephalopathy 32 OMIM:616366
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 was changed from None to None
Early onset or syndromic epilepsy v2.327 KCNA2 Sarah Leigh Phenotypes for gene: KCNA2 were changed from Epileptic encephalopathy, early infantile, 32; EPILEPTIC ENCEPHALOPATHY to Developmental and epileptic encephalopathy 32 OMIM:616366; developmental and epileptic encephalopathy, 32 MONDO:0014607
Early onset or syndromic epilepsy v2.326 KCNA2 Sarah Leigh Publications for gene: KCNA2 were set to Syrbe et al (2015) Nat Genet 47(4): 393-9
Early onset or syndromic epilepsy v2.325 NEUROD2 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 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Classified gene: NEUROD2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.325 NEUROD2 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 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Gene: neurod2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NEUROD2.
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova edited their review of gene: NEUROD2: Added comment: - Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word); Changed rating: GREEN
Early onset or syndromic epilepsy v2.324 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042; seizures to Congenital disorder of glycosylation, type Iu, OMIM:615042
Early onset or syndromic epilepsy v2.323 DPM2 Arina Puzriakova commented on gene: DPM2
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Classified gene: KCNH1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Added comment: Comment on list classification: Sufficient number of unrelated cases (>3) of epilepsy in patients with variants in the KCNH1 gene. Inclusion on this panel would be of particular benefit to individuals without typical gingival and/or nail anomalies and only mild developmental delays - who may not be tested under other panels (e.g. Limb disorders, ID) and thus may otherwise be missed in analysis.
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Gene: kcnh1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.322 KCNH1 Arina Puzriakova gene: KCNH1 was added
gene: KCNH1 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: KCNH1.
Mode of inheritance for gene: KCNH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH1 were set to 18203178; 20009591; 20683999; 21626675; 23994350; 25420144; 33811134
Phenotypes for gene: KCNH1 were set to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Review for gene: KCNH1 was set to GREEN
Added comment: Well-established cause of Temple-Baraitser syndrome (MIM #611816) and Zimmermann-Laband syndrome (MIM #135500) characterised by ID with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia. Overall, sufficient number of cases with epilepsy to rate Green on this panel (PMIDs: 18203178; 20009591; 20683999; 21626675; 23994350; 25420144)

- PMID: 33811134 (2021) - 7 patients with de novo KCNH1 variants presenting mild/moderate to severe DD/ID, but without any distinctive features of TBS/ZLS such as gingival hyperplasia and nail anomalies. Four patients had epilepsy starting in infancy, with generalised tonic–clonic (4/4), myoclonic (2/4), focal motor (2/4) and tonic (1/4) seizures. One patient experienced status epilepticus. Epilepsy was pharmacoresponsive in all individuals. This study provides evidence of KCNH-related encephalopathy even without the presence of other extra-neurological symptoms that are typically associated with pathogenic variants in this gene.
Sources: Literature
Early onset or syndromic epilepsy v2.321 IRF2BPL Sarah Leigh Publications for gene: IRF2BPL were set to 30057031; 28135719; 25363768
Early onset or syndromic epilepsy v2.320 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures 618088 to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Early onset or syndromic epilepsy v2.319 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: Seizures
Early onset or syndromic epilepsy v2.319 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; Seizures to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Early onset or syndromic epilepsy v2.318 KCNQ2 Arina Puzriakova Publications for gene: KCNQ2 were set to Dedek et al (2003) Epilepsy Res 54: 21-27
Early onset or syndromic epilepsy v2.317 KCNQ2 Arina Puzriakova Phenotypes for gene: KCNQ2 were changed from BENIGN NEONATAL EPILEPSY TYPE 1 (EBN1); EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 7 (EIEE7); Epileptic encephalopathy, early infantile, 7; Myokymia; Seizures, benign neonatal, 1 to Developmental and epileptic encephalopathy 7, OMIM:613720; Seizures, benign neonatal, 1, OMIM:121200
Early onset or syndromic epilepsy v2.316 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder 616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Early onset or syndromic epilepsy v2.315 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.315 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.314 MED27 Arina Puzriakova gene: MED27 was added
gene: MED27 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: MED27.
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Review for gene: MED27 was set to GREEN
Added comment: MED27 is currently not associated with any phenotype in OMIM (last edited on 08/03/2012), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'MED27-related neurodevelopmental disorder'

- PMID: 33443317 (2021) - 16 individuals from 11 families with a neurodevelopmental syndrome characterised by mild to profound GDD/ID (14/14), axial hypotonia (14/15), distal spasticity and dystonic movements (13/15), cerebellar hypoplasia (12/14), cataracts (10/15), epilepsy (9/15), and microcephaly (4/14). Age of seizure onset ranged from 20 days to 5 years and seizure types were varied. Epilepsy was drug-resistant in 3/9 patients. Exome sequencing revealed biallelic variants in the MED27 gene, including 3 recurrent variants found in 2 or more families with different background.

Overall sufficient (>3) unrelated cases with epilepsy in patients with MED27 variants for inclusion on this panel as diagnostic-grade (Green).
Sources: Literature
Early onset or syndromic epilepsy v2.313 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to
Early onset or syndromic epilepsy v2.312 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency 271980 to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Early onset or syndromic epilepsy v2.311 ADPRHL2 Sarah Leigh Publications for gene: ADPRHL2 were set to 30100084
Early onset or syndromic epilepsy v2.310 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Intellectual disability, cerebellar atrophy, ataxia and epilepsy to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Early onset or syndromic epilepsy v2.309 NEUROD2 Arina Puzriakova Publications for gene: NEUROD2 were set to 30323019; 16504944
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova edited their review of gene: NEUROD2: Changed publications: 16504944, 30323019, 33438828
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova reviewed gene: NEUROD2: Rating: ; Mode of pathogenicity: None; Publications: 30323019, 16504944; Phenotypes: Developmental and epileptic encephalopathy 72, OMIM:618374; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova Phenotypes for gene: NEUROD2 were changed from Epileptic encephalopathy, early infantile, 72, MIM# 618374 to Developmental and epileptic encephalopathy 72, OMIM:618374
Early onset or syndromic epilepsy v2.307 SLC7A6OS Sarah Leigh Added comment: Comment on phenotypes: Based on the phenotypic spectrum reported in PMID 33085104, this gene may be suitable for additional panels.
Early onset or syndromic epilepsy v2.307 SLC7A6OS Sarah Leigh Phenotypes for gene: SLC7A6OS were changed from Progressive myoclonus epilepsy to Epilepsy, progressive myoclonic, 12 OMIM:619191
Early onset or syndromic epilepsy v2.306 SLC7A6OS Sarah Leigh changed review comment from: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one variant reported in two familes, shown to share common ancestors by haplotype analysis (PMID 33085104).; to: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one variant reported in two families, shown to share common ancestors by haplotype analysis (PMID 33085104).
Early onset or syndromic epilepsy v2.306 PIGU Arina Puzriakova Phenotypes for gene: PIGU were changed from Glycosylphosphatidylinositol biosynthesis defect 2, 618590; myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis, OMIM:618590
Early onset or syndromic epilepsy v2.305 SETD1B Arina Puzriakova Phenotypes for gene: SETD1B were changed from Epilepsy with myoclonic absences; intellectual disability to Intellectual developmental disorder with seizures and language delay, OMIM:619000; Intellectual developmental disorder with seizures and language delay, MONDO:0033559
Early onset or syndromic epilepsy v2.304 SETD1B Arina Puzriakova Publications for gene: SETD1B were set to 20648245; 27106595; 25428890; 22369279; 29322246; 31440728; 31685013
Early onset or syndromic epilepsy v2.303 PROSC Arina Puzriakova Tag curated_removed tag was added to gene: PROSC.
Early onset or syndromic epilepsy v2.303 CDK19 Julia Baptista reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: 33495529, 33568421, 32330417; Phenotypes: developmental delay, hypotonia, seizures, autism/autistic traits; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Tag Q2_21_rating tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh edited their review of gene: SCAMP5: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (18/02/2021). At single heterozygous variant (NM_001178111.1: c.538G>T, p.Gly180Trp) has been reported to be associated with intellectual disability; seizures; autism in at least six unrelated cases (PMID 33390987; 31439720).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.303 SCAMP5 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 v2.303 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.302 SCAMP5 Sarah Leigh Added comment: Comment on phenotypes: OMIM does not have a phenotype associated with variants in this gene (18/02/21).
Early onset or syndromic epilepsy v2.302 SCAMP5 Sarah Leigh Phenotypes for gene: SCAMP5 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Early onset or syndromic epilepsy v2.301 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363
Early onset or syndromic epilepsy v2.300 SLC7A6OS Sarah Leigh Classified gene: SLC7A6OS as Red List (low evidence)
Early onset or syndromic epilepsy v2.300 SLC7A6OS Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one variant reported in two familes, shown to share common ancestors by haplotype analysis (PMID 33085104).
Early onset or syndromic epilepsy v2.300 SLC7A6OS Sarah Leigh Gene: slc7a6os has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.299 SLC7A6OS Sarah Leigh Publications for gene: SLC7A6OS were set to 33085104
Early onset or syndromic epilepsy v2.298 SLC7A6OS Sarah Leigh Tag founder-effect tag was added to gene: SLC7A6OS.
Early onset or syndromic epilepsy v2.298 SLC7A6OS Zornitza Stark gene: SLC7A6OS was added
gene: SLC7A6OS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SLC7A6OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC7A6OS were set to 33085104
Phenotypes for gene: SLC7A6OS were set to Progressive myoclonus epilepsy
Review for gene: SLC7A6OS was set to RED
Added comment: Two unrelated families reported with same homozygous splice site variant, shared haplotype (founder effect). Limited functional data.
Sources: Literature
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Tag watchlist tag was added to gene: CCDC186.
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Classified gene: CCDC186 as Red List (low evidence)
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Added comment: Comment on list classification: Not associated with a relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in cases with failure to thrive and developmental delay, epileptic encephalopathy was rerported in one case (PMID33259146).
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Gene: ccdc186 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.297 CCDC186 Sarah Leigh Publications for gene: CCDC186 were set to 33259146
Early onset or syndromic epilepsy v2.296 LMBRD2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both of the references for this entry suggest a gain-of-function action for LMBRD2 variants.
Early onset or syndromic epilepsy v2.296 LMBRD2 Sarah Leigh Mode of pathogenicity for gene: LMBRD2 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 v2.295 ADAM22 Sarah Leigh changed review comment from: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a boarderline case.; to: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a borderline case.
Early onset or syndromic epilepsy v2.295 ADAM22 Sarah Leigh Classified gene: ADAM22 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.295 ADAM22 Sarah Leigh Added comment: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a boarderline case.
Early onset or syndromic epilepsy v2.295 ADAM22 Sarah Leigh Gene: adam22 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.294 SATB1 Arina Puzriakova Classified gene: SATB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.294 SATB1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next major review.
Early onset or syndromic epilepsy v2.294 SATB1 Arina Puzriakova Gene: satb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.293 SATB1 Arina Puzriakova gene: SATB1 was added
gene: SATB1 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: SATB1.
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SATB1 were set to 33513338
Phenotypes for gene: SATB1 were set to Neurodevelopmental disorder
Review for gene: SATB1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited: 30/09/2020) but has a 'confirmed' disease confidence rating for 'SATB1-related developmental disorder (monoallelic)' in Gene2Phenotype.

- Den Hoed et al. 2021 (PMID: 33513338) - Total of 42 individuals from 35 families with SATB1 variants (including previously reported cases) - 30 patients harboured 15 unique SATB1 missense variants, including three recurrent variants; 10 had premature protein truncating variants; and and 2 individuals carried a (partial) gene deletion. 28 variants occurred de novo, 3 were inherited from an affected parent, 5 resulted from suspected parental mosaicism (2 inherited from an unaffected parent indicating reduced penetrance), and unknown inheritance in remaining 4 variants.

Phenotypes include neurodevelopmental delay (35/36, 97%), intellectual disability (28/31, 90%), muscle tone abnormalities (abnormal tone 28/37, 76%; hypotonia 28/37, 76%; spasticity 10/36, 28%), epilepsy (22/36, 61%), facial dysmorphisms (24/36, 67%), and dental abnormalities (24/34, 71%). Variable seizure phenotypes described but multiple refractory early-onset cases.

Missense variants were associated with a more severe phenotype - for instance, 57% of individuals with a missense variant had severe/profound ID whereas this level of ID was not observed for any individuals with truncating variants.
Sources: Literature
Early onset or syndromic epilepsy v2.292 HPDL Arina Puzriakova Phenotypes for gene: HPDL were changed from spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
Early onset or syndromic epilepsy v2.291 HPDL Arina Puzriakova Publications for gene: HPDL were set to PMID: 32707086; 33188300
Early onset or syndromic epilepsy v2.290 HPDL Arina Puzriakova Classified gene: HPDL as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.290 HPDL Arina Puzriakova Added comment: Comment on list classification: New gene added by Evan Reid (University of Cambridge). There is enough evidence for this gene to be rated Green at the next major review.
Early onset or syndromic epilepsy v2.290 HPDL Arina Puzriakova Gene: hpdl has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.289 HPDL Arina Puzriakova Tag Q2_21_rating tag was added to gene: HPDL.
Early onset or syndromic epilepsy v2.289 HPDL Arina Puzriakova reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707086, 33188300; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.289 FUK Sarah Leigh Phenotypes for gene: FUK were changed from Seizures; Generalized hypotonia; Feeding difficulties; Intellectual disability; Global developmental delay; Abnormality of vision; Congenital disorder of glycosylation with defective fucosylation 2, 618324 to Congenital disorder of glycosylation with defective fucosylation 2 OMIM:618324; congenital disorder of glycosylation with defective fucosylation 2 MONDO:0020777
Early onset or syndromic epilepsy v2.288 HPDL Evan Reid gene: HPDL was added
gene: HPDL was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to PMID: 32707086; 33188300
Phenotypes for gene: HPDL were set to spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability
Penetrance for gene: HPDL were set to Complete
Review for gene: HPDL was set to GREEN
Added comment: Newly identified gene that can give a phenotype ranging from infantile epileptic encephalopathy to juvenile onset progressive spastic paraplegia.
Sources: Literature
Early onset or syndromic epilepsy v2.288 PMPCB Ivone Leong Tag for-review was removed from gene: PMPCB.
Early onset or syndromic epilepsy v2.288 ADAM22 Sarah Leigh Tag for-review tag was added to gene: ADAM22.
Early onset or syndromic epilepsy v2.288 ADAM22 Sarah Leigh reviewed gene: ADAM22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.288 ADAM22 Sarah Leigh Phenotypes for gene: ADAM22 were changed from ?Epileptic encephalopathy, early infantile, 61 OMIM:617933 to ?Epileptic encephalopathy, early infantile, 61 OMIM:617933; developmental and epileptic encephalopathy, 61 MONDO:0033370
Early onset or syndromic epilepsy v2.287 ADAM22 Sarah Leigh Tag watchlist tag was added to gene: ADAM22.
Early onset or syndromic epilepsy v2.287 GALNT2 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, depending on the policy of inclusion of metabolic genes on this panel.; to: Comment on list classification:
For-review tag has been added to highlight that there is enough evidence for this gene to be rated GREEN at the next major review, depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.287 GALNT2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.287 GALNT2 Sarah Leigh commented on gene: GALNT2: For-review tag has been added to highlight whether this gene should be green on this panel due to the uncoupling of metabolic genes from Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.287 ALG14 Sarah Leigh commented on gene: ALG14: For-review tag has been added to highlight whether this gene should be green on this panel due to the uncoupling of metabolic genes from Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh changed review comment from: Taking account the review of Helen Lord and Konstantinos Varvagiannis, there is not enough convincing evidence for this gene to be rated GREEN on the Genetic epilepsy syndromes panel. The "for-review" tag has been replaced with the "watchlist" tag to highlight that further cases with seizures are needed for this gene to be rated Green on this panel.; to: Taking account the review of Helen Lord and Konstantinos Varvagiannis, there is not enough convincing evidence for this gene to be rated GREEN on the Genetic epilepsy syndromes panel. The "for-review" tag has been removed. The "watchlist" tag will remain to highlight that further cases with seizures are needed for this gene to be rated Green on this panel.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh Tag for-review was removed from gene: TET3.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh changed review comment from: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Taking account the review of Helen Lord and Konstantinos Varvagiannis, there is not enough convincing evidence for this gene to be rated GREEN on the Genetic epilepsy syndromes panel. The "for-review" tag has been replaced with the "watchlist" tag to highlight that further cases with seizures are needed for this gene to be rated Green on this panel.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007; 31928709
Early onset or syndromic epilepsy v2.286 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Beck-Fahrner syndrome 618798 to Beck-Fahrner syndrome OMIM:618798
Early onset or syndromic epilepsy v2.285 SNX27 Sarah Leigh Tag for-review was removed from gene: SNX27.
Tag watchlist tag was added to gene: SNX27.
Early onset or syndromic epilepsy v2.285 SNX27 Sarah Leigh edited their review of gene: SNX27: Added comment: Taking account of Helen Lord's review that there is insufficient evidence that seizures are associated with variants in SNX27, the "for review" tag has been replaced with the "watchlist" tag. The rating of this gene will remain amber on the Genetic epilepsy syndromes panel.; Changed rating: AMBER
Early onset or syndromic epilepsy v2.285 SLC5A6 Sarah Leigh changed review comment from: For review tag has been added, to allow for GMS discussion in relation to the metabolic role of this gene.; to: For review tag has been added, to allow for GMS discussion in relation to the metabolic role of this gene. There are insufficient cases with seizures to be green on the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.285 SEMA6B Sarah Leigh Phenotypes for gene: SEMA6B were changed from Epilepsy, progressive myoclonic, 11, 618876 to Epilepsy, progressive myoclonic, 11 OMIM:618876
Early onset or syndromic epilepsy v2.284 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures OMIM:618879
Early onset or syndromic epilepsy v2.283 GALNT2 Sarah Leigh Phenotypes for gene: GALNT2 were changed from Congenital disorder of glycosylation, type IIt 618885 to Congenital disorder of glycosylation, type IIt OMIM:618885
Early onset or syndromic epilepsy v2.282 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 15571623; 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Early onset or syndromic epilepsy v2.281 CCDC186 Zornitza Stark gene: CCDC186 was added
gene: CCDC186 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146
Phenotypes for gene: CCDC186 were set to Epileptic encephalopathy
Review for gene: CCDC186 was set to RED
Added comment: One individual reported with bi-allelic truncating variant and EE.
Sources: Literature
Early onset or syndromic epilepsy v2.281 TET3 Helen Lord reviewed gene: TET3: Rating: AMBER; Mode of pathogenicity: None; Publications: 31928709; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 SNX27 Helen Lord reviewed gene: SNX27: Rating: AMBER; Mode of pathogenicity: None; Publications: 31721175; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 SLC5A6 Helen Lord reviewed gene: SLC5A6: Rating: RED; Mode of pathogenicity: None; Publications: 31754459, 27904971; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 SEMA6B Helen Lord reviewed gene: SEMA6B: Rating: AMBER; Mode of pathogenicity: None; Publications: 32169168; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.281 RALGAPA1 Helen Lord reviewed gene: RALGAPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004447; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 PIGK Helen Lord reviewed gene: PIGK: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220290; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 LMBRD2 Helen Lord reviewed gene: LMBRD2: Rating: AMBER; 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: 32820033; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.281 GALNT2 Helen Lord reviewed gene: GALNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32293671, 27508872; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 GAD1 Helen Lord reviewed gene: GAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 320705143, 32282878; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 KATNB1 Arina Puzriakova Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly, 616212; seizures to Lissencephaly 6, with microcephaly, OMIM:616212, MONDO:0014534
Early onset or syndromic epilepsy v2.280 DHX16 Helen Lord reviewed gene: DHX16: Rating: AMBER; Mode of pathogenicity: None; Publications: 31256877; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.280 ADAM22 Sarah Leigh Phenotypes for gene: ADAM22 were changed from ?Epileptic encephalopathy, early infantile, 61, 617933 to ?Epileptic encephalopathy, early infantile, 61 OMIM:617933
Early onset or syndromic epilepsy v2.279 TMX2 Arina Puzriakova Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, OMIM:618730; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, MONDO:0032887
Early onset or syndromic epilepsy v2.278 ANKRD11 Sarah Leigh reviewed gene: ANKRD11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.278 SCN9A Sarah Leigh edited their review of gene: SCN9A: Added comment: This gene should remain Red on this panel.; Changed rating: RED
Early onset or syndromic epilepsy v2.278 CACNB4 Sarah Leigh Phenotypes for gene: CACNB4 were changed from {Epilepsy, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855; Intellectual disability to {Epilepsy, idiopathic generalized, susceptibility to, 9} OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6} OMIM:607682; Episodic ataxia, type 5 OMIM:613855; Intellectual disability
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh Tag for-review tag was added to gene: CPA6.
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh commented on gene: CPA6: After consultation Helen Lord, recommend change of MOI to BIALLELIC, autosomal or pseudosomal
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh edited their review of gene: CPA6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.277 CPA6 Helen Lord reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.277 ALG14 Sarah Leigh edited their review of gene: ALG14: Changed rating: GREEN
Early onset or syndromic epilepsy v2.277 ADAM22 Sarah Leigh Publications for gene: ADAM22 were set to 27066583; 30237576; 15876356
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Classified gene: SCN9A as Red List (low evidence)
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Added comment: Comment on list classification: Evidence presented by PMID 33216760 disputes the association between SCN9A and epilepsy, inparticular the serendipitous identification of the SCN9A p.(Asn641Tyr) variant within the Wisconsin Amish community with no epilepsy in their phenotypes. The authors report this lack of gene disease association was also evident in the UK Biobank.
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Gene: scn9a has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.275 SCN9A Sarah Leigh Publications for gene: SCN9A were set to 19763161; 29500686; 30834459; 23895530
Early onset or syndromic epilepsy v2.274 CEP85L Helen Lord reviewed gene: CEP85L: Rating: GREEN; Mode of pathogenicity: None; Publications: 32097630; Phenotypes: Lissencephaly 10; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 CDK19 Helen Lord changed review comment from: Chung et al 2020 - 3 iunrealrted indicuduals with de novo missense variants in CDK19 - presented with hypotonia, global developmental delay, epileptic encephalopathy and dysmorphic features. Two patients had the Thr196Ala variant and the other Tyr32His - predicted to be likely pathogenic. Fuinctional work suggests dominant loss of function variants.; to: Chung et al 2020 - 3 unrelated indiviuduals with de novo missense variants in CDK19 - presented with hypotonia, global developmental delay, epileptic encephalopathy and dysmorphic features. Two patients had the Thr196Ala variant and the other Tyr32His - predicted to be likely pathogenic. Fuinctional work suggests dominant loss of function variants.
Early onset or syndromic epilepsy v2.274 CDK19 Helen Lord reviewed gene: CDK19: Rating: AMBER; Mode of pathogenicity: None; Publications: 32330417; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 CACNB4 Helen Lord reviewed gene: CACNB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 32176688; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 SCN9A Helen Lord reviewed gene: SCN9A: Rating: RED; Mode of pathogenicity: None; Publications: 33216760; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.274 ANKRD11 Helen Lord reviewed gene: ANKRD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33476899; Phenotypes: KBG syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 ALG14 Helen Lord reviewed gene: ALG14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28733338, 30221345; Phenotypes: epilepsy, behavioural problems, severe developmental delay, mild dysmorphic features, severe neurodegeneration with myopathic and myasthenic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.274 ADAM22 Helen Lord reviewed gene: ADAM22: Rating: AMBER; Mode of pathogenicity: None; Publications: 31432233, 33397806; Phenotypes: Developmental and epileptic encephalopathy 61; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.274 ABCA2 Helen Lord reviewed gene: ABCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29302074, 31047799, 30237576; Phenotypes: intellectual delay, poor growth, ataxia, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Classified gene: UBR7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but sufficient number of unrelated cases with relevant phenotype to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Gene: ubr7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.273 UBR7 Arina Puzriakova gene: UBR7 was added
gene: UBR7 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: UBR7.
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: - PMID: 33340455 (2021) - At least 6 SNVs and 1 intragenic deletion reported in 7 individuals from 6 families with a comparable neurodevelopmental disorder. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile).
Sources: Literature
Early onset or syndromic epilepsy v2.272 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954
Early onset or syndromic epilepsy v2.271 PMPCB Sarah Leigh Tag for-review tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.271 FLNA Sarah Leigh Phenotypes for gene: FLNA were changed from Heterotopia, periventricular 300049 to Heterotopia, periventricular OMIM:300049
Early onset or syndromic epilepsy v2.270 ASNS Sarah Leigh Classified gene: ASNS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.270 ASNS 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 v2.270 ASNS Sarah Leigh Gene: asns has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.269 ASNS Sarah Leigh reviewed gene: ASNS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.269 ASNS Sarah Leigh Publications for gene: ASNS were set to
Early onset or syndromic epilepsy v2.268 ASNS Sarah Leigh Phenotypes for gene: ASNS were changed from Asparagine synthetase deficiency, MIM# 615574 to Asparagine synthetase deficiency OMIM:615574
Early onset or syndromic epilepsy v2.267 ASNS Sarah Leigh Tag for-review tag was added to gene: ASNS.
Early onset or syndromic epilepsy v2.267 APC2 Sarah Leigh Phenotypes for gene: APC2 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 Cortical dysplasia, complex, with other brain malformations 10 OMIM:618677
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh edited their review of gene: APC2: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 9 variants in 8 unrealated cases of Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay (PMID 31585108).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Tag for-review tag was added to gene: APC2.
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Classified gene: APC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.266 APC2 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 v2.266 APC2 Sarah Leigh Gene: apc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype, supported by functional data.
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.264 PPIL1 Arina Puzriakova gene: PPIL1 was added
gene: PPIL1 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: PPIL1.
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Review for gene: PPIL1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

- PMID: 33220177 (2021) - At least 12 variants identified in 17 individuals from 9 unrelated families. All displayed pontocerebellar hypoplasia and progressive congenital microcephaly. Infantile-onset seizures were reported in 7/9 families - medically controlled in only 1 individual.
Further common phenotypes included hypotonia, intellectual disability with delayed language and motor development, and cortical changes on brain MRI, most notably simplified gyri pattern. Pathogenicity is supported by mouse model.
Sources: Literature
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Classified gene: FGF13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype (early-onset epilepsy represents the main feature of the disorder), supported by functional data.
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Gene: fgf13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.262 FGF13 Arina Puzriakova Mode of pathogenicity for gene: FGF13 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Early onset or syndromic epilepsy v2.261 FGF13 Arina Puzriakova edited their review of gene: FGF13: Changed mode of pathogenicity: Other
Early onset or syndromic epilepsy v2.261 FGF13 Arina Puzriakova gene: FGF13 was added
gene: FGF13 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: FGF13.
Mode of inheritance for gene: FGF13 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: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Developmental and epileptic encephalopathy; Intellectual disability; Infantile-onset seizures
Mode of pathogenicity for gene: FGF13 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: FGF13 was set to GREEN
Added comment: - PMID: 33245860 (2021) - Three variants (c.31C>T, c.41G>C, c.32G>C) identified by WES/WGS in seven individuals from five unrelated families who presented with severe infantile-onset seizures and severe-to-profound ID. Supportive functional data indicating variants impair long-term inactivation of voltage-gated sodium channels while retaining pro-excitatory properties of A isoform - consistent with the epileptic potential of FGF13 variants
Sources: Literature
Early onset or syndromic epilepsy v2.260 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to 28777934
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Classified gene: TRAPPC12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Added comment: Comment on list classification: With addition of the recently reported case, there are now at least 3 unrelated patients with epilepsy and biallelic variants in this gene (PMIDs: 28777934 and 32369837).

This now reaches threshold for inclusion as diagnostic-grade, and therefore TRAPPC12 can be promoted to Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC12.
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Biallelic variants identified in two families with three individuals affected by neonatal lethal epileptic encephalopathy and respiratory insufficiency (PMID: 30575854). The variants were predicted to result in loss of function, supported by elevated glutamine in all cases.

Rating Amber, awaiting further cases/clinical evidence prior to inclusion as diagnostic-grade.
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.256 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328 to Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Changed mode of pathogenicity: Other
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31439720, 33390987; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.255 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957; 25326637
Early onset or syndromic epilepsy v2.254 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cortical dysplasia, complex, with other brain malformations 5, 615763; infantile-onset epilepsy to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Classified gene: GRN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Gene: grn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.252 GRN Ivone Leong gene: GRN was added
gene: GRN was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 31855245; 28404863; 30922528
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; neuronal ceroid lipofuscinosis 1, MONDO:0013866
Review for gene: GRN was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Biallic variants in GRN cause Ceroid lipofuscinosis, neuronal, 11, which is characterised by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be considered for Green status at the next review.

This gene is also on the Retinal disorders panel (Version 2.71), with the following review:
"Multiple individuals reported with bi-allelic variants and CLN phenotype. Please also note literature regarding retinal abnormalities in those with mono-allelic variants.
Zornitza Stark (Australian Genomics), 11 Oct 2020"
Sources: Literature
Early onset or syndromic epilepsy v2.251 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Early onset or syndromic epilepsy v2.251 RALGAPB Zornitza Stark gene: RALGAPB was added
gene: RALGAPB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RALGAPB were set to 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to AMBER
Added comment: PMID: 32853829 - 2 patients with de novo missense variants, 1 patient with a de novo PTC with autism spectrum disorder from a large cohort.
Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense, epilepsy only present in 2/10 and ID in 1/10.

Variants in this gene cause a neurodevelopmental disorder, but autism seems to be the most prominent feature.
Sources: Literature
Early onset or syndromic epilepsy v2.251 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, 617193; seizures; West syndrome to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Early onset or syndromic epilepsy v2.250 CPA6 Zornitza Stark reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: 25875328, 21922598, 23105115; Phenotypes: Epilepsy, familial temporal lobe, 5 MIM#614417, Febrile seizures, familial, 11 MIM#614418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.250 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590; seizures; EPILEPTIC ENCEPHALOPATHY; Rett-like phenotype to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Early onset or syndromic epilepsy v2.249 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from ?Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Early onset or syndromic epilepsy v2.248 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911; 29545233; 27567911
Early onset or syndromic epilepsy v2.247 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Early onset or syndromic epilepsy v2.246 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.245 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.243 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.242 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Early onset or syndromic epilepsy v2.241 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.239 CSNK1G1 Arina Puzriakova Mode of inheritance for gene: CSNK1G1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.238 EXT2 Zornitza Stark edited their review of gene: EXT2: Changed publications: 26246518, 30288735, 30997052, 30075207; Changed phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM# 616682
Early onset or syndromic epilepsy v2.238 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Early onset or syndromic epilepsy v2.237 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Tag new-gene-name tag was added to gene: NARS.
Tag for-review tag was added to gene: NARS.
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Early onset or syndromic epilepsy v2.234 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Early onset or syndromic epilepsy v2.233 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO28 were set to 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy
Review for gene: FBXO28 was set to GREEN
Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag for-review tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Seizures are prevalent among affected individuals, often triggered by infections. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.232 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, MIM 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Classified gene: PNPT1 as No list
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Gene: pnpt1 has been removed from the panel.
Early onset or syndromic epilepsy v2.229 PNPT1 Arina Puzriakova Tag for-review tag was added to gene: PNPT1.
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Classified gene: CEP85L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Gene: cep85l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.228 CEP85L Arina Puzriakova gene: CEP85L was added
gene: CEP85L was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CEP85L.
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CEP85L were set to 32097630; 32097629
Phenotypes for gene: CEP85L were set to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Review for gene: CEP85L was set to GREEN
Added comment: - PMID: 32097630 (2020) - 13 patients from 9 unrelated families with lissencephaly and heterozygous variants in the CEP85L gene. Seizures are part of the phenotype, present in all cases (except 1 unknown) which were intractable in most. Age of seizure onset was variable, ranging from 5 months to 14 years. Mouse model supports a role of CEP85L in neuronal migration. Gene-disease association included in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v2.227 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Tag Skewed X-inactivation tag was added to gene: TFE3.
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Early onset or syndromic epilepsy v2.226 TFE3 Arina Puzriakova Mode of inheritance for gene: TFE3 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: RED; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh Publications for gene: LMNB2 were set to 16826530
Early onset or syndromic epilepsy v2.224 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643; floppy child; dystonia; hypotonia; developmental delay; oculogyric crisis to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh changed review comment from: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).; to: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 1 was found in 2 unrelated patients who also had epileptic seizures (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh 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 to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder
Early onset or syndromic epilepsy v2.222 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.220 LMNB1 Sarah Leigh Tag watchlist tag was added to gene: LMNB1.
Early onset or syndromic epilepsy v2.220 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:32703943) reporting seizures in 3/6 individuals from 2 families with variants in this gene.
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Gene: fam50a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, 618548 as the name for this phenotype (12/11/2020).
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Multiple congenital anomalies-hypotonia-seizures syndrome-4, OMIM:618548
Early onset or syndromic epilepsy v2.217 PIGQ Sarah Leigh Publications for gene: PIGQ were set to 24463883; 25558065; 31148362
Early onset or syndromic epilepsy v2.216 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Early onset or syndromic epilepsy v2.215 TFE3 Sarah Leigh Publications for gene: TFE3 were set to 30595499; 31833172; https://doi.org/10.1126/scisignal.aax0926
Early onset or syndromic epilepsy v2.214 TFE3 Sarah Leigh Tag for-review tag was added to gene: TFE3.
Early onset or syndromic epilepsy v2.214 TFE3 Sarah Leigh reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30595499, 31833172, 32409512; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Tag for-review tag was added to gene: TBC1D2B.
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Classified gene: TBC1D2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32623794).

There are sufficient cases to rate this gene Green at the next GMS panel update (added 'for-review' tag) - all 4 individuals (3 families) present seizures, although the age of onset is variable (19-years, 18-months, 3-months).
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.213 ABCA2 Arina Puzriakova Phenotypes for gene: ABCA2 were changed from Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808 to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM:618808; Intellectual developmental disorder with poor growth and with or without seizures or ataxia, MONDO:0032930
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as 1) only 2 cases with seizures; 2) epilepsy is not a prominent feature of the overall phenotype; 3) seizures were either resolved or managed by medication.
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.211 ABCA2 Arina Puzriakova reviewed gene: ABCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30237576, 29302074, 31047799; Phenotypes: Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.211 NUS1 Eleanor Williams Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa, 617082; Mental retardation, autosomal dominant 55, with seizures, 617831; Abnormality of extrapyramidal motor function to ?Congenital disorder of glycosylation, type 1aa OMIM:617082; Mental retardation, autosomal dominant 55, with seizures OMIM:617831; Abnormality of extrapyramidal motor function
Early onset or syndromic epilepsy v2.210 NUS1 Eleanor Williams Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779
Early onset or syndromic epilepsy v2.209 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: 2 further heterozygous cases reported by Den et al 2019 (PMID: 31656175). 2 unrelated Japanese patients with a novel, recurrent, de novo NUS1 variant, who presented with epileptic seizures with involuntary movement, ataxia, intellectual disability and scoliosis. The variant c.691 + 1C > A, creates a new splice donor site resulting in a 91 bp deletion in exon 3.; Changed publications: 25066056, 29100083, 24824130, 30348779, 31656175
Early onset or syndromic epilepsy v2.209 PIGH Eleanor Williams Publications for gene: PIGH were set to 29603516; 29573052
Early onset or syndromic epilepsy v2.208 PIGH Eleanor Williams commented on gene: PIGH
Early onset or syndromic epilepsy v2.208 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating, 16 (MIM #617964) to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Early onset or syndromic epilepsy v2.207 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Early onset or syndromic epilepsy v2.207 TFE3 Sarah Leigh Publications for gene: TFE3 were set to 30595499; 31833172; https://doi.org/10.1126/scisignal.aax0926
Early onset or syndromic epilepsy v2.207 TFE3 Sarah Leigh Publications for gene: TFE3 were set to
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only 2 individuals with seizures (both early-onset, before age 6 months) reported at present
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.205 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: Rating: ; 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: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: New gene identified and reviewed by Konstantinos Varvagiannis. Following discussion with Helen Brittain (Genomics England Clinical Team) it has been agreed that this gene should be added as Amber.

Although number of unrelated cases (3) reaches threshold for inclusion, only 2 patients presented severe intractable seizures (could not find any evidence of epilepsy in the case from Pehlivan et al, as stated by external expert review). Furthermore, epilepsy was not a consistent finding (total 11 individuals from 9 families). Rating set to Amber, awaiting further cases.
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.204 DMXL2 Arina Puzriakova Tag for-review tag was added to gene: DMXL2.
Early onset or syndromic epilepsy v2.204 SETD1A Arina Puzriakova Phenotypes for gene: SETD1A were changed from Epilepsy to Epilepsy, early-onset, with or without developmental delay, 618832
Early onset or syndromic epilepsy v2.203 SATB2 Zornitza Stark gene: SATB2 was added
gene: SATB2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SATB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SATB2 were set to 32446642
Phenotypes for gene: SATB2 were set to Glass syndrome, MIM# 612313
gene: SATB2 was marked as current diagnostic
Added comment: In a cohort of 101 individuals with SATB2-associated syndrome, 41 had at least one prior abnormal EEG. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six individuals with definite clinical seizures needed polytherapy (35%).
Sources: Literature
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag) as there are sufficient unrelated cases to support a gene-disease association.
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.202 ZNF335 Arina Puzriakova gene: ZNF335 was added
gene: ZNF335 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: ZNF335.
Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF335 were set to 23178126; 27540107; 29652087; 30500859; 31187448
Phenotypes for gene: ZNF335 were set to Microcephaly 10, primary, autosomal recessive, 615095
Review for gene: ZNF335 was set to GREEN
Added comment: At least 6 unrelated families reported in literature with different biallelic variants in ZNF335. Microcephaly is the primary feature, but also commonly in association with a variable epilepsy phenotype.

Stouffs et al. (PMID:29652087) report 2 unrelated cases: patient A, demonstrating refractory seizures leading to death at age 5 days, whereas patient B lacked any clinical seizures, but had frequent spasms that have yet to be recorded by EEG. The proband in Sato et al. (PMID:27540107) had rare focal seizures controlled by treatment. Although not noted by Yang et al. (PMID:231781260), affected individuals in that family had seizures described as paroxysmal myoclonic jerks (personal communication with Stouffs et al). The case by Rana et al. (PMID:31187448) presented multifocal drug-resistant epilepsy, and while details were limited in McSherry et al. (PMID:30500859), authors did also note seizures.
Sources: Literature
Early onset or syndromic epilepsy v2.201 SLC5A6 Sarah Leigh commented on gene: SLC5A6: For review tag has been added, to allow for GMS discussion in relation to the metabolic role of this gene.
Early onset or syndromic epilepsy v2.201 SLC5A6 Sarah Leigh Tag for-review tag was added to gene: SLC5A6.
Early onset or syndromic epilepsy v2.201 SCN8A Arina Puzriakova Tag for-review tag was added to gene: SCN8A.
Early onset or syndromic epilepsy v2.201 SCN8A Arina Puzriakova commented on gene: SCN8A
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Classified gene: PIGP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Gene: pigp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.200 PIGP Arina Puzriakova Tag for-review tag was added to gene: PIGP.
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Classified gene: PUM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Gene: pum1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.199 PUM1 Arina Puzriakova Tag for-review tag was added to gene: PUM1.
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Classified gene: RALGAPA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Gene: ralgapa1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.198 RALGAPA1 Arina Puzriakova Tag for-review tag was added to gene: RALGAPA1.
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Classified gene: RARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Gene: rars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.197 RARS Arina Puzriakova Tag for-review tag was added to gene: RARS.
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Tag for-review tag was added to gene: RNF113A.
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Gene: rnf113a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Classified gene: RNF13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Gene: rnf13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.195 RNF13 Arina Puzriakova Tag for-review tag was added to gene: RNF13.
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Classified gene: SERPINI1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Gene: serpini1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.194 SERPINI1 Arina Puzriakova Tag for-review tag was added to gene: SERPINI1.
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Classified gene: SETD1A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Gene: setd1a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.193 SETD1A Arina Puzriakova Tag for-review tag was added to gene: SETD1A.
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Classified gene: SETD1B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Gene: setd1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.192 SETD1B Arina Puzriakova Tag for-review tag was added to gene: SETD1B.
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Classified gene: GAD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Gene: gad1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.191 GAD1 Arina Puzriakova Tag for-review tag was added to gene: GAD1.
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Classified gene: PCYT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Gene: pcyt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.190 PCYT2 Arina Puzriakova Tag for-review tag was added to gene: PCYT2.
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Classified gene: ANKRD11 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Gene: ankrd11 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.189 ANKRD11 Arina Puzriakova Tag for-review tag was added to gene: ANKRD11.
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.188 UGP2 Arina Puzriakova Tag for-review tag was added to gene: UGP2.
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Classified gene: TRAPPC4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Gene: trappc4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.187 TRAPPC4 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC4.
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Classified gene: KAT8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Gene: kat8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Classified gene: SEMA6B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Gene: sema6b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.185 SETD5 Arina Puzriakova Classified gene: SETD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.185 SETD5 Arina Puzriakova Gene: setd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Classified gene: SETD5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Gene: setd5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Classified gene: SNX27 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Gene: snx27 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.181 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Early onset or syndromic epilepsy v2.181 KAT8 Arina Puzriakova Tag for-review tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.181 SEMA6B Arina Puzriakova Tag for-review tag was added to gene: SEMA6B.
Early onset or syndromic epilepsy v2.181 SETD5 Arina Puzriakova Tag for-review tag was added to gene: SETD5.
Early onset or syndromic epilepsy v2.181 SNX27 Arina Puzriakova Tag for-review tag was added to gene: SNX27.
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Classified gene: PIGK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Gene: pigk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.180 PIGK Arina Puzriakova Tag for-review tag was added to gene: PIGK.
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Classified gene: TIMM50 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Gene: timm50 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.179 LMBRD2 Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber but there is a sufficient number of unrelated cases with the relevant phenotype to rate this gene GREEN at the next major review.
Early onset or syndromic epilepsy v2.179 UBE3A Sarah Leigh Phenotypes for gene: UBE3A were changed from Angelman syndrome to Angelman syndrome 105830
Early onset or syndromic epilepsy v2.178 USP7 Arina Puzriakova Publications for gene: USP7 were set to 26365382; 19946331
Early onset or syndromic epilepsy v2.177 USP7 Arina Puzriakova Phenotypes for gene: USP7 were changed from Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism to Hao-Fountain syndrome, 616863
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association. This gene has been added with an Amber rating but should be promoted to Green at the GMS panel update (added 'for-review' tag).

Note this is a metabolic gene and is already Green on the Inborn errors of metabolism (v2.3) panel.
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.175 CARS2 Arina Puzriakova gene: CARS2 was added
gene: CARS2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CARS2.
Mode of inheritance for gene: CARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CARS2 were set to 25361775; 25787132; 30139652; 32571458; 32348839
Phenotypes for gene: CARS2 were set to Combined oxidative phosphorylation deficiency 27, 616672
Review for gene: CARS2 was set to GREEN
Added comment: Associated with phenotype in OMIM and as a probable gene for Epileptic encephalopathy with complex movement disorder and regression in Gen2Phen.

At least 6 individuals from 5 unrelated families, all with different biallelic variants in CARS2 and a neurodegenerative disorder which includes early-onset seizures.
Sources: Literature
Early onset or syndromic epilepsy v2.174 TRPM3 Arina Puzriakova Publications for gene: TRPM3 were set to 31278393; 29156220
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Classified gene: TRPM3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the next GMS panel update, in view of recently published functional data and expert reviews.
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.172 TRPM3 Arina Puzriakova reviewed gene: TRPM3: Rating: ; 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: 32439617, 32343227, 32427099; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.172 FDFT1 Arina Puzriakova Phenotypes for gene: FDFT1 were changed from Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face to Squalene synthase deficiency, 618156
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Tag watchlist tag was added to gene: FDFT1.
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Classified gene: FDFT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Added comment: Comment on list classification: Expert review on FDFT1 following a publication by Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

FDFT1 is in OMIM based on this paper. As there are only two families classifying FDFT1 as Amber until more evidence is available (added 'watchlist' tag).
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Gene: fdft1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.170 KAT5 Arina Puzriakova Phenotypes for gene: KAT5 were changed from to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Early onset or syndromic epilepsy v2.169 KAT5 Arina Puzriakova Publications for gene: KAT5 were set to
Early onset or syndromic epilepsy v2.168 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Classified gene: KAT5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber. There is a sufficient number of unrelated cases reported in PMID:32822602 to promoted this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Gene: kat5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.166 KAT5 Arina Puzriakova Tag for-review tag was added to gene: KAT5.
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Classified gene: SCAF4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next GMS panel update - sufficient number of unrelated cases presenting seizures due to distinct variants in SCAF4
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Gene: scaf4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.165 SCAF4 Arina Puzriakova gene: SCAF4 was added
gene: SCAF4 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: SCAF4.
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAF4 were set to 32730804
Phenotypes for gene: SCAF4 were set to SCAF4-related Neurodevelopmental Disorder; Intellectual disability; Seizures; Behavioural abnormalities
Review for gene: SCAF4 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on 23/09/2014), but is a probable gene SCAF4-related Neurodevelopmental Disorder in Gen2Phen.

PMID: 32730804 (2020) - At least 8 unrelated patients with likely pathogenic variants in SCAF4 and mild DD/ID, behavioural abnormalities, and various skeletal, renal and cardiac anomalies. 7 de novo and 1 inherited variant. Seizures occurred in 4 individuals (50%) and included myoclonic seizures in two and intractable seizures in one.
Sources: Literature
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Classified gene: USP18 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update - seizures reported in all families described to date.
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Gene: usp18 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.163 USP18 Arina Puzriakova commented on gene: USP18: Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
Early onset or syndromic epilepsy v2.163 USP18 Arina Puzriakova gene: USP18 was added
gene: USP18 was added to Genetic epilepsy syndromes. Sources: Literature
treatable, for-review tags were added to gene: USP18.
Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP18 were set to 12833411; 27325888; 31940699
Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2, 617397
Review for gene: USP18 was set to GREEN
Added comment: - PMID: 27325888 (2016) - Three sibs from a consanguineous Turkish family with a homozygous variant (c.652C>T, p.Q218X) in USP18. Antenatal presentation in one sib led to termination of pregnancy at 22 wk of gestation, and in the remaining two children presentation was neonatal and resulted in death within 2 weeks of life. In the latter two individuals manifestations included severe intracerebral haemorrhages, liver dysfunction, ascites, and lactic acidosis. One sib additionally had severe thrombocytopenia with petechiae, while the other developed seizures.

Two German sibs, previously reported in PMID: 12833411 (2013), were found to be compound het for the same p.Q218X variant and a cryptic 3-prime deletion of the USP18 gene. They presented thrombocytopenia, petechiae, ascites, hepatomegaly, and systemic calcifications. Within the first days of life, they developed seizures and died from severe cerebral haemorrhage.

Haplotype analysis of the region containing the Q218X mutation suggested a common ancestor between the 2 families and a founder effect.

- PMID: 31940699 (2020) - One Saudi Arabian boy with a homozygous splice-site variant (c.1073+1G>A) in USP18, presented hydrocephalus with seizures, intraventricular haemorrhage, brain calcifications, necrotizing cellulitis, systemic inflammation, multiple organ failure, and respiratory failure. This was the only patient to survive beyond the perinatal period owing to supportive care and prompt treatment with ruxolitinib. At the time of publication, the child was 3-years-old and was in full remission of clinical manifestations while continuing to receive oral ruxolitinib. He continues to grow normally, however authors note delay in developmental milestones.
Sources: Literature
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Tag for-review tag was added to gene: MADD.
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Classified gene: MADD as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There is enough evidence to support a gene-disease association. The gene has been given an Amber rating and will be promoted to Green at the next review.
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Gene: madd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Classified gene: DLL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Added comment: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Gene: dll1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.160 DLL1 Catherine Snow reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, 618709; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.160 MADD Ivone Leong Phenotypes for gene: MADD were changed from Global developmental delay / Intellectual disability / Seizures; Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system to Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Added comment: Comment on list classification: Seizures reported in only 2 unrelated individuals (PMID:32006098). Rating Amber in anticipation of further publications/clinical evidence to support this association.
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Classified gene: UGDH as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Multiple patients from over 20 unrelated families with severe epilepsy, mostly ranging from neonatal to infantile onset developmental epileptic encephalopathy.
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Gene: ugdh has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.157 UGDH Arina Puzriakova Tag for-review tag was added to gene: UGDH.
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 7 unrelated cases presenting seizures, including tonic clonic, generalised, absence, and focal seizures.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 6 unrelated cases presenting epilepsy in association with different NR4A2 variants, including tonic clonic, generalised, absence, and focal seizures.
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Classified gene: NR4A2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 7 unrelated cases presenting seizures, including tonic clonic, generalised, absence, and focal seizures.
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Gene: nr4a2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.156 NR4A2 Arina Puzriakova Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Early onset or syndromic epilepsy v2.155 NR4A2 Arina Puzriakova Tag for-review tag was added to gene: NR4A2.
Early onset or syndromic epilepsy v2.155 KPTN Zornitza Stark edited their review of gene: KPTN: Added comment: Two further publications (PMID 32358097; 32808430), more individuals reported with seizures, suggest upgrade to Green.; Changed publications: 32358097, 32808430
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Classified gene: CUL3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on external expert review and evidence provided by Konstantinos Varvagiannis. Only two unrelated cases reported and therefore not yet reaching threshold for inclusion.
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Gene: cul3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.154 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; 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 v2.154 DHX16 Sarah Leigh Tag watchlist tag was added to gene: DHX16.
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Classified gene: DHX16 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Gene: dhx16 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.153 DHX16 Sarah Leigh gene: DHX16 was added
gene: DHX16 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures 618733
Review for gene: DHX16 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Intellectual Disability, Central Nervous System anomalies and Seizures. At least 4 variants reported as de novo heterozygous variants in 4 unrelated probands as a result of trio exome sequencing and seizures were reported in 2 of these cases. No functional studies were reported.
Sources: Literature
Early onset or syndromic epilepsy v2.152 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to AMBER
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Early onset or syndromic epilepsy v2.152 TANC2 Arina Puzriakova Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Seizures; Epilepsy to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Three patients from two unrelated families with myoclonic seizures, and additional focal epilepsy with versive head movement in one patient (onset at birth/6 months, respectively).

Additional unrelated cases required before inclusion on a diagnostic panel; and therefore, rating Amber in anticipation of further publications (added to watchlist).
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.149 EXOC7 Arina Puzriakova Tag watchlist tag was added to gene: EXOC7.
Early onset or syndromic epilepsy v2.149 EXOC7 Arina Puzriakova gene: EXOC7 was added
gene: EXOC7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to Brain atrophy; Seizures; Developmental delay; Microcephaly
Added comment: PMID: 32103185 (2020) - 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Literature
Early onset or syndromic epilepsy v2.148 TRIP13 Zornitza Stark changed review comment from: Phenotype is highly variable but seizures reported in 2/6 cases.; to: Phenotype is highly variable but seizures reported in 2/6 cases. Note 5/6 families had the same homozygous variant, p.Arg354X, suggestive of founder effect.
Early onset or syndromic epilepsy v2.148 TRIP13 Zornitza Stark edited their review of gene: TRIP13: Changed rating: AMBER
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Classified gene: LMBRD2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Gene: lmbrd2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.147 LMBRD2 Arina Puzriakova Tag for-review tag was added to gene: LMBRD2.
Early onset or syndromic epilepsy v2.147 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Early onset or syndromic epilepsy v2.146 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least four unrelated individuals with three distinct TUBGCP2 variants, associated with generalised seizures.
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.145 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive microcephaly (4/4), developmental delay (5/5, mild-severe), generalised seizures (4/5, onset at 6yrs-9m, 5m, and 7m). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Classified gene: DDC as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Added comment: Comment on list classification: This is a metabolic gene and is green on the Inborn errors of metabolism (https://panelapp.genomicsengland.co.uk/panels/467/gene/DDC/), therefore it is rated as amber on the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Gene: ddc has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.143 DDC Sarah Leigh Tag for-review tag was added to gene: DDC.
Early onset or syndromic epilepsy v2.143 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: 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: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.143 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Early onset or syndromic epilepsy v2.143 MADD Konstantinos Varvagiannis gene: MADD was added
gene: MADD was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MADD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MADD were set to 28940097; 29302074; 32761064
Phenotypes for gene: MADD were set to Global developmental delay / Intellectual disability / Seizures; Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system
Penetrance for gene: MADD were set to Complete
Review for gene: MADD was set to GREEN
Added comment: There are 3 reports on the phenotype of individuals with biallelic pathogenic MADD variants. Clinical presentation appears to be relevant for inclusion of this gene in both ID and epilepsy panels. A recent study provides extensive clinical details and suggests that the phenotype may range from DD/ID to a severe pleiotropic disorder characterized by severe DD (and ID), sensory and autonomic dysfunction, exocrine and endocrine insufficiency and haematological anomalies). Seizures have been reported in several individuals with either presentation.
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Anazi et al (2017 - PMID: 28940097) identified MADD as a potential ID gene. The authors described a girl with profound DD and seizures among other features. The child, deceased at the age of 14m, was born to consanguineous Saoudi parents and was found to harbour a homozygous missense SNV [NM_003682.3:c.2930T>G:p.(Val977Gly)]. Through GeneMatcher, the authors identified a further 6 y.o. girl, compound heterozygous for a missense and a stopgain variant [NM_003682.3:c.593G>A:p.(Arg198His) and c.979C>T:p.(Arg327*)]. The child had normal development and milestones until the age of 15m, when she demonstrated delay in speech, social interactions, poor eye contact and was later diagnosed with ASD.
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Hu et al (2019 - PMID: 29302074) provided details on a 22- and 30- y.o. female born to (reportedly) unrelated parents. Formal evaluation (WAIS-IV) suggested ID in the mild to moderate range(IQs of 50 and 60 respectively). Both were homozygous for an indel [NM_003682:c.3559del / p.(Met1187*)].
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Schneeberger et al (2020 - PMID: 32761064) report on 23 affected subjects.

The authors categorized the phenotypes in 2 groups. 9 individuals belonging to group 1 presented with hypotonia, DD (9/9) with speech impaiment, ID (5/5) and seizures (6/9). 14 patients, belonging to group 2 had DD (9/9 - severe), ID (3/3), seizures (9/14), endo- and exocrine dysfunction, impairment of sensory and autonomic nervous system, haematological anomalies. The course was fatal in some cases, within the later group. Some facial features appeared to be more frequent (e.g. full cheeks, small mouth, tented upper lip - small palpebral fissures in some, etc). Genital anomalies were also common in males from both groups.

All were found to harbor biallelic MADD variants (21 different - missense and pLoF SNVs as well as an intragenic deletion). Variants in all cases affected all 7 isoforms. Data did not allow genotype-phenotype correlations e.g. individuals with missense and a pLoF variant (in trans) were identified within either group.

Studies using patient-derived fibroblasts supported the role of the variants, e.g. lower mRNA levels for those where NMD would apply, deficiency or drastic reduction of the protein upon immunobloting (also the case for missense variants) and mRNA analyses demonstrating aberrant transcripts for 2 relevant variants.

MADD encodes the MAPK-activating protein containing a death domain implicated among others in neurotransmission (Rab3 GEF and effector playing a role in formation/trafficking of synaptic vessicles), cell survival (pro-apoptotic effects/protection against apoptosis upon TNF-a treatment), etc. The gene has relevant expression pattern in fetal and adult brain (discussed by Hu et al).

Studies in patient fibroblasts provide evidence of reduced activation of MAP kinases ERK1/2 upon treatment with TNF-a, activation of the intrinsic (TNF-a-dependent-) apoptosis. MADD deficiency was shown to result to decreased EGF endocytosis (likely mediated by Rab3).

Mouse model further supports the role of MADD (summary by MGI: "Mice homozygous for a knock-out allele die shortly after birth due to respiratory failure, are hyporesponsive to tactile stimuli, and exhibit defects in neurotransmitter release with impaired synaptic vesicle trafficking and depletion of synaptic vesicles at the neuromuscular junction.").

You may consider inclusion in other gene panels e.g. for hematologic (low Hb and thrombocytopenia in several) or GI (e.g diarrhea) disorders.
Sources: Literature
Early onset or syndromic epilepsy v2.143 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Penetrance for gene: FAM50A were set to unknown
Review for gene: FAM50A was set to AMBER
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference.

The authors provide clinical details on 6 affected individuals from 5 families.

Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6).

In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam).

In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40).

Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3).

Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones).

Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt.

Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish.

Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins.

Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism.

Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).

Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families).
Sources: Literature
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Tag for-review tag was added to gene: TET3.
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh edited their review of gene: TET3: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Added comment: Comment on phenotypes: This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#). to Beck-Fahrner syndrome 618798
Early onset or syndromic epilepsy v2.142 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face to This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Classified gene: TET3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases. Seizures were reported in 2 unrelated cases of monoallelic and 2 unrelated cases of biallelic 2 cases TET3 DNA Demethylation Disorder.
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Gene: tet3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.140 TET3 Sarah Leigh Tag watchlist tag was added to gene: TET3.
Early onset or syndromic epilepsy v2.140 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Early onset or syndromic epilepsy v2.139 TET3 Sarah Leigh Mode of inheritance for gene: TET3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.138 AFF3 Sarah Leigh Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh edited their review of gene: OXR1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Tag for-review tag was added to gene: OXR1.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Classified gene: OXR1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Gene: oxr1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.136 OXR1 Sarah Leigh Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Early onset or syndromic epilepsy v2.135 OXR1 Sarah Leigh Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh edited their review of gene: MTHFS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Tag for-review tag was added to gene: MTHFS.
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Classified gene: MTHFS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases.
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Gene: mthfs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.133 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Classified gene: EIF2AK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Added comment: Comment on list classification: Currently, only half of reported cases present seizures which seem to follow after developmental concerns are apparent. Therefore rated Amber, awaiting further publications/clinical evidence to elucidate the contribution of EIF2AK2 variants to this phenotype.
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Gene: eif2ak2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.132 EIF2AK2 Arina Puzriakova gene: EIF2AK2 was added
gene: EIF2AK2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877
Added comment: Association with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation reported in both OMIM and G2P (probable).

PMID: 32197074 (2020) - Distinct de novo missense variants were identified in eight unrelated individuals who all share a notable phenotypic overlap of developmental delay, cognitive impairment, white matter alterations, dysarthria or lack of speech, and neurologic regression with febrile illness. Other variable features included hypotonia (7/8), hypertonia (7/8), ataxia (6/8), dystonia (5/8), tremor (3/8) and seizures (4/8). Functional data confirm reduced kinase activity compared to the wildtype protein product, and authors predict a dominant-negative effect.
Sources: Literature
Early onset or syndromic epilepsy v2.131 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: ; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.131 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Early onset or syndromic epilepsy v2.131 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Early onset or syndromic epilepsy v2.131 LMAN2L Arina Puzriakova Classified gene: LMAN2L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.131 LMAN2L Arina Puzriakova Gene: lman2l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.130 LMAN2L Arina Puzriakova gene: LMAN2L was added
gene: LMAN2L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMAN2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMAN2L were set to 31020005; 26566883
Phenotypes for gene: LMAN2L were set to Intellectual disability; Epilepsy
Review for gene: LMAN2L was set to AMBER
Added comment: PMID: 26566883 (2015) - One consanguineous family with 7 individuals with ID and epilepsy. Five individuals presented mild epileptic seizures in the first year of life, until the age of 5 years when seizures stopped spontaneously without any medication. Typical seizure episodes lasted for 3 to 5 min. Epilepsy was also reported in two other family members, who died at the age of 7 and 16 years and therefore could not be included in the study. A homozygous LMAN2L missense variant (c.158 G>A, p.R53Q) segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies.

PMID: 31020005 (2019) - One non-consanguineous family with 4 affected, harbouring a heterozygous frameshift LMAN2L variant (c.1073delT, p.Phe358Serfs*16) which segregated with disease in the family. All suffered generalised tonic‐clonic seizures in childhood, however all had undergone remission with normalized EEG by adolescence. Functional studies show the variant eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane.
Sources: Literature
Early onset or syndromic epilepsy v2.129 TUBB2A Arina Puzriakova reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571897; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.129 SETD1B Arina Puzriakova reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1AS null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams Tag for-review tag was added to gene: EEF1A2.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams edited their review of gene: EEF1A2: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 32160274
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams commented on gene: EEF1A2
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Classified gene: HERC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 distinct variants in unrelated cases presenting the relevant phenotype.
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Gene: herc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.128 HERC2 Arina Puzriakova Tag for-review tag was added to gene: HERC2.
Early onset or syndromic epilepsy v2.128 SEC31A Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature
Early onset or syndromic epilepsy v2.128 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 32699352
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Penetrance for gene: LARS were set to Complete
Review for gene: LARS was set to GREEN
Added comment: Please consider inclusion with amber/green rating in the current panel.

Biallelic pathogenic LARS1 variants cause Infantile liver failure syndrome 1, MIM# 615438.

Lenz et al (2020 - PMID: 32699352) review the phenotype of 25 affected individuals from 15 families.

Seizures occurred in 19/24 and were commonly associated with infections. Encephalopathic episodes (in 13 patients) accompanied by seizures up to status epilepticus occurred independently of hepatic decompensation.

In addition 22/24 presented with neurodevelopmental delay. The authors comment that cognitive impairment was present in 13/17 individuals (mild-severe) whereas most presented with learning disabilities.

These patients will be most likely investigated for their liver disease (although presentation was highly variable and/or very mild in few).

The gene encodes a cytoplasmic amino-acyl tRNA synthetase (ARS) with neurologic manifestations observed in almost all patients (and seizures / DD and ID common to other disorders due to mutations in other genes encoding for ARSs).

Please note that the HGNC approved symbol for this gene is LARS1.
Sources: Literature
Early onset or syndromic epilepsy v2.128 ASTN1 Arina Puzriakova edited their review of gene: ASTN1: Changed rating: RED
Early onset or syndromic epilepsy v2.128 EIF2A Arina Puzriakova gene: EIF2A was added
gene: EIF2A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EIF2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2A were set to 31130284
Phenotypes for gene: EIF2A were set to Intellectual disability; Seizures; ASD
Review for gene: EIF2A was set to RED
Added comment: Gene is not associated with any phenotype in OMIM or G2P.

PMID: 31130284 - Distinct homozygous variants were identified in two cases presenting an overlapping phenotype of ID and epilepsy (intractable in one patient), as part of a large screening study of a highly consanguineous Saudi population. However, no segregation or follow-up functional studies were conducted to validate the variants, and there is currently no other publication data supporting this candidate gene and the relationship with epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Classified gene: ASTN1 as Red List (low evidence)
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Added comment: Comment on list classification: Epilepsy only reported in a single patient. Further cases required to ascertain the contribution of ASTN1 variants to this phenotype.
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Gene: astn1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.126 ASTN1 Arina Puzriakova reviewed gene: ASTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26539891, 27431290, 29706646; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.126 LIPT1 Sarah Leigh Publications for gene: LIPT1 were set to 29681092; 31042466
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Classified gene: LIPT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Added comment: Comment on list classification: This metabolic gene is associated with Lipoyltransferase 1 deficiency 616299 in OMIM and as a probable gene for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. In addition to the six variants that have been reported in five cases Lipoyltransferase 1 deficiency 616299, two further variants have been reported in two unrelated cases of Lipoyltransferase 1 deficiency 616299 who also have epieptic seizures (PMID 29681092; 31042466).
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Gene: lipt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.124 LIPT1 Sarah Leigh gene: LIPT1 was added
gene: LIPT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LIPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIPT1 were set to 29681092; 31042466
Phenotypes for gene: LIPT1 were set to Lipoyltransferase 1 deficiency 616299
Review for gene: LIPT1 was set to AMBER
Added comment: Sources: Literature
Early onset or syndromic epilepsy v2.123 PTPN23 Eleanor Williams Added comment: Comment on phenotypes: Added disease association from OMIM.
Early onset or syndromic epilepsy v2.123 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Rare severe autosomal-recessive developmental and epileptic encephalopathy to Rare severe autosomal-recessive developmental and epileptic encephalopathy; Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity MIM#618890
Early onset or syndromic epilepsy v2.122 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures, which were intractable in three of the individuals. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function

This gene has also been added to the Intellectual Disability and Severe Microcephaly panels with a suggested Green classification at the next major review.
Early onset or syndromic epilepsy v2.122 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964)
Penetrance for gene: TMEM106B were set to Complete
Mode of pathogenicity for gene: TMEM106B 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: TMEM106B was set to AMBER
Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature
Early onset or syndromic epilepsy v2.122 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to GREEN
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Early onset or syndromic epilepsy v2.122 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Penetrance for gene: ABCA2 were set to Complete
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808).

There are 3 relevant publications (01-07-2020) :
- Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations.
- Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures.
- Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype.

All subjects harbored biallelic pLoF variants.

N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency.

Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Literature
Early onset or syndromic epilepsy v2.122 HERC2 Konstantinos Varvagiannis gene: HERC2 was added
gene: HERC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HERC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HERC2 were set to 23065719; 23243086; 30902390; 32571899; 27848944; 26077850; 27759030
Phenotypes for gene: HERC2 were set to Mental retardation, autosomal recessive 38 (MIM 615516)
Penetrance for gene: HERC2 were set to Complete
Review for gene: HERC2 was set to GREEN
Added comment: Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.
Sources: Literature
Early onset or syndromic epilepsy v2.122 SEC31A Sarah Leigh gene: SEC31A was added
gene: SEC31A was added to Genetic epilepsy syndromes. Sources: Literature
watchlist tags were added to gene: SEC31A.
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to 30464055
Phenotypes for gene: SEC31A were set to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651
Review for gene: SEC31A was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature
Early onset or syndromic epilepsy v2.121 RUSC2 Sarah Leigh edited their review of gene: RUSC2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrelated cases. No functional studies have been reported, although authors of PMID 27612186 suggest that p.R866* results in total loss of function as the sibs biallelic with this variant have a more severe phenotype than the case who is biallelic for p.R1318*, which they conclude results in partial loss of function. Refractory seizures were seen in the sibs with p.R866*.; Changed rating: RED
Early onset or syndromic epilepsy v2.121 RUSC2 Sarah Leigh Phenotypes for gene: RUSC2 were changed from to Mental retardation, autosomal recessive 61 617773
Early onset or syndromic epilepsy v2.120 RUSC2 Sarah Leigh Publications for gene: RUSC2 were set to
Early onset or syndromic epilepsy v2.119 OTUD7A Sarah Leigh commented on gene: OTUD7A: Review by Zornitza Stark on Intellectual disability panel https://panelapp.genomicsengland.co.uk/panels/285/: One patient with severe global developmental delay, language impairment and epileptic encephalopathy reported. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Mouse model and other data support the role of this gene in neurodevelopmental phenotypes but nevertheless, single family to date.
Early onset or syndromic epilepsy v2.119 OTUD7A Sarah Leigh gene: OTUD7A was added
gene: OTUD7A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, intellectual disability
Review for gene: OTUD7A was set to RED
Added comment: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Sources: Literature
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Classified gene: GALNT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.117 GALNT2 Sarah Leigh gene: GALNT2 was added
gene: GALNT2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: GALNT2.
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 27508872; 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation, type IIt 618885
Review for gene: GALNT2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Sources: Literature
Early onset or syndromic epilepsy v2.116 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.116 ADARB1 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 v2.116 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.115 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh changed review comment from: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature; to: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous (p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Classified gene: ALG14 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Gene: alg14 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.114 ALG14 Sarah Leigh gene: ALG14 was added
gene: ALG14 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: ALG14.
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 28733338; 23404334; 30221345
Phenotypes for gene: ALG14 were set to Congenital myasthenic syndrome; ?Myasthenic syndrome, congenital, 15, without tubular aggregates, 616227
Review for gene: ALG14 was set to AMBER
Added comment: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature
Early onset or syndromic epilepsy v2.113 ADARB1 Arina Puzriakova gene: ADARB1 was added
gene: ADARB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Review for gene: ADARB1 was set to GREEN
Added comment: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures, which were intractable in three of the individuals. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature
Early onset or syndromic epilepsy v2.113 SLC5A6 Sarah Leigh commented on gene: SLC5A6: Watchlist tag was added to take account of the potential therapeutic options of this cause of seizures.
Early onset or syndromic epilepsy v2.113 SLC5A6 Sarah Leigh Tag watchlist tag was added to gene: SLC5A6.
Early onset or syndromic epilepsy v2.113 PTEN Sarah Leigh reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.113 PTEN Sarah Leigh Tag mosaicism was removed from gene: PTEN.
Tag somatic was removed from gene: PTEN.
Tag for-review tag was added to gene: PTEN.
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh commented on gene: NRROS: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh Classified gene: NRROS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh Gene: nrros has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.112 NRROS Sarah Leigh gene: NRROS was added
gene: NRROS was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: NRROS.
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075; 28459434
Phenotypes for gene: NRROS were set to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Review for gene: NRROS was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Sources: Literature
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh edited their review of gene: CDK19: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Sources: Literature; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417). PMID 20563892 reports a de novo pericentric inversion in chromosome 6 with breakpoints in 6p12.1 and 6q21 reported in a female patient with microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation. Supporting in vitro and drosophila model data also included.
Sources: Literature
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh Phenotypes for gene: CDK19 were changed from to Epileptic encephalopathy, early infantile 87 618916
Early onset or syndromic epilepsy v2.110 CDK19 Sarah Leigh Publications for gene: CDK19 were set to
Early onset or syndromic epilepsy v2.109 CDK19 Sarah Leigh Classified gene: CDK19 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.109 CDK19 Sarah Leigh Gene: cdk19 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.108 CDK19 Sarah Leigh gene: CDK19 was added
gene: CDK19 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CDK19.
Mode of inheritance for gene: CDK19 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: CDK19 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Sources: Literature
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh edited their review of gene: CACNB4: Added comment: There is enough evidence for this gene to be rated GREEN for epilepsy at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh Tag for-review tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to 20561025; 20378313; 10762541; 32176688 25529582
Early onset or syndromic epilepsy v2.106 CACNB4 Sarah Leigh Phenotypes for gene: CACNB4 were changed from to {Epilepsy, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855; Intellectual disability
Early onset or syndromic epilepsy v2.105 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to
Early onset or syndromic epilepsy v2.104 CACNB4 Sarah Leigh Mode of inheritance for gene: CACNB4 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Classified gene: CACNB4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional data.
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.102 MCM3AP Eleanor Williams gene: MCM3AP was added
gene: MCM3AP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MCM3AP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM3AP were set to 32202298
Phenotypes for gene: MCM3AP were set to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development 618124
Review for gene: MCM3AP was set to RED
Added comment: PMID: 32202298 - Woldegebriel et al 2020 - report a further two families, one in the Netherlands and one in Estonia, with probands with compound heterozygous variants in MCM3AP and a peripheral neuropathy with or without impaired intellectual development (MIM 618124) phenotype. The two siblings from the Estonian family had severe generalized epilepsy and mild spastic diplegia. Functional studies using skin fibroblasts from these and other affected patients showed that disease variants result in depletion of GANP (encoded by MCM3AP) except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants.
Sources: Literature
Early onset or syndromic epilepsy v2.101 DMXL2 Eleanor Williams Added comment: Comment on mode of inheritance: All cases with epilepsy have been biallelic
Early onset or syndromic epilepsy v2.101 DMXL2 Eleanor Williams Mode of inheritance for gene: DMXL2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Classified gene: DMXL2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Added comment: Comment on list classification: Promoting to amber for now. There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Gene: dmxl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.99 DMXL2 Eleanor Williams Phenotypes for gene: DMXL2 were changed from Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113 to Epileptic encephalopathy, early infantile, 81, MIM 618663; Ohtahara syndrome
Early onset or syndromic epilepsy v2.98 DMXL2 Eleanor Williams Mode of inheritance for gene: DMXL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.97 DMXL2 Eleanor Williams reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31688942, 30237576; Phenotypes: Ohtahara syndrome, Epileptic encephalopathy, early infantile, 81, 618663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.97 PIGS Sarah Leigh Tag watchlist tag was added to gene: PIGS.
Early onset or syndromic epilepsy v2.97 PIGS Sarah Leigh Phenotypes for gene: PIGS were changed from Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143 to Glycosylphosphatidylinositol biosynthesis defect 18 618143
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases, seizures were evident in 2 unrelated cases.
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Classified gene: PIGK as Green List (high evidence)
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Added comment: Comment on list classification: Zornitza Stark loaded PIGK as a green gene on Intellectual disability (https://panelapp.genomicsengland.co.uk/panels/285/gene/PIGK/#!review). and suggested that it was also suitable for the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Gene: pigk has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.94 PIGK Sarah Leigh gene: PIGK was added
gene: PIGK was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: PIGK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGK were set to 32220290
Phenotypes for gene: PIGK were set to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Review for gene: PIGK was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 7 variants reported in at least 5 unrelated cases with seizures.
Sources: Expert list
Early onset or syndromic epilepsy v2.93 DDC Lothar Schlueter edited their review of gene: DDC: Changed publications: 28100251, 30952622, 20505134, 19172410, 32369189, 18754761, 32409695
Early onset or syndromic epilepsy v2.93 DDC Lothar Schlueter changed review comment from: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures.
Sources: Literature; to: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures. In recent cohort analysis they concluded that about 30% of AADCD patients have been initially diagnosed with epilepsy (Pearson et al.2020, Wen et al. 2020)
Sources: Literature

Update: Added more literature
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo, however, one of these cases also had a 290Kb deletion at
13q12.11.
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.92 CDC42BPB Sarah Leigh Added comment: Comment on mode of inheritance: Unknown mode of inheritance has been assigned as the majority of variants in this gene (11/14) in PMID 32031333 are de novo.
Early onset or syndromic epilepsy v2.92 CDC42BPB Sarah Leigh Mode of inheritance for gene: CDC42BPB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo.
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Green List (high evidence)
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and of these cases were de novo.
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.90 CDC42BPB Sarah Leigh Added comment: Comment on phenotypes: CDC42BPB-related Neurodevelopmental Disorder is assigned by Gen2Phen.
Early onset or syndromic epilepsy v2.90 CDC42BPB Sarah Leigh Phenotypes for gene: CDC42BPB were changed from Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to CDC42BPB-related Neurodevelopmental Disorder; Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Early onset or syndromic epilepsy v2.89 GRM7 Zornitza Stark gene: GRM7 was added
gene: GRM7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 32286009; 32248644
Phenotypes for gene: GRM7 were set to Epilepsy, microcephaly, developmental delay
Review for gene: GRM7 was set to GREEN
gene: GRM7 was marked as current diagnostic
Added comment: Eleven individuals from six families reported, three different homozygous variants (two missense, one LoF). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Supportive mouse model.
Sources: Literature
Early onset or syndromic epilepsy v2.89 STARD7 Rebecca Foulger changed review comment from: Comment on list classification: Added as Amber awaiting clinical review as to whether gene and/or a new STR should be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.; to: Comment on list classification: Added gene as Amber based on advice from Genomics England Clinical team: the causative variants are the repeat expansion, and therefore the STR will be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Classified gene: SRPX2 as Red List (low evidence)
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Added comment: Comment on list classification: Based evidence that the gene / disease associate has been refuted (PMID 24995671).
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Gene: srpx2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Classified gene: SNX27 as Green List (high evidence)
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited on 05/23/2012) or in Gen2Phen. However, five variants in three unrelated cases (displaying seizures), together with supportive functional studies and mouse model.
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Gene: snx27 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.87 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to 31754459; 27904971
Early onset or syndromic epilepsy v2.86 SLC5A6 Sarah Leigh Phenotypes for gene: SLC5A6 were changed from Developmental delay; epilepsy; neurodegeneration to SLC5A6-related Neurodevelopmental Disorder
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 4 variants published in two unrelated famililies (3 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies. One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459).
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.84 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
Early onset or syndromic epilepsy v2.84 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Classified gene: SETD5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Added comment: Comment on list classification: Review article PMID 29484850 reports seizures in 10/42 (23.8%) cases of autism spectrum disorders carrying heterozygous SETD5 variants.
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Gene: setd5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.83 SETD5 Sarah Leigh Publications for gene: SETD5 were set to 25138099; 24680889
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger changed review comment from: PMID:27000257. Alrayes et al., 2016 report a homozygous frameshift variant in AGMO- p.(Glu324LysfsTer12) in 2 brothers from a consanguineous Saudi family with syndromic microcephaly, and global developmental delay. Epilepsy is not mentioned amongst their phenotypes.; to: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family. Epilepsy is not mentioned amongst their phenotypes.
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Classified gene: AGMO as Red List (low evidence)
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Amber by Zornitza Stark. Only 1 of the 3 individuals from PMIDs:31555905 and 27000257 is reported with epilepsy. Therefore rated Red awaiting further evidence.
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Gene: agmo has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl had variants p.Trp130Ter & p.Gly238Cys. The boy had variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. They demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl had variants p.Trp130Ter & p.Gly238Cys. The boy had variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger commented on gene: AGMO: PMID:27000257. Alrayes et al., 2016 report a homozygous frameshift variant in AGMO- p.(Glu324LysfsTer12) in 2 brothers from a consanguineous Saudi family with syndromic microcephaly, and global developmental delay. Epilepsy is not mentioned amongst their phenotypes.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger Phenotypes for gene: AGMO were changed from microcephaly; intellectual disability; epilepsy to microcephaly; intellectual disability; epilepsy; generalized tonic-clonic seizures
Early onset or syndromic epilepsy v2.80 AGMO Rebecca Foulger commented on gene: AGMO
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger changed review comment from: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype.; to: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype. Therefore updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Classified gene: SEMA6B as Green List (high evidence)
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype.
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Gene: sema6b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.79 SEMA6B Rebecca Foulger Added comment: Comment on mode of pathogenicity: The authors of PMID:32169168 suggest a dominant-negative or gain-of-function effect rather than haploinsufficiency.
Early onset or syndromic epilepsy v2.79 SEMA6B Rebecca Foulger Mode of pathogenicity for gene: SEMA6B was changed from None to Other
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger changed review comment from: PMID:32169168. In 4 unrelated patients (2 Japanese, ISraeli and Malaysian) with progressive myoclonic epilepsy, Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene. Variants were predicted to result in truncated proteins. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. In an animal model, the authors found that zebrafish with truncating sema6b variants were more susceptible to seizures.; to: PMID:32169168. In 4 unrelated patients (2 Japanese, 1 Israeli and 1 Malaysian) with progressive myoclonic epilepsy, Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene. Variants were predicted to result in truncated proteins. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. In an animal model, the authors found that zebrafish with truncating sema6b variants were more susceptible to seizures.
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger commented on gene: SEMA6B
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger Phenotypes for gene: SEMA6B were changed from Progressive myoclonic epilepsy to Epilepsy, progressive myoclonic, 11, 618876
Early onset or syndromic epilepsy v2.77 KAT8 Rebecca Foulger Mode of pathogenicity for gene: KAT8 was changed from None to Other
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger Tag missense tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger commented on gene: KAT8: Added 'missense' tag because all de novo variants in PMID:31794431 are missense. Note that for the biallelic case in the same paper, one of the variants is nonsense.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.; to: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. Not yet associated with a disorder in OMIM or G2P. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.75 KAT8 Rebecca Foulger Added comment: Comment on mode of inheritance: Individual T9 inherited biallelic variants from her asymptomatic parents. Her sister carried 1 variant and showed no obvious symptoms. This may be due to incomplete genetic penetrance, or the two variants act differently from the de novo heterozygous variants identified. Since this is the only example of biallelic variants so far, I have set the MOI to 'monoallelic'.
Early onset or syndromic epilepsy v2.75 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Classified gene: KAT8 as Green List (high evidence)
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Gene: kat8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Tag watchlist was removed from gene: TIMM50.
Tag for-review tag was added to gene: TIMM50.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger commented on gene: TIMM50: Removed 'watchlist' tag, since this gene is no longer Amber. Note that TIMM50 is Green on the Intellectual disability panel (V3.73) and on the IEM panel (V2.8). Therefore added 'for-review' tag for discussion of alignment of epilepsy and metabolism panels.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Deleted their comment
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Classified gene: TIMM50 as Green List (high evidence)
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Added comment: Comment on list classification: Previous Amber rating was based on insufficient evidence (PMID:27573165/Shahrour et al 2017 who report 4 cases from 2 consanguineous families, plus a conference abstract reporting 3 further siblings). Zornitza Stark and Konstantinos Varvagiannis point out 2 new papers each with an additional case of TIMM50 variants in epileptic patients. Therefore have updated the rating from Amber to Green.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Gene: timm50 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.72 TIMM50 Rebecca Foulger Phenotypes for gene: TIMM50 were changed from 3-methylglutaconic aciduria, type IX, 617698; intellectual disability and seizure; epilepsy and developmental delay to 3-methylglutaconic aciduria, type IX, 617698; intellectual disability and seizure; epilepsy and developmental delay; epileptic encephalopathy
Early onset or syndromic epilepsy v2.71 TIMM50 Rebecca Foulger Publications for gene: TIMM50 were set to 27573165; Serajee F, Hu A. A distinct type of 3-methylglutaconic aciduria due to a mutation in the Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene. ASHG meeting 2015 Abstract Nr 2299, 2015.
Early onset or syndromic epilepsy v2.70 TIMM50 Rebecca Foulger Added comment: Comment on publications: 27573165; 30190335; 31058414; Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T)
Early onset or syndromic epilepsy v2.70 TIMM50 Rebecca Foulger Publications for gene: TIMM50 were set to 27573165; Serajee F, Hu A. A distinct type of 3-methylglutaconic aciduria due to a mutation in the Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene. ASHG meeting 2015 Abstract Nr 2299, 2015.
Early onset or syndromic epilepsy v2.69 TIMM50 Rebecca Foulger commented on gene: TIMM50: PMID:31058414 (Tort et al., 2019) report compound het TIMM50 variants in a boy with 3-MGA-uria (p.Arg114Gln, p.Gly269Ser). At 3.5 months, a diagnosis of West syndrome was made, and he showed a good response to ACTH and antiepileptic treatment.
Early onset or syndromic epilepsy v2.69 TIMM50 Rebecca Foulger commented on gene: TIMM50: PMID:30190335. Reyes et al., 2018 report a third unrelated family. WES identified compound het pathogenic TIMM50 variants (p.S112* and p.G190A) in an infant with rapidly progressive, severe encephalopathy, including infantile seizures and severe epilepsy. Sanger sequencing confirmed the two variants in the proband and showed that the two parents were each heterozygous for one of them. In the ExAc database, the p.G190A variant was present in <200,000 alleles, with the nonsense change not reported.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence (PMID:31735293). Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Classified gene: TMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Gene: tmx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.68 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy
Early onset or syndromic epilepsy v2.67 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730 to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures
Early onset or syndromic epilepsy v2.66 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Classified gene: TRAPPC4 as Green List (high evidence)
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Gene: trappc4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.64 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger Tag for-review tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger commented on gene: TRPM3: Excluding the individual harbouring a VUS, 7 individuals from PMID:31278393 (Dyment et al 2019) had the same de novo heterozygous variant in TRPM3 (p.Val837Met). This paper was considered when previously reviewed by GLHs. An Amber rating was chosen because public databases confirm that heterozygous loss-of-function variants of TRPM3 are observed in the general population (heterozygous gnomAD truncating variants occur in 18 of 25 canonical coding exons) and therefore the authors reasoned that simple haploinsufficiency was unlikely to be the mechanism of disease in their cohort. Therefore added 'for-review' tag, for reassesment at next GLH review.
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Classified gene: TUBA8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now, following Zornitza Stark's recent (Jan 2020) review. Additional case in PMID:31481326 (2020) but 2 Pakistani families (4 patients) previously reported may be related so remains a borderline case.
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.62 TUBA8 Rebecca Foulger commented on gene: TUBA8: Reviewing 2020 review comment by Zornitza noting additional publication: PMID:31481326. PMID:31481326. Lee et al., 2020 used targeted gene sequencing to identify malformations of cortical development in 81 patients. A homozygous TUBA8 p.Asn356ProfsTer63 variant was identified in one patient with 'Polymicrogyria, agenesis of CC, ventriculomegaly'. All patients had a confirmed diagnosis of epilepsy or DD.
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Classified gene: UGP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (MIM:618744) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Gene: ugp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.61 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; seizures
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger commented on gene: WDR45B: Added 'for-review' tag based on Zornitza's Green review on a gene where an Amber rating was decided at the last GLH review. Of the publications listed, PMID:28503735 (Suleiman et al) report 3 families (2 with seizures). PMID:21937992. Najmabadi et al 2011 identify WDR45B (WDR45L) as a candidate gene for ID. PMID:27431290 (Anazi et al., 2017) identified likely pathogenic alleles in WDR45B in ID individuals. Little information provided about WDR45B phenotype.
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Tag for-review tag was added to gene: WDR45B.
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Publications for gene: WDR45B were set to 21937992; 28503735
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Classified gene: ANKRD11 as Green List (high evidence)
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Added comment: Comment on list classification: Added to panel and reviewed Green by Tracy Lester. Although KBG syndrome has variable symptoms, epilepsy can be amongst the phenotypes. Based on literature review and Tracy Lester's review, updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Gene: ankrd11 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:27900361. Kleyner et al., 2016 describe a 13 yr old male with phenotypes including epilepsy, severe DD, distinct facial features and hand anomalies. Exome sequencing identified a novel de novo heterozygous LOF single bp duplication (c.6015dupA) in ANKRD11, leading to a premature stop codon.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:25543316. Samanta et al., 2015 report a 7 yr old boy with a ANKRD11 variant and developmental delay, focal epilepsy and behavioral concerns. He had frequent focal seizures but had enjoyed seizure-free state intermittently up to 9 months. He also had rare secondarily generalized tonic–clonic seizures, less than one episode in a year. After normal EEGs age 1 and 3, an EEG age 5 revealed EEG abnormalities.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger Publications for gene: ANKRD11 were set to 29565525
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger commented on gene: ANKRD11
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger Phenotypes for gene: ANKRD11 were changed from KBG syndrome to KBG syndrome, 148050
Early onset or syndromic epilepsy v2.56 ANKRD11 Tracy Lester gene: ANKRD11 was added
gene: ANKRD11 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: ANKRD11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD11 were set to 29565525
Phenotypes for gene: ANKRD11 were set to KBG syndrome
Penetrance for gene: ANKRD11 were set to Complete
Review for gene: ANKRD11 was set to GREEN
Added comment: KBG syndrome - EEG abnormalities, with or without seizures, have been reported in about 50% of affected individuals [Skjei et al 2007]. Age of onset can range from infancy to the teenage years [Low et al 2016]. The type of epilepsy is variable. Although tonic-clonic seizures are most common, no one specific type of epilepsy has been associated with the syndrome. Treatment with antiepileptic medication has proven effective in the majority of affected individuals. Many have remission of symptoms after adolescence [Lo-Castro et al 2013]. A few affected individuals have reportedly had severe seizures at a young age (described as infantile spasms / epileptic encephalopathy), in some cases drug resistant [C Ockeloen, personal communication; Samanta & Willis 2015]. - taken from GeneReviews, KBG syndrome, last updated Mar2018.
Penetrance of KBG syndrome is thought to be complete, but with variable expressivity.
Also associated with 16q24.3 deletions.
Sources: Expert Review
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger Tag for-review tag was added to gene: ALKBH8.
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger commented on gene: ALKBH8: Kept rating as Amber following advice from the Genomics England Clinical Team since Amber was the GLH opinion. This is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Have added 'for-review' tag to highlight the Green review from Zornitza. Note that Zornitza's review focuses on the differing ratings of ALKBH8 on the ID and Epilepsy panels, which I will align for consistency: no new evidence in the review.
Early onset or syndromic epilepsy v2.56 STARD7 Rebecca Foulger Phenotypes for gene: STARD7 were changed from Epilepsy, familial adult myoclonic, 2, 607876 to Epilepsy, familial adult myoclonic, 2, 607876; Familial adult myoclonic epilepsy-2; FAME-2
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Classified gene: STARD7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Added comment: Comment on list classification: Added as Amber awaiting clinical review as to whether gene and/or a new STR should be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Gene: stard7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.54 STARD7 Rebecca Foulger gene: STARD7 was added
gene: STARD7 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: STARD7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STARD7 were set to 11701600; 24114805; 31664034
Phenotypes for gene: STARD7 were set to Epilepsy, familial adult myoclonic, 2, 607876
Added comment: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.

OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' (previously associated with ADRA2B) is now associated with the STARD7 gene.
Sources: Literature, Other
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger commented on gene: ADRA2B: Added 'for-review' tag to alert GLH to downgraded rating.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Classified gene: ADRA2B as Red List (low evidence)
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Added comment: Comment on list classification: Downgraded rating from Amber to Red following PMID:31664034 (2019) publication that finds an alternative cause for epilepsy in the earlier reported patients, suggesting the the ADRA2B allele is not causative. MIM:607876 is now associated with a repeat expansion in STARD7, and not ADRA2B.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Gene: adra2b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.52 ADRA2B Rebecca Foulger Publications for gene: ADRA2B were set to 11701600
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:18231815: Direct sequencing of the ADRA2B gene in pedigrees from southern Italy that were described as having familial adult myoclonic epilepsy by Madia et al. (2008) did not reveal any pathogenic mutations.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Added comment: Comment on phenotypes: OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' is now associated with the STARD7 gene. Therefore removed MIM:607876 from the phenotype field of ADRA2B.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Phenotypes for gene: ADRA2B were changed from Epilepsy, myoclonic, familial adult, 2, 607876 to Cortical myoclonus and epilepsy
Early onset or syndromic epilepsy v2.50 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy; Spastic paraplegia 82, autosomal recessive, 618770
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel and rated Green by Konstantinos Varvagiannis. Green rating confirmed by Genomics England Clinical Team.
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; Intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707
Early onset or syndromic epilepsy v2.47 NR4A2 Konstantinos Varvagiannis gene: NR4A2 was added
gene: NR4A2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Phenotypes for gene: NR4A2 were set to Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Penetrance for gene: NR4A2 were set to unknown
Review for gene: NR4A2 was set to GREEN
Added comment: Seizures have been reported in at least 6 unrelated individuals with NR4A2 variants (not including cases with contiguous gene deletions spanning also this gene). Please consider inclusion with amber or green rating.
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Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.

Previous reviews for the ID panel:
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In a study of 457 autism families (Feliciano et al. - doi.org/10.1101/516625) the authors provide phenotypic information on a further individual with ASD and ID. This subject (SP0041645 - SPARK cohort) harbored a de novo frameshift variant (p.G231fs using ENST00000409572.1 as reference). Table 2 includes also the individual previously reported by Iossifov et al. who also presented with ASD and ID (11172.p1 - SSC cohort - PMID and details discussed below).
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Recent publications provide several lines of evidence that pathogenic NR4A2 variants cause DD/ID and/or autism spectrum disorder (ASD).

Lévy et al. (PMID: 29770430) summarize the phenotype of 2q24.1 microdeletions spanning either only NR4A2 [2 new patients as well as an individual reported by Reuter et al (PMID: 28544326)] or both NR4A2 and GPD2 (1 patient from this study as well as 2 further from Leppa et al. (PMID: 27569545) and Barge-Schaapveld et al. (PMID: 23554088)]. All these CNVs had occurred as de novo events. Common features included - among others - language impairment (6/6), ID (6/6), ASD (3/4) or abnormal behaviour (4/4).

As the authors note, NR4A2 belongs to a subfamily of highly conserved transcription factors. The gene is involved in several developmental processes, among others in neuronal development. Previous studies have also shown high expression in human fetal brain as well as a role in the development of language-related brain regions.

The absence of CNVs in general population encompassing NR4A2 (and presence of such CNVs spanning GDP2) as well as the minimal deletions confined to NR4A2 suggest that happloinsufficiency of NR4A2 is responsible for the DD/ID/ASD phenotypes. This is also supported by the HI index of 1.28 as well as pLI of 0.99.

Guo et al. (PMID: 30504930) report on a patient with de novo frameshift variant (p.P201Rfs*82) and provide a summary of individuals with de novo missense variants (schematic overview in suppl. fig. S4) previously reported in larger DD/ID/ASD cohorts, namely :

- The DDD study (PMID: 28135719) : subjects DDD4K.00386 (R312Q - https://decipher.sanger.ac.uk/ddd/research-variant/1e7622c3a0ba1b506c5808ccea46e759#overview) and DDD4K.04161 (R289P - https://decipher.sanger.ac.uk/ddd/research-variant/673e8e570d28dd0c5797ddafb22e53eb#overview)

- By Lelieveld et al. (PMID: 27479843) : patient with ID and V307G

- By Iossifov et al. (PMID: 25363768) : subject with ASD and Y275H.

[All these appear to cluster in a region of missense constraint : https://decipher.sanger.ac.uk/gene/NR4A2#overview/protein-info].

NR4A2 is not associated with any phenotype in OMIM, nor in G2P.

The gene is included in gene panels for intellectual disability offered by diagnostic laboratories (incl. Radboudumc).

As a result, it could be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Sources: Literature
Early onset or syndromic epilepsy v2.47 CUL3 Konstantinos Varvagiannis gene: CUL3 was added
gene: CUL3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUL3 were set to 32341456
Phenotypes for gene: CUL3 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496
Penetrance for gene: CUL3 were set to unknown
Review for gene: CUL3 was set to AMBER
Added comment: Epilepsy has been reported in at least 2 relevant individuals in the literature.
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Nakashima et al (2020 - PMID:32341456) provide clinical details on 3 unrelated individuals with de novo CUL3 variants.

Features included DD, variable degrees of ID (P1: severe, P3: mild, P2: NA although he displayed motor and severe speech and language delay and had severe learning difficulties). Two out of three had intractable seizures (onset 2 - 6 months). One presented with congenital heart defects (ASD, PV stenosis) and another submucosal palatoschisis/bifid uvula. There were no facial dysmorphisms reported.

CUL3 encodes Cullin-3, a core piece of the E3 ubiquitin ligase complex, thus playing a role in the ubiquitin-proteasome system. [ https://ghr.nlm.nih.gov/gene/CUL3 ]. Germline variants in some other Cullin family genes (eg. CUL4B, CUL7) cause disorders with ID as a feature.

The 3 individuals reported by Nakashima had variable previous investigations (karyotype, CMA, metabolic testing) which were non-diagnostic. Singleton or trio exome sequencing identified 2 frameshift and 1 missense variant (NM_003590.4:c.854T>C / p.Val285Ala), further confirmed with Sanger sequencing. De novo occurrence was confirmed by analysis of microsatellite markers in an individual with singleton ES.

While the frameshift variants were presumed to lead to NMD (not studied), studies in HEK293T cells suggested that the Val285Ala reduced binding ability with KEAP1, possibly leading to instability of the Cullin-RING ligase (CRL) complex and impairment of the ubiquitin-proteasome system.

In OMIM, the phenotype associated with heterozygous CUL3 mutations is Pseudohypoaldosteronism type IIE (PHA2E - # 614496). As OMIM and Nakashima et al comment, PHA2E-associated variants are clustered around exon 9, most lead to skipping of exon 9 and produce an in-frame deletion of 57 aa in the cullin homology domain. Few (probably 3) missense variants in exon 9 have also been reported. Individuals with PHA2E do not display DD/ID and conversely individuals with NDD did not display features of PHA2E.

Nakashima et al summarize the phenotypes associated with 12 further de novo CUL3 variants in the literature with most pLOF ones detected in individuals with autism and/or developmental disorders and in few cases with congenital heart disease. Few additional missense variants and a stoploss one have been reported in individuals with NDD and one in SCZ.

Heterozygous Cul3 (/tissue-specific) deletion in mice resulted in autism-like behavior. Cul3 deficient mice also demonstrated NMDAR hypofunction and decreased spine density. [PMIDs cited : 31455858, 31780330]

Overall haploinsufficiency is favored as the underlying mechanism of variants associated with NDD. Nakashima et al comment that the pathogenesis of missense variants remains unknown and/or that a dominant-negative effect on CRL may be possible.

Studies on larger cohorts reporting on individuals with relevant phenotypes due to de novo CUL3 variants (eg. DDD study - PMID: 28135719, Lelieveld et al - PMID: 27479843), are better summarized in denovo-db (after filtering for coding variants):

http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=cul3
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Please consider inclusion in other panels if appropriate (e.g. for ASD).
Sources: Literature
Early onset or syndromic epilepsy v2.47 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Early onset or syndromic epilepsy v2.47 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to AMBER
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Early onset or syndromic epilepsy v2.47 SPTBN4 Konstantinos Varvagiannis gene: SPTBN4 was added
gene: SPTBN4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519
Penetrance for gene: SPTBN4 were set to Complete
Review for gene: SPTBN4 was set to GREEN
Added comment: Biallelic pathogenic SPTBN4 variants cause Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519).

There are several reports on the phenotype of relevant affected individuals with severe/profound DD/ID in at least 9 individuals :

- Knierim et al (2017 - PMID: 28540413) [1 affected individual]
- Anazi et al (2017 - PMID: 28940097) [1]
- Wang et al (2018 - PMID: 29861105) [6]
- Pehlivan et al (2019 - PMID: 31230720) [1]

A recent article by Häusler et al (2019 - PMID: 31857255) describes the phenotype of 2 sibs, both presenting with motor and speech delay, although the older one had reportedly 'normal' cognitive performance allowing attendance of regular school at the age of 6 years.

Features include congenital hypotonia, severe DD and ID (in most as outlined above, ID was the primary indication for testing on several occasions), poor or absent reflexes and weakness secondary to axonal motor neuropathy, feeding and respiratory difficulties, hearing and visual impairment. Seizures have been reported in at least 4 unrelated individuals (3 by Wang et al / 1 by Pehlivan et al).

Variants in most cases were nonsense/frameshift although biallelic missense variants have also been reported. Sibs in the report by Häusler et al harbored a homozygous splicing variant.

SPTBN4 encodes a member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle.

βIV spectrin links ankyrinG and clustered ion channels (at axon initial segments and nodes of Ranvier) to the axonal cytoskeleton. Pathogenic variants are proposed to disrupt the cytoskeletal machinery controlling proper localization of ion channels and function of axonal domains where ion channels are normally clustered in high density. Among the evidence provided : nerve biopsies from an affected individual displayed reduced nodal Na+ channels and no nodal KCNQ2 K+ channels / Loss of AnkyrinG and βIV spectrin in animal model resulted in loss of KCNQ2- and KCNQ3- subunit containing K+ channels.

Apart from the ID / epilepsy panels please consider inclusion in other relevant ones.
Sources: Literature
Early onset or syndromic epilepsy v2.47 CDC42BPB Konstantinos Varvagiannis gene: CDC42BPB was added
gene: CDC42BPB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CDC42BPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDC42BPB were set to 32031333
Phenotypes for gene: CDC42BPB were set to Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Penetrance for gene: CDC42BPB were set to unknown
Review for gene: CDC42BPB was set to AMBER
Added comment: Chilton et al (2020 - PMID: 32031333) report on 14 individuals with missense and loss-of-function CDC42BPB variants.

Features included hypotonia (8/11), DD (12/13 - the 14th was a fetus), ID (7/13), ASD (8/12), clinical seizures (in 3 - a 4th had abnormal EEG without seizures), behavioral abnormalities. Variable non-specific dysmorphic features were reported in some (sparse hair being the most frequent - 4/8). Additional features were observed in few (=<4) incl. cryptorchidism, ophthalmological issues, constipation, kidney abnormalities, micropenis, etc.

All individuals had non-diagnostic prior genetic testing (incl. CMA, FMR1, MECP2, Angelman/Prader-Willi methylation studies, autism gene panel - suggesting relevance to the current panel) or metabolic testing.

Variants were identified following clinical exome sequencing with Sanger confirmation. Most occurred as de novo events (11/14) while inheritance was not available for few (3/14). Missense variants did not display (particular) clustering.

Almost all variants were absent from gnomAD and were predicted to be deleterious in silico (among others almost all had CADD scores >25).

As the authors comment, CDC42BPB encodes myotonic dystrophy-related Cdc42-binding kinase β (MRCKβ) a serine/threonine protein kinase playing a role in regulation of cytoskeletal reorganization and cell migration in nonmuscle cells (through phosporylation of MLC2).

Previous studies have demonstrated that it is ubiquitously expressed with prenatal brain expression.

The gene appears to be intolerant to pLoF (pLI of 1) as well as to missense variants (Z-score of 3.66).

CDC42BPB is a downstream effector of CDC42. Mutations of the latter cause Takenouchi-Kosaki syndrome with DD/ID and some further overlapping features (with CDC42BPB-associated phenotypes).

Homozygous Cdc42bpb KO in mouse appears to be nonviable (MGI:2136459). Loss of gek in the eyes of Drosophila results in disrupted growth cone targeting to the lamina (gek is the fly CDC42BPB ortholog).
Sources: Literature
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger changed review comment from: Comment on list classification: 2 Families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.; to: Comment on list classification: Added to panel and rated Amber by Zornitza Stark. 2 families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Classified gene: ADAM22 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Added comment: Comment on list classification: 2 Families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Gene: adam22 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.46 ADAM22 Rebecca Foulger Publications for gene: ADAM22 were set to 27066583; 30237576
Early onset or syndromic epilepsy v2.45 ADAM22 Rebecca Foulger commented on gene: ADAM22: Mouse model: Adam22-/- mice develop lethal seizures during the first postnatal weeks (e.g. PMID:15876356).
Early onset or syndromic epilepsy v2.45 ADAM22 Rebecca Foulger Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, 617933 to ?Epileptic encephalopathy, early infantile, 61, 617933
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:30237576 (Maddirevula et al., 2019) searched their database of clinical exomes for homozygous variants and report an 18 year old male with an Arg860* variant in ADAM22. Seizures started age 5 months with a focal seizure, and continued with generalized tonic clonic seizures and status epilepticus (Supplementary Table). His development was normal until 5 months when he had a slower gain of milestones. He has ID with severely delayed speech. Family history revealed ID and epilepsy in his old brother and in wider family.
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger commented on gene: ADAM22
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, MIM# 617933 to Epileptic encephalopathy, early infantile, 61, 617933
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Classified gene: CTU2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Added comment: Comment on list classification: Added to panel as Amber: Sufficient cases of seizures but 1 patient shows febrile seizures, and phenotype is variable. Plus just one study so far. Therefore Amber is appropriate, awaiting further evidence.
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.42 CTU2 Rebecca Foulger gene: CTU2 was added
gene: CTU2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 31301155
Phenotypes for gene: CTU2 were set to seizures; DREAM‐PL syndrome; Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
Added comment: Added to panel based on PMID:31301155 (Shaheen et al., 2019) who characterise the phenotype of 5 patients with DREAM-PL syndrome (Dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly) and summarise 4 Founder patients from previous studies (PMID:27480277, PMID:26633546). In total 6/10 patients had seizures including Generalized epilepsy, atypical absence seizures, complex febriles seizures and focal epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v2.41 CACNA1H Sarah Leigh Publications for gene: CACNA1H were set to 12891677; 32227660
Early onset or syndromic epilepsy v2.40 SAMD12 Zornitza Stark gene: SAMD12 was added
gene: SAMD12 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SAMD12 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SAMD12 were set to 30194086; 29507423
Phenotypes for gene: SAMD12 were set to Epilepsy, familial adult myoclonic, 1, MIM# 601068
Mode of pathogenicity for gene: SAMD12 was set to Other
Review for gene: SAMD12 was set to GREEN
gene: SAMD12 was marked as current diagnostic
Added comment: Repeat expansions of intronic TTTCA and TTTTA motifs within SAMD12 have been identified in over 50 Japanese and Chinese families. Most families with affected individuals were heterozygous however 4 patients from 3 families had homozygous repeat expansions, which was associated with a more severe phenotype. Western blot analysis showed decreased levels of the protein in patient brains. Note these were identified on long-read sequencing and may not be detectable by all assays.
Sources: Literature
Early onset or syndromic epilepsy v2.40 CACNA1H Sarah Leigh Phenotypes for gene: CACNA1H were changed from to Hyperaldosteronism, familial, type IV 617027; {Epilepsy, childhood absence, susceptibility to, 6} 611942; {Epilepsy, idiopathic generalized, susceptibility to, 6} 611942
Early onset or syndromic epilepsy v2.39 CACNA1H Sarah Leigh Added comment: Comment on publications: PMID 32227660 presents further evidence refuting a monogenic contribution of this gene to epilepsy.
Early onset or syndromic epilepsy v2.39 CACNA1H Sarah Leigh Publications for gene: CACNA1H were set to 12891677
Early onset or syndromic epilepsy v2.38 SEMA6B Zornitza Stark gene: SEMA6B was added
gene: SEMA6B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SEMA6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA6B were set to 32169168
Phenotypes for gene: SEMA6B were set to Progressive myoclonic epilepsy
Review for gene: SEMA6B was set to GREEN
Added comment: Five individuals from unrelated families reported with de novo variants in the last exon, escaping NMD.
Sources: Literature
Early onset or syndromic epilepsy v2.38 GAD1 Sarah Leigh Phenotypes for gene: GAD1 were changed from Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele to ?Cerebral palsy, spastic quadriplegic, 1 603513; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Early onset or syndromic epilepsy v2.37 GAD1 Sarah Leigh Publications for gene: GAD1 were set to https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Early onset or syndromic epilepsy v2.36 GAD1 Sarah Leigh Classified gene: GAD1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.36 GAD1 Sarah Leigh Gene: gad1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.35 GAD1 Sarah Leigh gene: GAD1 was added
gene: GAD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GAD1 were set to https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Phenotypes for gene: GAD1 were set to Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Review for gene: GAD1 was set to GREEN
Added comment: Five biallelic loss of function variants reported in 11 cases in 6 unrelated families. All cases had epilepsy syndrome, 10 profound intellectual disabilty (1 case died at day 9 of life) and other nuerological and developement features. Supportive functional studies were also presented.
Sources: Literature
Early onset or syndromic epilepsy v2.34 SETD1B Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases (PMID29322246; 31440728 31685013). Strucutral variants have also been reported that encompass SETD1B (PMID 20648245; 27106595; 25428890; 22369279).; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases who displayed epilepsy (PMID29322246; 31440728 31685013). Strucutral variants have also been reported that encompass SETD1B (PMID 20648245; 27106595; 25428890; 22369279).
Early onset or syndromic epilepsy v2.34 SETD1B Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases. Strucutral variants have also been reported that encompass SETD1B.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases (PMID29322246; 31440728 31685013). Strucutral variants have also been reported that encompass SETD1B (PMID 20648245; 27106595; 25428890; 22369279).
Early onset or syndromic epilepsy v2.34 SETD1B Sarah Leigh Publications for gene: SETD1B were set to 29322246; 31440728; 31685013
Early onset or syndromic epilepsy v2.33 SETD1B Sarah Leigh Classified gene: SETD1B as Green List (high evidence)
Early onset or syndromic epilepsy v2.33 SETD1B Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases. Strucutral variants have also been reported that encompass SETD1B.
Early onset or syndromic epilepsy v2.33 SETD1B Sarah Leigh Gene: setd1b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.32 SETD1B Sarah Leigh Phenotypes for gene: SETD1B were changed from to Epilepsy with myoclonic absences; intellectual disability
Early onset or syndromic epilepsy v2.31 SETD1B Sarah Leigh Added comment: Comment on mode of inheritance: Mode of inheritance obtained from Gen2Phen
Early onset or syndromic epilepsy v2.31 SETD1B Sarah Leigh Mode of inheritance for gene: SETD1B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.30 SETD1B Sarah Leigh Publications for gene: SETD1B were set to
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for intellectual disability. At least 4 variants reported, 3 de novo and 1 segrating in a family.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for intellectual disability. At least 4 variants reported, 3 de novo and 1 segregating in a family.
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh Classified gene: SETD1A as Green List (high evidence)
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for intellectual disability. At least 4 variants reported, 3 de novo and 1 segrating in a family.
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh Gene: setd1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.28 SERPINI1 Sarah Leigh Classified gene: SERPINI1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.28 SERPINI1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in unrelated cases.
Early onset or syndromic epilepsy v2.28 SERPINI1 Sarah Leigh Gene: serpini1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.27 SERPINI1 Sarah Leigh Phenotypes for gene: SERPINI1 were changed from Encephalopathy, familial, with neuroserpin inclusion bodies MIM#604218 to Encephalopathy, familial, with neuroserpin inclusion bodies 604218
Early onset or syndromic epilepsy v2.26 RNF13 Sarah Leigh Classified gene: RNF13 as Green List (high evidence)
Early onset or syndromic epilepsy v2.26 RNF13 Sarah Leigh Gene: rnf13 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.25 RNF13 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies.; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies. Gain-of-function mechanism has been reported, therefore the mutational spectrum may be limited and is still to be determined through further cases or further functional studies (view of Helen Britain, GeL Clincial Fellow).
Early onset or syndromic epilepsy v2.25 SCAMP5 Sarah Leigh Tag watchlist tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v2.25 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered. ; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Early onset or syndromic epilepsy v2.25 PTEN Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote AKT1 from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote PTEN from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Early onset or syndromic epilepsy v2.25 SCN8A Sarah Leigh Added comment: Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy. This differs from the previosly reported gain of function, monoallelic variants (PMID 24194747;22365152).
Early onset or syndromic epilepsy v2.25 SCN8A Sarah Leigh Mode of pathogenicity for gene: SCN8A was changed from Other to Other
Early onset or syndromic epilepsy v2.24 SCN8A Sarah Leigh Added comment: Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy.
Early onset or syndromic epilepsy v2.24 SCN8A Sarah Leigh Mode of pathogenicity for gene: SCN8A was changed from None to Other
Early onset or syndromic epilepsy v2.23 SCN8A Sarah Leigh Added comment: Comment on mode of inheritance: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy.
Early onset or syndromic epilepsy v2.23 SCN8A Sarah Leigh Mode of inheritance for gene: SCN8A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.22 SCN8A Sarah Leigh Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia; Intellectual disability; Epileptic encephalopathy, early infantile, 13 to ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080
Early onset or syndromic epilepsy v2.21 SCN8A Sarah Leigh Publications for gene: SCN8A were set to Trudeau et al (2004) J Med Genet 43: 527_530; O'Brien and Meisler (2013) Frontiers in Genet 4(213): 1-9; Veeramah et al (2012) Am J Hum Genet 90: 502_510
Early onset or syndromic epilepsy v2.20 SCAMP5 Sarah Leigh Added comment: Comment on mode of pathogenicity: Heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease.
Early onset or syndromic epilepsy v2.20 SCAMP5 Sarah Leigh Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh commented on gene: SCAMP5: PMID 32020363 reports a homozygous variant (NM_001178111:c.271C>T, p.R91W rs747966691) in two sibs of a Chinese consanguienious family, with early onset epilepsy and Parkinson’s disease (the heterozygous parents had a normal phenotype). The p.R91W knock-in mouse showed typical early-onset epilepsy and functional studies showed dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain. The patients with this variant did not show signs of autism, intellectual disability, or other growth and developmental disorders.
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.16 SCAMP5 Sarah Leigh Added comment: Comment on mode of inheritance: Based on the reporting of a de novo heterozygous varaiant (NM_001178111.1:c.538G>T) in two unrelated cases (PMID: 31439720) and a homozygous variant (NM_001178111:c.271C>T, rs747966691) in two members of a Chinese consanguienious family (PMID: 32020363).
Early onset or syndromic epilepsy v2.16 SCAMP5 Sarah Leigh Mode of inheritance for gene: SCAMP5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.15 SCAMP5 Sarah Leigh Mode of inheritance for gene: SCAMP5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.14 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347
Early onset or syndromic epilepsy v2.13 RNF13 Sarah Leigh reviewed gene: RNF13: 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: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.13 RNF113A Sarah Leigh Classified gene: RNF113A as Green List (high evidence)
Early onset or syndromic epilepsy v2.13 RNF113A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for X-linked trichothiodystrophy. At least 3 terminating variants reported in unrelated cases. Supportive functional studies also reported.
Early onset or syndromic epilepsy v2.13 RNF113A Sarah Leigh Gene: rnf113a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.12 RARS Sarah Leigh Classified gene: RARS as Green List (high evidence)
Early onset or syndromic epilepsy v2.12 RARS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported in at least 9 cases of Hypomyelinating Leukodystrophy exhibinting epilepsy. Supportive functional studies were also reported.
Early onset or syndromic epilepsy v2.12 RARS Sarah Leigh Gene: rars has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.11 RARS Sarah Leigh commented on gene: RARS
Early onset or syndromic epilepsy v2.11 RARS Sarah Leigh Tag new-gene-name tag was added to gene: RARS.
Early onset or syndromic epilepsy v2.11 RALGAPA1 Sarah Leigh Classified gene: RALGAPA1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.11 RALGAPA1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for RALGAPA1-related neurodevelopmental disorder. At least 5 variants reported in at least 4 unrelated cases.
Early onset or syndromic epilepsy v2.11 RALGAPA1 Sarah Leigh Gene: ralgapa1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.10 RALGAPA1 Sarah Leigh Added comment: Comment on phenotypes: Intellectual disability;hypotonia;infantile spasms
Early onset or syndromic epilepsy v2.10 RALGAPA1 Sarah Leigh Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to .Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation 618797
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Classified gene: PUM1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 SNVs in at least 5 unrelated cases and CNVs spanning PUM1 in 9 cases. Supportive functional studies also reported.
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Gene: pum1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.8 PUM1 Sarah Leigh Added comment: Comment on phenotypes: Global developmental delay;Intellectual disability;Seizures;Abnormality of the face;Ataxia;Cryptorchidism
Early onset or syndromic epilepsy v2.8 PUM1 Sarah Leigh Phenotypes for gene: PUM1 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism to Spinocerebellar ataxia 47 617931
Early onset or syndromic epilepsy v2.7 PUM1 Sarah Leigh Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Early onset or syndromic epilepsy v2.6 PIGP Sarah Leigh Classified gene: PIGP as Green List (high evidence)
Early onset or syndromic epilepsy v2.6 PIGP Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported (rs768633670, rs778481061). rs768633670 were reported as a compound heterozygotes in one case and was present in at least two geographically separated consanguineous European families; suggesting a founder effect in the European population (PMID 32042915).
Supportive functional studies are also presented.
Early onset or syndromic epilepsy v2.6 PIGP Sarah Leigh Gene: pigp has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.5 PIGP Sarah Leigh 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 Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Early onset or syndromic epilepsy v2.4 PIGP Sarah Leigh Publications for gene: PIGP were set to 28334793; 31139695
Early onset or syndromic epilepsy v2.3 SRPX2 Zornitza Stark reviewed gene: SRPX2: Rating: RED; Mode of pathogenicity: None; Publications: 16497722, 23933820, 23871722; Phenotypes: Rolandic epilepsy, mental retardation, and speech dyspraxia, MIM# 300643; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v2.3 SNIP1 Zornitza Stark reviewed gene: SNIP1: Rating: RED; Mode of pathogenicity: None; Publications: 22279524; Phenotypes: Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.3 DDC Lothar Schlueter gene: DDC was added
gene: DDC was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDC were set to 28100251; 30952622; 20505134; 19172410
Phenotypes for gene: DDC were set to Aromatic L-amino acid decarboxylase deficiency 608643; floppy child; dystonia; hypotonia; developmental delay; oculogyric crisis
Review for gene: DDC was set to GREEN
Added comment: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures.
Sources: Literature
Early onset or syndromic epilepsy v2.3 Rebecca Foulger Panel version has been signed off
Early onset or syndromic epilepsy v2.0 TRAPPC4 Zornitza Stark reviewed gene: TRAPPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794024; Phenotypes: intellectual disability, epilepsy, spasticity, microcephaly; Mode of inheritance: None
Early onset or syndromic epilepsy v2.0 TMX2 Zornitza Stark reviewed gene: TMX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31735293, 31586943; Phenotypes: Microcephaly, ID, brain malformations, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 SNX27 Zornitza Stark reviewed gene: SNX27: Rating: GREEN; Mode of pathogenicity: None; Publications: 25894286, 31721175, 21300787, 23524343; Phenotypes: intellectual disability, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905, 30903679, 31859446; Phenotypes: intellectual disability, epilepsy, Spinocerebellar ataxia 47, MIM# 617931; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 PMPCB Zornitza Stark reviewed gene: PMPCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29576218; Phenotypes: Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 OXR1 Zornitza Stark reviewed gene: OXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31785787, 22028674; Phenotypes: Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay, MIM# 213000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 NSF Zornitza Stark reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: 31675180; Phenotypes: Seizures, EEG with burst suppression, Global developmental delay, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 KAT8 Zornitza Stark reviewed gene: KAT8: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31794431; Phenotypes: Intellectual disability, seizures, autism, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 SERPINI1 Zornitza Stark gene: SERPINI1 was added
gene: SERPINI1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: SERPINI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SERPINI1 were set to 28631894; 25401298; 12103288
Phenotypes for gene: SERPINI1 were set to Encephalopathy, familial, with neuroserpin inclusion bodies MIM#604218
Review for gene: SERPINI1 was set to GREEN
gene: SERPINI1 was marked as current diagnostic
Added comment: >3 unrelated families with progressive myoclonus epilepsy
Sources: Expert list
Early onset or syndromic epilepsy v2.0 CERS1 Zornitza Stark reviewed gene: CERS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30800706, 21625621; Phenotypes: Epilepsy, progressive myoclonic, 8 MIM#616230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 RALGAPA1 Zornitza Stark gene: RALGAPA1 was added
gene: RALGAPA1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: RALGAPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RALGAPA1 were set to 32004447
Phenotypes for gene: RALGAPA1 were set to Intellectual disability; hypotonia; infantile spasms.
Review for gene: RALGAPA1 was set to GREEN
gene: RALGAPA1 was marked as current diagnostic
Added comment: Four unrelated individuals reported.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 ALKBH8 Zornitza Stark reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079898; Phenotypes: Intellectual developmental disorder, autosomal recessive 71, MIM# 618504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 SLC39A8 Zornitza Stark gene: SLC39A8 was added
gene: SLC39A8 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: SLC39A8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A8 were set to 26637978; 26637979
Phenotypes for gene: SLC39A8 were set to Congenital disorder of glycosylation, type IIn , MIM#16721
Review for gene: SLC39A8 was set to GREEN
gene: SLC39A8 was marked as current diagnostic
Added comment: 6 individuals from Hutterite descent and two other unrelated families reported. Seizures reported in 2 Hutterite individuals and also in the other two unrelated families.
Sources: Expert Review
Early onset or syndromic epilepsy v2.0 PIGS Zornitza Stark gene: PIGS was added
gene: PIGS was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: PIGS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGS were set to 30269814
Phenotypes for gene: PIGS were set to Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143
Review for gene: PIGS was set to GREEN
gene: PIGS was marked as current diagnostic
Added comment: Three unrelated families reported. Severe neurological phenotype ranging from fetal akinesia (one family) to ID/EE (two families). Although pregnancies were terminated in one family, features observed in the affected fetuses suggest a severe neurological phenotype and hence we have rated this gene Green on our Epilepsy and our ID panels. I have added the gene to your CDG panel.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 WDR45B Zornitza Stark reviewed gene: WDR45B: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 28503735, 27431290; Phenotypes: Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, MIM# 617977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 UGP2 Zornitza Stark reviewed gene: UGP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31820119; Phenotypes: Epileptic encephalopathy, intellectual disability, microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 TUBA8 Zornitza Stark edited their review of gene: TUBA8: Added comment: Another affected individual reported as part of a bigger brain malformations cohort.; Changed publications: 31481326
Early onset or syndromic epilepsy v2.0 TRPM3 Zornitza Stark reviewed gene: TRPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31278393; Phenotypes: Intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 TIMM50 Zornitza Stark Deleted their comment
Early onset or syndromic epilepsy v2.0 TIMM50 Zornitza Stark commented on gene: TIMM50: At least 4 families reported, seizures in all reported individuals.
Early onset or syndromic epilepsy v2.0 TIMM50 Zornitza Stark edited their review of gene: TIMM50: Added comment: More families reported, supporting gene-disease association; note seizures reported in all.; Changed rating: GREEN; Changed publications: 27573165, 30190335, 31058414
Early onset or syndromic epilepsy v2.0 ST3GAL3 Zornitza Stark edited their review of gene: ST3GAL3: Added comment: Additional family reported recently with seizure phenotype.; Changed rating: AMBER; Changed publications: 23252400, 31584066
Early onset or syndromic epilepsy v2.0 SLC5A6 Zornitza Stark gene: SLC5A6 was added
gene: SLC5A6 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A6 were set to 31754459; 27904971
Phenotypes for gene: SLC5A6 were set to Developmental delay; epilepsy; neurodegeneration
Review for gene: SLC5A6 was set to GREEN
gene: SLC5A6 was marked as current diagnostic
Added comment: Two unrelated families reported, functional data and some evidence of response to treatment.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 SETD5 Zornitza Stark reviewed gene: SETD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29484850; Phenotypes: Intellectual disability, autosomal dominant 23 (MIM # 615761); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 SETD1B Zornitza Stark edited their review of gene: SETD1B: Added comment: Another individual with a de novo variant in this gene and epilepsy reported in 31440728 bringing the total to three, and possibly two more in 31685013.; Changed rating: GREEN; Changed publications: 29322246, 31440728, 31685013; Changed phenotypes: Epilepsy with myoclonic absences, intellectual disability; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 SETD1A Zornitza Stark gene: SETD1A was added
gene: SETD1A was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: SETD1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD1A were set to 31197650
Phenotypes for gene: SETD1A were set to Epilepsy
Review for gene: SETD1A was set to GREEN
gene: SETD1A was marked as current diagnostic
Added comment: Four unrelated families reported: in three, the variants occurred de novo, and in the fourth, it segregated with disease. Some functional data.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 RNF13 Zornitza Stark reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595371; Phenotypes: Epileptic encephalopathy, early infantile, 73, MIM# 618379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 PTEN Zornitza Stark commented on gene: PTEN: Cowden and BRRS are germline PTEN-related conditions and can present with macrocephaly/neurodevelopmental phenotype in childhood, including ID/autism and sometimes seizures as outlined in the previous reviews. The associated cancer risk makes the condition important to diagnose.

There are also somatic PTEN-related conditions such as Proteus, but these are not under consideration for this panel. One of the reviews below refers to AKT1, which is confusing.
Early onset or syndromic epilepsy v2.0 NUP214 Zornitza Stark gene: NUP214 was added
gene: NUP214 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128; 30758658
Phenotypes for gene: NUP214 were set to Encephalopathy, acute, infection-induced, susceptibility to, 9, MIM# 618426; epileptic encephalopathy; developmental regression; microcephaly
Review for gene: NUP214 was set to GREEN
gene: NUP214 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 NEDD4L Zornitza Stark edited their review of gene: NEDD4L: Added comment: Seizures are a frequently reported feature in this brain development disorder.; Changed publications: 28515470, 23934111, 28212375, 27694961
Early onset or syndromic epilepsy v2.0 NEUROD2 Zornitza Stark gene: NEUROD2 was added
gene: NEUROD2 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: NEUROD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NEUROD2 were set to 30323019; 16504944
Phenotypes for gene: NEUROD2 were set to Epileptic encephalopathy, early infantile, 72, MIM# 618374
Review for gene: NEUROD2 was set to GREEN
gene: NEUROD2 was marked as current diagnostic
Added comment: Two unrelated individuals with de novo missense variants in this gene, two animal models.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 MTHFS Zornitza Stark reviewed gene: MTHFS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30031689, 31844630, 22303332; Phenotypes: Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 MED17 Zornitza Stark reviewed gene: MED17: Rating: GREEN; Mode of pathogenicity: None; Publications: 30345598; Phenotypes: Microcephaly postnatal progressive with seizures and brain atrophy, 613668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 MAGI2 Zornitza Stark reviewed gene: MAGI2: Rating: RED; Mode of pathogenicity: None; Publications: 31056551; Phenotypes: Epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 GRIA2 Zornitza Stark reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31300657; Phenotypes: Intellectual disability, autism, Rett-like features, epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 GLS Zornitza Stark gene: GLS was added
gene: GLS was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: GLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLS were set to 30575854
Phenotypes for gene: GLS were set to Epileptic encephalopathy, early infantile, 71, MIM# 618328
Review for gene: GLS was set to AMBER
Added comment: Three individuals from two unrelated families reported with early neonatal refractory seizures, structural brain abnormalities and oedema; significantly increased glutamine levels.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 GABRB1 Zornitza Stark reviewed gene: GABRB1: Rating: ; Mode of pathogenicity: None; Publications: 23934111, 27273810, 31618474; Phenotypes: Epileptic encephalopathy, early infantile, 45, MIM# 617153; Mode of inheritance: None; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 FOXRED1 Zornitza Stark edited their review of gene: FOXRED1: Added comment: A couple more cases reported in the literature in 2019 bringing the total to 6, including another one with seizures are part of the phenotype (31434271).; Changed rating: GREEN; Changed publications: 20858599, 20818383, 31434271
Early onset or syndromic epilepsy v2.0 FGFR3 Zornitza Stark edited their review of gene: FGFR3: Added comment: This condition is well documented as being associated with epilepsy. It can be difficult to recognise clinically, particularly in infancy and therefore we consider this gene merits as much inclusion in an Epilepsy panel as other syndromic diagnoses (e.g. EFTUD2 etc).; Changed publications: 24630288, 27485793, 23649205, 12794698
Early onset or syndromic epilepsy v2.0 FDFT1 Zornitza Stark reviewed gene: FDFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29909962; Phenotypes: Squalene synthase deficiency, MIM# 618156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 EXT2 Zornitza Stark reviewed gene: EXT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26246518, 30288735, 30997052; Phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM# 616682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 DOLK Zornitza Stark edited their review of gene: DOLK: Added comment: Early presentation with seizures and demise reported in some individuals. Transferrin isoforms are not a reliable test in the newborn period to guide appropriate genomic analysis towards a CDG/metabolic panel; we also note the 25% recurrence risk, and hence we have included this gene as Green on our panel.; Changed publications: 23890587, 28816422, 24144945
Early onset or syndromic epilepsy v2.0 DMXL2 Zornitza Stark reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31688942, 30237576; Phenotypes: Epileptic encephalopathy, early infantile, 81, MIM# 618663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 DLL1 Zornitza Stark reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Intellectual disability, autism, seizures, variable brain abnormalities, scoliosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 DEAF1 Zornitza Stark reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30923367; Phenotypes: Dyskinesia, seizures, and intellectual developmental disorder 617171, autosomal dominant mental retardation 24, MIM# 615828; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 SCN8A Zornitza Stark reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31625145; Phenotypes: Epileptic encephalopathy, early infantile, 13, MIM# 614558, dominant and recessive; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 STXBP1 Zornitza Stark reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31855252; Phenotypes: Epileptic encephalopathy, early infantile, 4, MIM#612164; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 CPLX1 Zornitza Stark gene: CPLX1 was added
gene: CPLX1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: CPLX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPLX1 were set to 26539891; 28422131
Phenotypes for gene: CPLX1 were set to Epileptic encephalopathy, early infantile, 63, MIM# 617976
Review for gene: CPLX1 was set to GREEN
gene: CPLX1 was marked as current diagnostic
Added comment: Five individuals from three unrelated families reported in larger neurodevelopmental cohorts.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 AGMO Zornitza Stark gene: AGMO was added
gene: AGMO was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: AGMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGMO were set to 31555905; 27000257
Phenotypes for gene: AGMO were set to microcephaly; intellectual disability; epilepsy
Review for gene: AGMO was set to AMBER
Added comment: Three unrelated families reported, though epilepsy not an invariable feature.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 NPRL2 Louise Daugherty Tag watchlist was removed from gene: NPRL2.
Early onset or syndromic epilepsy v2.0 NPRL2 Louise Daugherty commented on gene: NPRL2
Early onset or syndromic epilepsy v2.0 KIAA1109 Louise Daugherty Tag watchlist was removed from gene: KIAA1109.
Early onset or syndromic epilepsy v2.0 KIAA1109 Louise Daugherty commented on gene: KIAA1109
Early onset or syndromic epilepsy v2.0 KCNQ5 Louise Daugherty Tag watchlist was removed from gene: KCNQ5.
Early onset or syndromic epilepsy v2.0 KCNQ5 Louise Daugherty commented on gene: KCNQ5
Early onset or syndromic epilepsy v2.0 HNRNPR Louise Daugherty Tag watchlist was removed from gene: HNRNPR.
Early onset or syndromic epilepsy v2.0 HNRNPR Louise Daugherty commented on gene: HNRNPR
Early onset or syndromic epilepsy v2.0 GOT2 Louise Daugherty commented on gene: GOT2
Early onset or syndromic epilepsy v2.0 GOT2 Louise Daugherty Tag watchlist was removed from gene: GOT2.
Early onset or syndromic epilepsy v2.0 EIF2B3 Louise Daugherty Tag watchlist was removed from gene: EIF2B3.
Early onset or syndromic epilepsy v2.0 EIF2B3 Louise Daugherty commented on gene: EIF2B3
Early onset or syndromic epilepsy v2.0 EIF2B1 Louise Daugherty Tag watchlist was removed from gene: EIF2B1.
Early onset or syndromic epilepsy v2.0 EIF2B1 Louise Daugherty commented on gene: EIF2B1
Early onset or syndromic epilepsy v2.0 CSNK2B Louise Daugherty Tag watchlist was removed from gene: CSNK2B.
Early onset or syndromic epilepsy v2.0 CSNK2B Louise Daugherty commented on gene: CSNK2B
Early onset or syndromic epilepsy v2.0 CNPY3 Louise Daugherty Tag watchlist was removed from gene: CNPY3.
Early onset or syndromic epilepsy v2.0 CNPY3 Louise Daugherty commented on gene: CNPY3
Early onset or syndromic epilepsy v2.0 ARV1 Louise Daugherty Tag watchlist was removed from gene: ARV1.
Early onset or syndromic epilepsy v2.0 ARV1 Louise Daugherty commented on gene: ARV1
Early onset or syndromic epilepsy v2.0 AFF3 Louise Daugherty changed review comment from: As a result of watchlist tag audit the watchlist tag was removed from AFF3- this is now a green gene. Preprint information is now available Voisin et al, 2019; to: As a result of watchlist tag audit the watchlist tag was removed from AFF3- this is now a green gene. Preprint information is now available Voisin et al, 2019 https://www.biorxiv.org/content/10.1101/693937v1
Early onset or syndromic epilepsy v2.0 AFF3 Louise Daugherty Tag watchlist was removed from gene: AFF3.
Early onset or syndromic epilepsy v2.0 AFF3 Louise Daugherty commented on gene: AFF3
Early onset or syndromic epilepsy v2.0 TET3 Konstantinos Varvagiannis gene: TET3 was added
gene: TET3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TET3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Phenotypes for gene: TET3 were set to Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face
Penetrance for gene: TET3 were set to Complete
Review for gene: TET3 was set to AMBER
Added comment: Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants.

For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc).

Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing.

TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC].

5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc).

6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES.

All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it.

Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization).

DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID.

Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116].
Sources: Literature
Early onset or syndromic epilepsy v2.0 PIGP Konstantinos Varvagiannis edited their review of gene: PIGP: Added comment: Please consider upgrading this gene to Green.

In a recent study, Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.; Changed publications: 28334793, 31139695, https://doi.org/10.1212/NXG.0000000000000387
Early onset or syndromic epilepsy v2.0 CACNA2D2 Louise Daugherty commented on gene: CACNA2D2
Early onset or syndromic epilepsy v2.0 CACNA2D2 Louise Daugherty Tag watchlist was removed from gene: CACNA2D2.
Early onset or syndromic epilepsy v2.0 ASTN1 Zornitza Stark gene: ASTN1 was added
gene: ASTN1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: ASTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Phenotypes for gene: ASTN1 were set to Intellectual disability; epilepsy; cortical malformations
Review for gene: ASTN1 was set to GREEN
gene: ASTN1 was marked as current diagnostic
Added comment: Three families reported as part of large cohorts albeit proposing multiple novel candidate genes with minimal detail and no functional validation.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 ASNS Zornitza Stark gene: ASNS was added
gene: ASNS was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: ASNS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ASNS were set to Asparagine synthetase deficiency, MIM# 615574
Review for gene: ASNS was set to GREEN
Added comment: Encephalopathy, including seizures is a feature of this metabolic condition.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 APC2 Zornitza Stark reviewed gene: APC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31585108; Phenotypes: Cortical dysplasia, complex, with other brain malformations 10, MIM#618677; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 ADRA2B Zornitza Stark reviewed gene: ADRA2B: Rating: RED; Mode of pathogenicity: None; Publications: 24114805, 21937992; Phenotypes: Cortical myoclonus and epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 ADAM22 Zornitza Stark gene: ADAM22 was added
gene: ADAM22 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: ADAM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM22 were set to 27066583; 30237576
Phenotypes for gene: ADAM22 were set to Epileptic encephalopathy, early infantile, 61, MIM# 617933
Review for gene: ADAM22 was set to AMBER
Added comment: Two families reported; the second one as part of a large consanguineous cohort.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 RNF113A Konstantinos Varvagiannis gene: RNF113A was added
gene: RNF113A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RNF113A 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: RNF113A were set to 25612912; 31880405; 31793730; 29133357; 30506991; 15256591; 24026126; 23555887
Phenotypes for gene: RNF113A were set to ?Trichothiodystrophy 5, nonphotosensitive, 300953
Penetrance for gene: RNF113A were set to Complete
Review for gene: RNF113A was set to GREEN
Added comment: The gene has been reviewed for the ID panel. Seizures have been reported in 4 affected males from 3 families.

From the ID panel:
Nonphotosensitive trichothiodystrophy-5 (TTD5 - #300953) is caused by mutation in the RNF113A gene on Xq24. DD, ID and seizures are part of the phenotype in males. (Several) heterozygous females have not been reported to exhibit these features (DD/ID/seizures) although a single female in the first report had speech/motor delay and learning difficulties.

Corbett et al (2015 - PMID: 25612912) reported on 2 cousins with profound ID and epilepsy among other principal features of the disorder. Linkage analysis (probably low(?) LOD score) localized the gene to a 7.75 Mb region on Xq and subsequent Sanger and exome sequencing identified an RNF113A stopgain variant in both (NM_006978.2:c.901C>T / p.Q301*). Other X-chr variants did not segregate with the disorder. Previously sequencing of other trichothiodystrophy genes (in both) and CMA (X-chromosome BAC array / ISCA CMA) were non-diagnostic. The variant in this family was identified in a previous study (Tarpey et al 2009 - PMID: 19377476) but was 'incorrectly' discarded at the time due to a sequencing error in a control DNA sample (analysis repeated by Corbett et al). The same variant was also reported in 2 fetuses in a later report (PMID: 31793730).

Mendelsohn et al (2019 - PMID: 31880405) reported on 2 unrelated affected males. The 1st presented with severe DD/ID (independent walking at 7y, single words/non-verbal with with special educational needs at 11y), seizures as well as typical features of the disorder. Metabolic work-up (incl. 7-DHCR) and genetic testing (Allagile, PFIC genes, CMA) were non-diagnostic. Duo WES revealed a frameshift variant [c.903_910delGCAGACCCA / p.(Gln302fs*12)] inherited from the mother. Maternal XCI was completely skewed (100:0). The 2nd individual (briefly reported as REQ18-0616 by Monies et al - PMID: 31130284) presented global DD and seizures along with all other core features of the disorder at the age of 16m. Karyotype was normal. Exome revealed a frameshift variant [NM_006978.3:c.897_898delTG / p.(Cys299*)].

Further evidence is based on the role of the RNA113A, being involved in mRNA splicing (/spiceosome function) [Gatti da Silva et al 2018 - PMID: 30506991 & many other Refs] as well in DNA repair (E3 ubiquitin-protein ligase in a mechanism for sensing DNA damage induced by alkylation) [Brickner et al 2017 - PMID: 29133357]. In the latter study, LCLs from individuals harboring Q301* were shown to be hypersensitive to an alkylating agent (MMS) which was also the case for an RNF113A knockdown cell line. The cells had reduced ASCC alkylation repair complex foci formation, which was rescued upon reconstitution of patient cells with wt RNF113A.

Animal models :
Disruption of rnf113a in zebrafish resulted among others in small head and underdeveloped gut (PMID cited : 15256591 - Amsterdam et al) similar to the microcephaly observed in several individuals and/or abnormal gut development/diarrhoea reported in few.
Knockdown of the Drosophila ortholog (mdlc) led to reduced proliferation of neuroblasts. Neuronal differentiation was initiated but not completed. Expression of the full-length human gene rescued the CNS defects (discussed by Mendelsohn et al citing PMID: 24026126 - Carney et al). RNA-seq data from the same study were analyzed by Corbett et al, and differentialy expressed genes were enriched for genes involved in DNA damage response and repair.
Knockdown of RNF-113 in C.elegans sensitises cells to UVA-induced DNA damage. RNF-113 was shown to be involved in interstrand DNA crosslink repair and interact with a RAD51C homolog (PMID cited: 23555887 - Lee et al).

[Please consider upgrade/inclusion in other relevant panels eg. the 'Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome panel' where the gene has red rating].
Sources: Literature
Early onset or syndromic epilepsy v2.0 MTHFS Konstantinos Varvagiannis gene: MTHFS was added
gene: MTHFS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFS were set to 30031689; 31844630; 22303332; https://doi.org/10.1007/978-3-642-40337-8_10
Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Penetrance for gene: MTHFS were set to Complete
Review for gene: MTHFS was set to GREEN
Added comment: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
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Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
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Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
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A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
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In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.

[Please consider inclusion in other possibly relevant panels e.g. for metabolic disorders]
Sources: Literature
Early onset or syndromic epilepsy v2.0 PUM1 Konstantinos Varvagiannis gene: PUM1 was added
gene: PUM1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Phenotypes for gene: PUM1 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism
Penetrance for gene: PUM1 were set to unknown
Review for gene: PUM1 was set to GREEN
Added comment: 5 unrelated individuals with de novo pathogenic PUM1 variants have been reported in the literature. DD (5/5), ID (4/5 - relevant severity to the current panel), seizures (4/4 - absence/tonic-clonic, abnormal EEG) and variable other features (incl. facial dysmorphism, ataxia, cryptorchidism) appear to be part of the phenotype. 9 individuals with deletions spanning PUM1 and proximal genes presented similar features.

[1] PMID: 29474920 - Gennarino et al (2018)
[2] PMID: 30903679 - Bonnemason-Carrere et al (2019)
[3] PMID: 31859446 - Voet et al (2019) [with review of the literature]

SNVs in relevant individuals were identified by exome sequencing and were in all cases de novo.

Arg1147Trp was a recurrent variant reported in 3 unrelated subjects with ID and seizures (Refs 1,2,3 / NM_001020658.1:c.3439C>T). A nonsense variant was reported in an additional one with DD, ID, seizures and additional features (c.2509C>T / p.Arg837* - Ref3). One individual with a de novo missense variant (c.3416G>A / p.Arg1139Trp) with DD and ataxia, though without ID was reported in Ref1.

Details on 9 individuals with 0.3 - 5.6 Mb deletions spanning PUM1 and other genes are provided in Ref1. Features also included DD, ID, seizures, ataxia, etc.

Extensive initial investigations were reported for individuals in Refs 2 and 3 (various investigations incl. karyotype, SNP-array, targeted sequencing of OPHN1, KANSL1 or of a small panel of ID genes, biopsies and/or metabolic work-up) to rule out alternative causes. These only revealed a likely benign CNV and a GRIA3 SNV of uncertain significance in the case of an individual harboring the recurrent Arg1147Trp variant [Ref2].

Role of the gene (from OMIM):
Pumilio proteins, such as PUM1, negatively regulate gene expression by repressing translation of mRNAs to which they bind (Lee et al., 2016). A clinically significant PUM1 target is ataxin (ATXN1; 601556), mutation in which causes spinocerebellar ataxia-1 (SCA1; 601556).

Variant studies:
- Arg1147Trp was shown to be associated with normal PUM1 mRNA levels, but reduced (to ~43%) PUM1 protein levels in patient fibroblasts. ATXN1 mRNA and protein levels, as well as protein and/or mRNA levels of other PUM1 targets were shown to be increased (Ref1).
- In Ref1, in vitro transfection assays with wt or mt PUM1 were performed in HEK293T cells to evaluate repression of ATXN1 and E2F3. While overexpression of wt and Arg1147Trp were able to reduce ATXN1 and E2F3 levels, Arg1139Trp was not able to repress ATXN1 or E2F3.
- Upon overexpression in mouse hippocampal neurons, PUM1 missense mutations (among others Arg1139Trp and Arg1147Trp) were shown to alter neuronal morphology.

Overall haploinsufficiency is the proposed mechanism for the disorder for which the acronym PADDAS is used (Pumilio1-associated developmental disability, ataxia and seizure).

Milder mutations reducing PUM1 levels by 25% are associated with adult-onset ataxia without ID (PRCA or Pumilio1-related cerebellar ataxia) [Ref1].

Mouse models:
The role of PUM1 was first suggested in mouse models where Pum1 mutations were shown to lead to a SCA1-like phenotype (PMID cited : 12086639 - Watase et al 2002) further shown to be caused by increased Atxn1 mRNA and protein levels (PMID cited : 25768905 - Gennarino et al 2015).
The mouse model seems to recapitulate several of the features observed in affected individuals : Pum1 homozygous ko mice display among others hyperactivity, progressive cerebellar signs, spontaneous seizures as also observed in affected individuals (PMID cited : 25768905 - Gennarino et al 2015). Cryptorchidism was observed in 2 patients similar to testicular hypoplasia reported in Pum1 ko mice (PMID cited : 22342750 - Chen et al 2012).
- Heterozygous mice were evaluated in Ref1 with 69% or 75% exhibiting spontaneous seizures by the end of 30 or 35 wks respectively, with abnormal EEG activity already by 16 wks.

Additional individuals with PUM1 variants and a relevant phenotype of ID with or without seizures have been reported as part of the DDD study or as external submissions to Decipher and ClinVar :

https://decipher.sanger.ac.uk/search?q=PUM1#research-variants/results [ DDD4K.01387 participant ]
https://decipher.sanger.ac.uk/search?q=pum1#consented-patients/results [ external submission(s) ]
https://www.ncbi.nlm.nih.gov/clinvar/variation/431110/ [ splice-site variant in an individual with ID submitted prior to the 1st publication on the disorder ]
Sources: Literature
Early onset or syndromic epilepsy v2.0 DLL1 Konstantinos Varvagiannis gene: DLL1 was added
gene: DLL1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLL1 were set to 31353024
Phenotypes for gene: DLL1 were set to Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis
Penetrance for gene: DLL1 were set to unknown
Review for gene: DLL1 was set to AMBER
Added comment: Gene added to the ID panel. Epilepsy has been reported in 6 unrelated individuals. Please consider inclusion with amber/green rating.

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Heterozygous DLL1 pathogenic variants cause Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (# 618709).

Fischer-Zirnsak et al (2019 - PMID: 31353024) reported on 15 affected individuals from 12 unrelated families.

Most common features included DD/ID (12/14), ASD (6/14 - belonging to 6 families) or other behavioral abnormalities, seizures (6/14 - from 6 unrelated families) and various brain MRI abnromalities. As commented by OMIM (based on the same ref) "Cognitive function ranges from severely impaired to the ability to attend schools with special assistance". Among other features, scoliosis was observed in 4. The authors could not identify a distinctive facial gestalt.

Variable initial investigations (where discussed/performed - also suggesting relevance to the current panel) included CMA, FMR1, FLNA, mitochondrial DNA analysis and metabolic work-up but had not revealed an alternative cause.

The DLL1 variants were identified by WES (with the exception of a 122-kb microdeletion spanning DLL1 and FAM120B detected by CMA). Nonsense, frame-shift, splice-site variants in positions predicted to result to NMD were identified in most. One individual was found to harbor a missense variant (NM_005618.3:c.536G>T / p.Cys179Phe) and another the aforementioned microdeletion.

The variant in several individuals had occurred as a de novo event. In 2 families, it was inherited from an also affected parent (an unaffected sib was non-carrier) while in 3 families parental studies were not possible/complete.

In frame insertion of 4 residues was demonstrated for a splice site variant, from LCLs of the corresponding individual. For another individual, material was unavailable for mRNA studies. The missense variant affected a cysteine (of the DSL domain) conserved in all Notch ligands while AA changes affecting the same position of JAG1 (another Notch ligand) have been described in patients with Alagille s.

Based on the variants identified and reports of deletions spanning DLL1 in the literature, haploinsufficiency is the proposed underlying mechanism. The gene has also a pLI of 1 and %HI of 4.65.

DLL1 encodes the Delta-like canonical Notch ligand 1. Notch signaling is an established pathway for brain morphogenesis. Previous in vivo and in vitro studies have demonstrated the role of DLL1 in CNS. The gene is highly expressed in neuronal precursor cells during embryogenesis. Expression of Dll1 (and other molecules of the Notch signalling pathway) in an oscillatory/sustained pattern and cell-cell interactions important for this pathway have been demonstrated to play a role in neuronal differentiation. [Most discussed by Fischer-Zirnsak et al with several refs provided / also Gray et al., 1999 - PMID: 10079256 & OMIM].

Animal models as summarized by the authors:
[Mouse] Loss of Dll1 in mice has been shown to increase neuronal differentiation, cause CNS hyperplasia and increased number of neurons (PMIDs cited: 9109488, 12397111, 20081190). Reduced Dll1 expression was associated with scoliosis and mild vertebral defects (cited PMIDs: 19562077, 14960495, 22484060 / among others Dll1 haploinsufficiency and dominant negative models studied). Scoliosis and vertebral segmentation defects were features in 4 and 1 individual, respectively in the cohort of 15.
[Zebrafish] Homozygous mutations in dlA, the zebrafish ortholog, disrupted the Delta-Notch signaling and led to patterning defects in the hindbrain and overproduction of neurons (cited: 15366005).
Sources: Literature
Early onset or syndromic epilepsy v2.0 TFE3 Konstantinos Varvagiannis reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595499, 31833172, https://doi.org/10.1126/scisignal.aax0926; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of skin pigmentation, Coarse facial features, Seizures; Mode of inheritance: Other
Early onset or syndromic epilepsy v2.0 UGP2 Konstantinos Varvagiannis gene: UGP2 was added
gene: UGP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UGP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGP2 were set to 31820119
Phenotypes for gene: UGP2 were set to Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Penetrance for gene: UGP2 were set to Complete
Review for gene: UGP2 was set to GREEN
Added comment: Perenthaler et al. (2019 - PMID: 31820119) provide evidence that homozygosity for a variant abolishing the start codon of the UGP2 transcript (NM_001001521.1) encoding the predominant (short) protein isoform in brain, leads to a severe epileptic encephalopathy.

This variant (chr2:64083454A>G / NM_001001521.1:c.1A>G - p.?) is also predicted to result in a substitution of a methionine at position 12 by a valine of the longer UGP2 transcript (NM_006759.3:c.34A>G - p.Met12Val).

The 2 isoforms differ only by 11 amino acids at the N-terminal and are otherwise expected to be functionally equivalent.

The authors provide details on 22 individuals from 15 families (some of which consanguineous).

Features included intractable seizures (in all), absence of developmental milestones (in all), progressive microcephaly, visual impairment. The authors reported also presence of somewhat similar facial features. Some of these individuals passed away early.

Previous work-up in several of them (incl. SNP-array, gene panel testing and metabolic investigations) had not revealed any abnormality, apart from ROH in some individuals. In all cases, the homozygous UGP2 SNV was the only P/LP variant for the neurodevelopmental phenotype following exome/genome sequencing. Segregation studies in affected/unaffected family members were compatible.

Families came from the Netherlands (but mostly from) India, Pakistan and Iran. Presence of a region of homozygosity shared between individuals from different families suggested that the variant might represent a mutation that originated several generations ago (in the area of Balochistan). The variant is present 15x in gnomAD, only in heterozygous state (in Asian mostly, reported once in Ashkenazi Jewish or Europeans) [ https://gnomad.broadinstitute.org/variant/2-64083454-A-G ].

UGP2 encodes UDP-glucose pyrophosphorylase which is an essential enzyme in sugar metabolism, catalyzing conversion of glucose-1-phosphate to UDP-glucose. UDP-glucose, in turn, serves as precursor for production of glycogen by glycogen synthase.

The authors provide several lines of evidence for a the role of the gene in the CNS as well as for the deleterious effect of the specific variant :
- In patient fibroblasts total UGP2 levels were not signifficantly different compared to parent / control fibroblasts, the longer isoform being upregulated (and stable) when the shorter is missing. Immunocytochemistry demonstrated similar localization of UGP2 in the case of mutant or wt cells. Enzymatic activity (/capacity to produce UDP-glucose) was similar between homozygous mut, heterozygous and wt fibroblasts.
- In H9-derived neural stem cells, Western Blot, RT-PCR and qRT-PCR suggested that the short isoform is the predominant one. (In embryonic stem cells, or fibroblasts the ratio between short and long isoform was lower).
- Analysis of RNA-seq data from human fetal tissues suggested that the short isoform is the predominant in brain.
- UGP2 was detected upon immunohistochemistry in fetal brain tissues from first to third trimester of pregnancy while Western Blot confirmed preferential expression of the shorter isoform.
- Homozygous embryonic (ESC) or neural stem cells (NSC) for the variant (knock-in/KI) or for a frameshift variant (knock-out/KO) were generated. Study of NSCs demonstrated reduced total UGP2 protein expression upon Western Blot in the case of KI cells and depleted in KO ones. Transcriptome analysis did not show major transcriptome alterations in KI/KO ESCs compared to wt. In NSC KI/KO cells transcriptome alterations were observed compared to wt with upregulation among others of genes for synaptic processes and genes implicated in epilepsy.
- The absence of UGP2 was shown to result in reduced ability of KO/KI NSCs to produce UDP-glucose, reduced capacity to synthesize glycogen under hypoxia (rescued in the case of KO cells by overexpression of wt or long isoform), defects of protein glycosylation as well as in increased unfolded protein response (/susceptibility to ER stress). These alterations are commented to be possibly implicated in pathogenesis of epilepsy, progressive microcephaly, etc.
- A CRISPR-Cas9 zebrafish model leading with loss of ugp2a and hypomorphic ugp2b (the zebrafish homologs of UGP2) demonstrated abnormal behavior, reduced eye movements and increased frequency/duration of movements upon stimulation with a potent convulsant (suggestive of increased seizure susceptibility).
- UGP knockout in drosophila is lethal while flies compound heterozygous for hypomorphic alleles are viable but show a movement defects due to altered synaptogenesis secondary to glycosylation defects (cited PMID: 27466186).
- The authors make speculations as for the occurrence of a single variant (and not others) eg. absence of UGP2 (in the case of LoF variants affecting both isoforms) would possibly be incompatible with life, Met12Val being tolerable for the long transcript not affecting stability/enzymatic activity (which may not be the case for other substitutions affecting Met12), etc.
Sources: Literature
Early onset or syndromic epilepsy v2.0 ADPRHL2 Louise Daugherty Tag new-gene-name tag was added to gene: ADPRHL2.
Early onset or syndromic epilepsy v2.0 ADPRHL2 Louise Daugherty commented on gene: ADPRHL2
Early onset or syndromic epilepsy v2.0 KAT8 Konstantinos Varvagiannis gene: KAT8 was added
gene: KAT8 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KAT8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KAT8 were set to 31794431
Phenotypes for gene: KAT8 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Penetrance for gene: KAT8 were set to unknown
Review for gene: KAT8 was set to GREEN
Added comment: Heterozygous pathogenic missense KAT8 variants have been reported in individuals with DD, ID and epilepsy. Variants occurred as de novo events within the chromobarrel or the acetyltransferase domain and were all shown to affect H4K16 acetylation, as would be predicted by the gene's function (lysine acetyltransferase). Evidence from brain specific Kat8 knockout in mouse, supports the role of the gene in brain development. One similarly affected individual compound heterozygous for a nonsense and a missense variant (the former affecting subnuclear localization and the latter H4K16ac) was also reported, with carrier relatives being unaffected. Mutations in genes of the MSL/NSL complexes (with which KAT8 forms multisubunit complexes) or genes in other acetyltransferases of the same subfamily (MYST) as KAT8 cause neurodevelopmental disorders [Details provided below].
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Li et al. (2019 - PMID: 31794431) report on 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants, as well as an additional one compound heterozygous for a nonsense and a missense one.

Overlapping phenotype consisted of DD/ID (8/8), seizures/epilepsy (6/8), brain MRI anomalies as well as presence of variable facial dysmorphic features. Less frequent features included abnormal vision (5/8), feeding difficulties (3/8), cardiac anomalies (3/8), autism (in 1).

The (9th) individual with biallelic variants had similar phenotype of DD/ID, epilepsy, autism and dysmorphic facial features. Heterozygous parents and sister, the latter carrier for the missense variant, were all unaffected.

All individuals had undergone exome sequencing, while extensive other investigations for at least 7/9 had only revealed variants of uncertain significance/contribution to the phenotype or were normal.

KAT8 encodes lysine acetyltransferase 8, which acetylates histone H4 at lysine 16 (H4K16). It belongs to the MYST subfamily of lysine acetyltransferases, the other members of which include KAT6A, KAT6B (both involved in neurodevelopmental disorders) and KAT5.

KAT8 forms two stoichiometric multisubunitcomplexes, one with the MSL complex and the other with the NSL. Mutations in genes encoding for subunits of the NSL or MSL complex (eg. KANSL1 and MSL3) are associated with neurodevelopmental disorders.

Overall 6 missense SNVs were reported among the heterozygous patients, p.Tyr90Cys (NM_032188.2:c.269A>G) being a recurrent one seen in 3. The compound heterozygous patient had a missense (c.973C>T / p.Arg325Cys) and a nonsense variant (c.523A>T / p.Lys175*). All missense variants lied either in the chromobarrel domain or the acetyltransferase domain. Variants in the latter domain localized within the KAT8/Mof-specific region or - in the case of the compound heterozygous individual - within the acetyl-CoA binding motif.

FLAG-tagged KAT8 (either wt or for all missense SNVs) was transfected in HEK293 cells with vectors for HA-tagged MSL proteins. While the nonsense variant was difficult to express, missense SNVs were expressed to similar levels to wt, promoted expression of MSL proteins but resulted in defective H4K16 acetylation and to a lesser extent H4K5 acetylation. As a result all missense variants impaired acetylation. This was also the case for chromobarrel domain variants, while expression of a KAT8 lacking the chromobarrel domain confirmed its ability to form complex with the MSL proteins and the impairment of H4K16 acetylation.

The nonsense variant demonstrated abnormal subnuclear localization.

The mouse model provides extensive evidence for the involvement of KAT8 in cerebral development. Cerebrum-specific Kat8 knockout mice presented postnatal growth retardation, hyperactivity/irritability, pre-weaning lethality, and cerebral hypoplasia upon autopsy. Loss of Kat8 reduced the number of neural stem and progenitor cells available for embryonic cerebrocortical development, impaired cell proliferation and stimulated apoptosis. The article also provides additional evidence from mouse model.
Sources: Literature
Early onset or syndromic epilepsy v2.0 RARS Konstantinos Varvagiannis gene: RARS was added
gene: RARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RARS were set to 31814314; 28905880; 24777941
Phenotypes for gene: RARS were set to Leukodystrophy, hypomyelinating, 9 616140
Penetrance for gene: RARS were set to Complete
Review for gene: RARS was set to GREEN
Added comment: Biallelic pathogenic RARS1 variants cause Leukodystrophy, hypomyelinating, 9 (# 616140).

The current review was based primarily on PMID: 31814314 (Mendes et al, 2019) providing details on 20 affected individuals from 15 families. 5 of these patients were included in a previous publication (Wolf et al, 2014 - PMID: 24777941) sharing authors with this study.

Clinical presentation and severity can be highly variable. However, among the 15 patients of relevant age (5/20 deceased at an early age), ID was observed in 13 (in 6/13 mild-moderate, in 7/13 severe/profound). Epilepsy was reported in half (10/20) with seizures being refractory to treatment in most and the phenotype corresponding to an infantile epileptic encephalopathy. DD and seizures were the presenting feature in 7 and 5 patients respectively, while in other cases presenting features were less specific (eg. failure to thrive in 1/20, irritabilty in 2/20). As a result the gene appears to be relevant to both DD/ID and epilepsy panels.

RARS1 encodes the cytoplasmic arginyl-tRNA synthetase 1, which is a component of the aminoacyl-tRNA synthetase complex (OMIM and Wolf et al, 2014 - PMID: 24777941). Aminoacyl-tRNA synthetases catalyze the aminoacylation ('charging') of tRNA by (with) their cognate amino acid.

Utilisation of alternative initiation codons, from a single mRNA transcript, results in translation of a long and a short protein isoform (Zheng et al 2006 - PMID: 16430231). The long isoform is needed for the formation of the multi-synthetase complex (MSC), while the short is free in the cytoplasm and does not have any interaction with the MSC. The long isoform appears to be essential for protein synthesis (discussed with several refs provided in PMID: 28905880 - Nafisinia et al, 2017).

The role of variants has been supported in several patients by additional studies - among others :
[PMID 31814314] Impaired Arginyl-tRNA synthetase activity was demonstrated in fibroblasts from 3 patients. Activity was normal in one additional individual compound heterozygous for a variant affecting initiation codon and a missense one. Western blot however demonstrated presence mainly of the short protein isoform. The authors suggest that this isoform possibly contributed to enzymatic activity. The long isoform which is needed for the MSC complex was only represented by a faint band in the Western Blot of the same individual.
[PMID: 28905880] Using fibroblasts from an affected subject homozygous for a missense variant (NM_002887.3:c.5A>G / p.Asp2Gly) and controls, a 75% reduction of the long isoform was shown upon WB. The short isoform was present at similar levels. As the N-terminus (of the long isoform) mediates interaction with the MSC (and AIMP1), assembly of the latter was 99% reduced in patient fibroblasts. Proliferation of patient fibroblasts was significantly reduced when cultured in a medium with limited arginine, a finding which was thought to reflect inefficient protein synthesis.

Mutations in other genes encoding for aminoacyl-tRNA synthetases (eg. AARS1, VARS1) or scaffolding proteins of the multisynthetase complex (eg. AIMP1 and AIMP2) lead to neurodevelopmental disorders with overlapping phenotype [most genes rated green in both the ID and epilepsy panel].
Sources: Literature
Early onset or syndromic epilepsy v2.0 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
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In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
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As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

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Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
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In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
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As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

---------------

Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
Early onset or syndromic epilepsy v2.0 Rebecca Foulger promoted panel to version 2.0
Early onset or syndromic epilepsy v1.498 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Early onset or syndromic epilepsy v1.497 TRAPPC4 Konstantinos Varvagiannis gene: TRAPPC4 was added
gene: TRAPPC4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC4 were set to 31794024
Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment
Penetrance for gene: TRAPPC4 were set to Complete
Review for gene: TRAPPC4 was set to GREEN
Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant.

Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy).

Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc).

Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members.

Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G].

mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls).

Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift).

TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article].

Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel).

Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals.

Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing).

TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts.
Sources: Literature
Early onset or syndromic epilepsy v1.497 SNX27 Konstantinos Varvagiannis gene: SNX27 was added
gene: SNX27 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SNX27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX27 were set to 25894286; 31721175; 21300787; 23524343
Phenotypes for gene: SNX27 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: SNX27 were set to Complete
Review for gene: SNX27 was set to AMBER
Added comment: (From the ID panel)

Evidence from 2 publications suggests that DD, ID and seizures are part of the phenotype of individuals with biallelic SNX27 pathogenic variants :
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Damseh, Danson et al (2015 - PMID: 25894286) first reported on a consanguineous family with 4 affected sibs, homozygous for an SNX27 pathogenic variant. Features incl. hypotonia soon after birth, failure to thrive, severely delayed psychomotor development with no milestone acquisition, occurrence of myoclonic seizures with 3 individuals deceased early. Exome sequencing in one revealed a few candidate variants, with an SNX27 frameshift one [NM_030918.6:c.515_516del - p.(His172Argfs*6) / absent from ExAC] being the only retained following Sanger segregation studies. Using fibroblasts from an affected individual, Western blot with an antibody which would also bind prior to the truncation site, was consistent with dramatically reduced/absent SNX27 truncated mutant protein. Protein levels of VPS35, a component of the retromer responsible for direct cargo binding (not mediated by a cargo adaptor as SNX27), were normal.
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Parente et al (2019 - PMID: 31721175) reported on a 13-year-old male with motor and language delay, ADHD, ID (kindergarten academic level at the age of 13) and seizures with onset at the age of 9 years (GTC, with abnormal EEG and postical SV tachycardia). Variable physical findings were reported. White matter hyperintesities were noted upon initial brain MRI (but were less marked in subsequent ones). Initial genetic testing (Alexander's disease, CMA, FMR1) was normal. Exome revealed compound heterozygosity for 2 SNX27 variants (NM_030918.5/NM_001330723.1 both apply c.510C>G - p.Tyr170* and c.1295G>A - p.Cys432Tyr) each inherited from healthy carrier parents. There were no other potentially causative variants. A parental history of - isolated - late onset seizures was reported (so this individual may not be considered for the seizure phenotype here).

The authors also reported on a further 31-year old affected male. This individual had infantile hypotonia, poor eye contact with subsequent significant DD, seizures (febrile/afebrile T-C with onset at the age of 14m) and ID estimated in the severe range. Variable - though somewhat different - physical findings were reported. Initial work-up included basic metabolic testing, standard karyotype, FISH for 15q11 and subtelomeric regions and PHF6 genetic testing - all normal. Exome (and subsequent Sanger confirmation/parental studies) revealed compound heterozygosity for a missense and a frameshift variant (c.989G>A / p.Arg330His and c.782dupT / p.Leu262Profs*6 same in NM_001330723.1, NM_030918.6).
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SNX27 encodes sorting nexin 27, a cargo adaptor for the retromer. The latter is a multi-protein complex essential for regulating the retrieval and recycling of transmembrane cargos from endosomes to the trans-Golgi network or the plasma membrane [Lucas et al 2016 - PMID: 27889239 / McNally et al 2018 - PMID: 30072228].

As summarized by Parente et al, the encoded protein by regulating composition of the cell surface influences several processes eg. neuronal excitability, synaptic plasticity, Wnt signaling etc. It has been shown to interact with surface receptors and their ligands including GIRK channels, 5-HT4, ionotropic glutamate receptors (incl. NMDA- and AMPA-type receptors) and mGluR5 [several refs. provided].

Knockout of Snx27 in mice resulted in embryonic lethality (16% hmz of the 25% expected), severe postnatal growth retardation and death within the first 3 weeks. Snx27(+/-) mice have normal neuroanatomy but exhibit cognitive deficits (in learning and memory) and defects in synaptic function/plasticity with reduced amounts of NMDA and AMPA receptors (Cai et al - PMID: 21300787, Wang et al - PMID: 23524343).
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There is no associated phenotype in OMIM/G2P.
Sources: Literature
Early onset or syndromic epilepsy v1.497 OXR1 Konstantinos Varvagiannis gene: OXR1 was added
gene: OXR1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Phenotypes for gene: OXR1 were set to Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum
Penetrance for gene: OXR1 were set to Complete
Review for gene: OXR1 was set to GREEN
Added comment: Wang et al (2019 - https://doi.org/10.1016/j.ajhg.2019.11.002 ) report on 5 individuals (from 3 families) with biallelic OXR1 LoF variants.

Common features included hypotonia (4/5), severe global DD (5/5) and speech delay (5/5), ID (5/5), epilepsy (5/5) with cerebellar dysplasia/atrophy (5/5) and in some scoliosis.

All were investigated by exome sequencing and were found to harbor biallelic loss-of-function variants (2 splice-site, a stopgain and a frameshift one) either in homozygosity (2 consanguineous families) or in compound heterozygosity. In all cases parental segregation studies were compatible and in one family, an unaffected sib shown to be carrier.

Althouhgh OXR1 has been shown to affect several processes (among others DNA lesions induced by oxidative stress in E.coli, neuronal maintenance, mitochondrial morphology and DNA maintenance, etc), its mechanism of action is still not well defined. There are 6 RefSeq transcripts, the longest (NM_018002.3) encoding 3 protein domains (LysM, GRAM, TLDc). The TLDc domain is encoded by all transcripts.

Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1.

Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families.

The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd.

Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function.

The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes).

Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction).

Overall the data presented suggest a critical role for OXR1 in lysosomal biology.

Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects.
Sources: Literature
Early onset or syndromic epilepsy v1.497 PCYT2 Ellen McDonagh reviewed gene: PCYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.497 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Early onset or syndromic epilepsy v1.496 WWOX Rebecca Foulger Publications for gene: WWOX were set to Tabarki (2015) Ben-Salam (2015) Mignot (2015)
Early onset or syndromic epilepsy v1.495 WWOX Rebecca Foulger Phenotypes for gene: WWOX were changed from to Epileptic encephalopathy, early infantile, 28, 616211
Early onset or syndromic epilepsy v1.494 WDR45 Rebecca Foulger Phenotypes for gene: WDR45 were changed from to Neurodegeneration with brain iron accumulation 5, 300894
Early onset or syndromic epilepsy v1.493 WDR45 Rebecca Foulger Publications for gene: WDR45 were set to Saitsu et al (2013) Nat Genet. 45(4):445-9
Early onset or syndromic epilepsy v1.492 STX1B Rebecca Foulger Phenotypes for gene: STX1B were changed from to Generalized epilepsy with febrile seizures plus, type 9, 616172
Early onset or syndromic epilepsy v1.491 STX1B Rebecca Foulger Mode of inheritance for gene: STX1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.490 SLC6A1 Rebecca Foulger Phenotypes for gene: SLC6A1 were changed from to Myoclonic-atonic epilepsy, 616421
Early onset or syndromic epilepsy v1.489 SLC6A1 Rebecca Foulger Publications for gene: SLC6A1 were set to Carvill et al (2015) Am J Hum Genet 96(5): 808-15
Early onset or syndromic epilepsy v1.488 PNPO Rebecca Foulger Phenotypes for gene: PNPO were changed from to Pyridoxamine 5'-phosphate oxidase deficiency, 610090
Early onset or syndromic epilepsy v1.487 NDUFS8 Rebecca Foulger Phenotypes for gene: NDUFS8 were changed from Mitochondrial complex I deficiency, nuclear type 2, 618222 to Mitochondrial complex I deficiency, nuclear type 2, 618222; Leigh syndrome due to mitochondrial complex I deficiency
Early onset or syndromic epilepsy v1.486 NDUFS8 Rebecca Foulger Phenotypes for gene: NDUFS8 were changed from to Mitochondrial complex I deficiency, nuclear type 2, 618222
Early onset or syndromic epilepsy v1.485 DNM1 Rebecca Foulger Mode of inheritance for gene: DNM1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.484 DNM1 Rebecca Foulger Publications for gene: DNM1 were set to EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11
Early onset or syndromic epilepsy v1.483 DNM1 Rebecca Foulger Phenotypes for gene: DNM1 were changed from to Epileptic encephalopathy, early infantile, 31, 616346
Early onset or syndromic epilepsy v1.482 CYFIP2 Rebecca Foulger Mode of pathogenicity for gene: CYFIP2 was changed from None to Other
Early onset or syndromic epilepsy v1.481 CYFIP2 Rebecca Foulger Publications for gene: CYFIP2 were set to 29534297
Early onset or syndromic epilepsy v1.480 CYFIP2 Rebecca Foulger Phenotypes for gene: CYFIP2 were changed from to Epileptic encephalopathy, early infantile, 65, 618008
Early onset or syndromic epilepsy v1.479 CSTB Rebecca Foulger Publications for gene: CSTB were set to
Early onset or syndromic epilepsy v1.478 CSTB Rebecca Foulger Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800
Early onset or syndromic epilepsy v1.477 PNPT1 Konstantinos Varvagiannis gene: PNPT1 was added
gene: PNPT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PNPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPT1 were set to 31752325
Phenotypes for gene: PNPT1 were set to Combined oxidative phosphorylation deficiency 13, MIM 614932
Penetrance for gene: PNPT1 were set to Complete
Review for gene: PNPT1 was set to GREEN
Added comment: Reviewed for the intellectual disability panel. Seizures may be observed in affected individuals (details below). Please consider inclusion with amber / green rating.

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Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.
Sources: Literature
Early onset or syndromic epilepsy v1.477 SCAMP5 Ellen McDonagh Added comment: Comment on mode of pathogenicity: A dominant negative effect is predicted.
Early onset or syndromic epilepsy v1.477 SCAMP5 Ellen McDonagh Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Added comment: Comment on list classification: Gene added by external Reviewer, and promoted to Amber due to review and overall evidence.
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.475 TMX2 Konstantinos Varvagiannis gene: TMX2 was added
gene: TMX2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31735293; 31270415
Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration
Penetrance for gene: TMX2 were set to Complete
Review for gene: TMX2 was set to GREEN
Added comment: This gene was reviewed for the intellectual disability panel. Epilepsy is part of the phenotype. Therefore green rating should be considered.

From the ID panel :
A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy.

As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating.

Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc.

All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below].

The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6.

*To the best of my understanding :

Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding.

Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life.

As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival.

Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase.

Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity.

TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions.

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Created: 26 Nov 2019, 11:21 p.m. | Last Modified: 26 Nov 2019, 11:21 p.m.
Panel Version: 2.1122

[Previous review]

PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI.

All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones.

Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families).

Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks.

The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals).

This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven.

TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article.

As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging).
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Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism).
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There is no associated phenotype in OMIM/G2P/SysID.
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Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence.
Sources: Literature
Sources: Literature
Early onset or syndromic epilepsy v1.475 IDH2 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green.Refers to glioma patients: not a seizure disorder. Demoted from Green to RED.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Refers to glioma patients- not a seizure disorder. Demoted from Green to RED.
Early onset or syndromic epilepsy v1.475 CYP27A1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.475 SCN9A Rebecca Foulger Publications for gene: SCN9A were set to 19763161; 29500686
Early onset or syndromic epilepsy v1.474 FLNA Rebecca Foulger changed review comment from: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was notes that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.; to: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was noted that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.
Early onset or syndromic epilepsy v1.474 PEX6 Rebecca Foulger Classified gene: PEX6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.474 PEX6 Rebecca Foulger Gene: pex6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.473 PEX6 Rebecca Foulger commented on gene: PEX6: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.473 PEX3 Rebecca Foulger Classified gene: PEX3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.473 PEX3 Rebecca Foulger Gene: pex3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.472 PEX3 Rebecca Foulger commented on gene: PEX3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.472 PEX2 Rebecca Foulger Classified gene: PEX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.472 PEX2 Rebecca Foulger Gene: pex2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.471 PEX2 Rebecca Foulger commented on gene: PEX2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.471 PEX19 Rebecca Foulger Classified gene: PEX19 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.471 PEX19 Rebecca Foulger Gene: pex19 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.470 PEX19 Rebecca Foulger commented on gene: PEX19: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.470 PEX13 Rebecca Foulger Classified gene: PEX13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.470 PEX13 Rebecca Foulger Gene: pex13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.469 PEX13 Rebecca Foulger commented on gene: PEX13: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.469 BSCL2 Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should change from 'BOTH monoallelic and biallelic' to 'BIALLELIC': just one monoallelic case so far, which could be a false positive.
Early onset or syndromic epilepsy v1.469 BSCL2 Rebecca Foulger Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.468 NDUFA1 Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should be updated from XLR to XLD.
Early onset or syndromic epilepsy v1.468 NDUFA1 Rebecca Foulger Mode of inheritance for gene: NDUFA1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females 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 v1.467 NSDHL Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should remain as XLR.
Early onset or syndromic epilepsy v1.467 NSDHL Rebecca Foulger Mode of inheritance for gene: NSDHL was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.466 ADAR Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should remain as BIALLELIC: No current evidence for seizures in monoallelic cases.
Early onset or syndromic epilepsy v1.466 ADAR Rebecca Foulger Mode of inheritance for gene: ADAR was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.465 DNAJC5 Rebecca Foulger Classified gene: DNAJC5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.465 DNAJC5 Rebecca Foulger Gene: dnajc5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.464 DNAJC5 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures present later. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.464 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.464 SGSH Rebecca Foulger commented on gene: SGSH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.464 EXT2 Rebecca Foulger Classified gene: EXT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.464 EXT2 Rebecca Foulger Gene: ext2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.463 EXT2 Rebecca Foulger commented on gene: EXT2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures not a presenting feature. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.463 CLPB Rebecca Foulger Classified gene: CLPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.463 CLPB Rebecca Foulger Gene: clpb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.462 CLPB Rebecca Foulger commented on gene: CLPB: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Although there are three cases, most patients don't have seizures. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.462 TMEM70 Rebecca Foulger Classified gene: TMEM70 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.462 TMEM70 Rebecca Foulger Gene: tmem70 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.461 TMEM70 Rebecca Foulger commented on gene: TMEM70: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Insufficient seizure evidence. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.461 SLC6A19 Rebecca Foulger Classified gene: SLC6A19 as Red List (low evidence)
Early onset or syndromic epilepsy v1.461 SLC6A19 Rebecca Foulger Gene: slc6a19 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.460 SLC6A19 Rebecca Foulger commented on gene: SLC6A19: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Epilepsy is not a key feature. Demoted from Green to Red.
Early onset or syndromic epilepsy v1.460 SLC35A1 Rebecca Foulger Publications for gene: SLC35A1 were set to 23873973; 15576474; 28856833; 30115659