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Genetic Epilepsy v0.1747 BCKDHB Zornitza Stark Publications for gene: BCKDHB were set to
Genetic Epilepsy v0.1746 BCKDHB Zornitza Stark Mode of inheritance for gene: BCKDHB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1745 BCKDHB Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association, seizures are part of the phenotype.
Genetic Epilepsy v0.1745 ETHE1 Zornitza Stark Tag treatable tag was added to gene: ETHE1.
Genetic Epilepsy v0.1745 BCKDHA Zornitza Stark Marked gene: BCKDHA as ready
Genetic Epilepsy v0.1745 BCKDHA Zornitza Stark Gene: bckdha has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1745 BCKDHA Zornitza Stark Phenotypes for gene: BCKDHA were changed from to Maple syrup urine disease, type Ia, MIM# 248600
Genetic Epilepsy v0.1744 BCKDHA Zornitza Stark Publications for gene: BCKDHA were set to
Genetic Epilepsy v0.1743 BCKDHA Zornitza Stark Mode of inheritance for gene: BCKDHA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1742 BCKDHA Zornitza Stark Mode of inheritance for gene: BCKDHA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1741 BCKDHA Zornitza Stark changed review comment from: Well established gene-disease association.; to: Well established gene-disease association. Seizures are part of the phenotype.
Genetic Epilepsy v0.1741 ATRX Zornitza Stark Marked gene: ATRX as ready
Genetic Epilepsy v0.1741 ATRX Zornitza Stark Gene: atrx has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1741 ATRX Zornitza Stark Phenotypes for gene: ATRX were changed from to Alpha-thalassemia/mental retardation syndrome, MIM# 301040; Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580
Genetic Epilepsy v0.1740 ATRX Zornitza Stark Mode of inheritance for gene: ATRX was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1739 ATRX Zornitza Stark reviewed gene: ATRX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Alpha-thalassemia/mental retardation syndrome, MIM# 301040, Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1739 ATP6AP2 Zornitza Stark Marked gene: ATP6AP2 as ready
Genetic Epilepsy v0.1739 ATP6AP2 Zornitza Stark Gene: atp6ap2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1739 ATP6AP2 Zornitza Stark reviewed gene: ATP6AP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked, syndromic, Hedera type MIM#300423; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1739 ATP6AP2 Zornitza Stark Phenotypes for gene: ATP6AP2 were changed from to Intellectual developmental disorder, X-linked, syndromic, Hedera type MIM#300423
Genetic Epilepsy v0.1738 ATP6AP2 Zornitza Stark Publications for gene: ATP6AP2 were set to
Genetic Epilepsy v0.1737 ATP6AP2 Zornitza Stark Mode of pathogenicity for gene: ATP6AP2 was changed from Other to Other
Genetic Epilepsy v0.1736 ATP6AP2 Zornitza Stark Mode of pathogenicity for gene: ATP6AP2 was changed from to Other
Genetic Epilepsy v0.1735 ATP6AP2 Zornitza Stark Mode of inheritance for gene: ATP6AP2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1734 ASPA Zornitza Stark Marked gene: ASPA as ready
Genetic Epilepsy v0.1734 ASPA Zornitza Stark Gene: aspa has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1734 ASPA Zornitza Stark Phenotypes for gene: ASPA were changed from Canavan disease MIM#271900; disorder of amino acid metabolism to Canavan disease MIM#271900; disorder of amino acid metabolism
Genetic Epilepsy v0.1733 ASPA Zornitza Stark Phenotypes for gene: ASPA were changed from Canavan disease MIM#271900; disorder of amino acid metabolism to Canavan disease MIM#271900; disorder of amino acid metabolism
Genetic Epilepsy v0.1732 ASPA Zornitza Stark Phenotypes for gene: ASPA were changed from to Canavan disease MIM#271900; disorder of amino acid metabolism
Genetic Epilepsy v0.1731 ASPA Zornitza Stark Publications for gene: ASPA were set to
Genetic Epilepsy v0.1730 ASPA Zornitza Stark Mode of inheritance for gene: ASPA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1729 ARX Zornitza Stark Marked gene: ARX as ready
Genetic Epilepsy v0.1729 ARX Zornitza Stark Gene: arx has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1729 ARX Zornitza Stark Phenotypes for gene: ARX were changed from Epileptic encephalopathy, early infantile, 1 MIM#308350; Hydranencephaly with abnormal genitalia MIM#300215; Lissencephaly, X-linked 2 MIM#300215; Mental retardation, X-linked 29 and others MIM#300419; Partington syndrome MIM#309510; Proud syndrome MIM#300004 to Epileptic encephalopathy, early infantile, 1 MIM#308350; Hydranencephaly with abnormal genitalia MIM#300215; Lissencephaly, X-linked 2 MIM#300215; Mental retardation, X-linked 29 and others MIM#300419; Partington syndrome MIM#309510; Proud syndrome MIM#300004
Genetic Epilepsy v0.1728 ARX Zornitza Stark Phenotypes for gene: ARX were changed from to Epileptic encephalopathy, early infantile, 1 MIM#308350; Hydranencephaly with abnormal genitalia MIM#300215; Lissencephaly, X-linked 2 MIM#300215; Mental retardation, X-linked 29 and others MIM#300419; Partington syndrome MIM#309510; Proud syndrome MIM#300004
Genetic Epilepsy v0.1727 ARX Zornitza Stark Publications for gene: ARX were set to
Genetic Epilepsy v0.1726 ARX Zornitza Stark Mode of inheritance for gene: ARX was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1725 ARV1 Zornitza Stark Marked gene: ARV1 as ready
Genetic Epilepsy v0.1725 ARV1 Zornitza Stark Gene: arv1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1725 ARV1 Zornitza Stark Phenotypes for gene: ARV1 were changed from to Developmental and epileptic encephalopathy 38, MIM# 617020
Genetic Epilepsy v0.1724 ARV1 Zornitza Stark Publications for gene: ARV1 were set to
Genetic Epilepsy v0.1723 ARV1 Zornitza Stark Mode of inheritance for gene: ARV1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1722 ARID1B Zornitza Stark Marked gene: ARID1B as ready
Genetic Epilepsy v0.1722 ARID1B Zornitza Stark Gene: arid1b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1722 ARID1B Zornitza Stark Phenotypes for gene: ARID1B were changed from to Coffin-Siris syndrome 1 MIM#135900
Genetic Epilepsy v0.1721 ARID1B Zornitza Stark Mode of inheritance for gene: ARID1B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1720 ARFGEF2 Zornitza Stark Marked gene: ARFGEF2 as ready
Genetic Epilepsy v0.1720 ARFGEF2 Zornitza Stark Gene: arfgef2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1720 ARFGEF2 Zornitza Stark Phenotypes for gene: ARFGEF2 were changed from to Periventricular heterotopia with microcephaly (MIM#608097)
Genetic Epilepsy v0.1719 ARFGEF2 Zornitza Stark Publications for gene: ARFGEF2 were set to
Genetic Epilepsy v0.1718 ARFGEF2 Zornitza Stark Mode of inheritance for gene: ARFGEF2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1717 AMT Zornitza Stark Marked gene: AMT as ready
Genetic Epilepsy v0.1717 AMT Zornitza Stark Gene: amt has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1717 AMT Zornitza Stark Phenotypes for gene: AMT were changed from to Glycine encephalopathy MIM#605899; disorder of glycine metabolism
Genetic Epilepsy v0.1716 AMT Zornitza Stark Publications for gene: AMT were set to
Genetic Epilepsy v0.1715 AMT Zornitza Stark Mode of inheritance for gene: AMT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1714 AMPD2 Zornitza Stark Marked gene: AMPD2 as ready
Genetic Epilepsy v0.1714 AMPD2 Zornitza Stark Gene: ampd2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1714 AMPD2 Zornitza Stark Phenotypes for gene: AMPD2 were changed from to Pontocerebellar hypoplasia, type 9, MIM#615809
Genetic Epilepsy v0.1713 AMPD2 Zornitza Stark Publications for gene: AMPD2 were set to
Genetic Epilepsy v0.1712 ALPL Zornitza Stark Marked gene: ALPL as ready
Genetic Epilepsy v0.1712 ALPL Zornitza Stark Gene: alpl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1712 ALPL Zornitza Stark Phenotypes for gene: ALPL were changed from to Hypophosphatasia, adult 146300 (AD, AR); Hypophosphatasia, childhood 241510 AR; Hypophosphatasia, infantile 241500 AR; Odontohypophosphatasia 146300 AD, AR
Genetic Epilepsy v0.1711 ALPL Zornitza Stark Publications for gene: ALPL were set to
Genetic Epilepsy v0.1710 ALPL Zornitza Stark Mode of pathogenicity for gene: ALPL was changed from to Other
Genetic Epilepsy v0.1709 ALPL Zornitza Stark Mode of inheritance for gene: ALPL was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1708 AKT3 Zornitza Stark Marked gene: AKT3 as ready
Genetic Epilepsy v0.1708 AKT3 Zornitza Stark Gene: akt3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1708 AKT3 Zornitza Stark Phenotypes for gene: AKT3 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 MIM#615937
Genetic Epilepsy v0.1707 AKT3 Zornitza Stark Publications for gene: AKT3 were set to
Genetic Epilepsy v0.1706 AKT3 Zornitza Stark Mode of pathogenicity for gene: AKT3 was changed from to Other
Genetic Epilepsy v0.1705 AKT3 Zornitza Stark Mode of inheritance for gene: AKT3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1704 ADSL Zornitza Stark Marked gene: ADSL as ready
Genetic Epilepsy v0.1704 ADSL Zornitza Stark Gene: adsl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1704 ADSL Zornitza Stark Phenotypes for gene: ADSL were changed from to Adenylosuccinase deficiency MIM#103050
Genetic Epilepsy v0.1703 ADSL Zornitza Stark Publications for gene: ADSL were set to
Genetic Epilepsy v0.1702 ADSL Zornitza Stark Mode of inheritance for gene: ADSL was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1701 ADAR Zornitza Stark Marked gene: ADAR as ready
Genetic Epilepsy v0.1701 ADAR Zornitza Stark Gene: adar has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1701 ADAR Zornitza Stark Phenotypes for gene: ADAR were changed from to Aicardi-Goutieres syndrome 6, MIM# 615010; Dyschromatosis symmetrica hereditaria, MIM# 127400
Genetic Epilepsy v0.1700 ADAR Zornitza Stark Mode of inheritance for gene: ADAR was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1699 FRMD5 Zornitza Stark Marked gene: FRMD5 as ready
Genetic Epilepsy v0.1699 FRMD5 Zornitza Stark Gene: frmd5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1699 FRMD5 Zornitza Stark Classified gene: FRMD5 as Green List (high evidence)
Genetic Epilepsy v0.1699 FRMD5 Zornitza Stark Gene: frmd5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1698 FRMD5 Zornitza Stark gene: FRMD5 was added
gene: FRMD5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder MONDO:0700092, FRMD5-related
Review for gene: FRMD5 was set to GREEN
Added comment: Eight individuals reported with missense variants in this gene, de novo in 6 where parents were available. Clinical presentation was with ID, seizures, ataxia. Fly model.
Sources: Literature
Genetic Epilepsy v0.1697 AMPD2 Bryony Thompson Mode of inheritance for gene: AMPD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1696 AMPD2 Bryony Thompson Deleted their review
Genetic Epilepsy v0.1696 AMPD2 Bryony Thompson commented on gene: AMPD2
Genetic Epilepsy v0.1696 AMPD2 Bryony Thompson Deleted their review
Genetic Epilepsy v0.1696 ATP1A2 Bryony Thompson Deleted their review
Genetic Epilepsy v0.1696 ATP1A2 Bryony Thompson commented on gene: ATP1A2
Genetic Epilepsy v0.1696 ATP1A2 Bryony Thompson Deleted their review
Genetic Epilepsy v0.1695 ADGRL1 Zornitza Stark Phenotypes for gene: ADGRL1 were changed from Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092) to Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065
Genetic Epilepsy v0.1694 ADGRL1 Zornitza Stark reviewed gene: ADGRL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, behavioral abnormalities, and neuropsychiatric disorders, MIM# 620065; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1694 GABBR1 Zornitza Stark Classified gene: GABBR1 as Red List (low evidence)
Genetic Epilepsy v0.1694 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1693 GABBR1 Karina Sandoval edited their review of gene: GABBR1: Added comment: GABBR1 should be Red for Genetic Epilepsy panel as only 1 patient out of the 4 presented with seizures.

In addition PMID:36103875 stated it was surprising another individual in the study with p.Gly673Asp, causing a complete loss of GBR function did NOT suffer from seizures.; Changed rating: RED
Genetic Epilepsy v0.1693 GABBR1 Karina Sandoval changed review comment from: 4 de novo individuals with dev and language delays of varying severities associated with hyptonia, intellectual disability. 2 also with sleep disorder, and 1 with epilepsy.
Common phenotypes with differing disease severity and in associated neurodevelopmental disorders and comorbid psychiatric disorders.

4.5yo with p.Glu368Asp suffered from seizures, however paper also stated it was surprising that another individual in the study with p.Gly673Asp, causing a complete loss of GBR function did NOT suffer from seizures. ; to: 4 de novo individuals with dev and language delays of varying severities associated with hyptonia, intellectual disability. 2 also with sleep disorder, and 1 with epilepsy.
Common phenotypes with differing disease severity and in associated neurodevelopmental disorders and comorbid psychiatric disorders.

Functional analyses reveal that all four variants produce dysfunctional receptors, supporting that these de novo variants are pathogenic.

4.5yo with p.Glu368Asp suffered from seizures, however paper also stated it was surprising that another individual in the study with p.Gly673Asp, causing a complete loss of GBR function did NOT suffer from seizures.
Genetic Epilepsy v0.1693 GABBR1 Karina Sandoval changed review comment from: 4 de novo individuals with dev and language delays of varying severities associated with hyptonia, intellectual disability. 2 also with sleep disorder, and 1 with epilepsy.
Common phenotypes with differing disease severity and in associated neurodevelopmental disorders and comorbid psychiatric disorders.; to: 4 de novo individuals with dev and language delays of varying severities associated with hyptonia, intellectual disability. 2 also with sleep disorder, and 1 with epilepsy.
Common phenotypes with differing disease severity and in associated neurodevelopmental disorders and comorbid psychiatric disorders.

4.5yo with p.Glu368Asp suffered from seizures, however paper also stated it was surprising that another individual in the study with p.Gly673Asp, causing a complete loss of GBR function did NOT suffer from seizures.
Genetic Epilepsy v0.1693 SLC32A1 Zornitza Stark Publications for gene: SLC32A1 were set to 34038384; 36073542
Genetic Epilepsy v0.1692 SLC32A1 Zornitza Stark Phenotypes for gene: SLC32A1 were changed from Genetic epilepsy with febrile seizures plus to Genetic epilepsy with febrile seizures plus; Developmental and epileptic encephalopathy MONDO:0100062, SLC32A1-related
Genetic Epilepsy v0.1691 SLC32A1 Zornitza Stark Publications for gene: SLC32A1 were set to 34038384
Genetic Epilepsy v0.1690 LETM1 Zornitza Stark Marked gene: LETM1 as ready
Genetic Epilepsy v0.1690 LETM1 Zornitza Stark Gene: letm1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1690 LETM1 Zornitza Stark Classified gene: LETM1 as Green List (high evidence)
Genetic Epilepsy v0.1690 LETM1 Zornitza Stark Gene: letm1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1689 LETM1 Zornitza Stark Classified gene: LETM1 as Green List (high evidence)
Genetic Epilepsy v0.1689 LETM1 Zornitza Stark Gene: letm1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1688 GABBR1 Zornitza Stark Classified gene: GABBR1 as Green List (high evidence)
Genetic Epilepsy v0.1688 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1687 DEPDC5 Zornitza Stark Mode of inheritance for gene: DEPDC5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1687 GABBR1 Zornitza Stark Marked gene: GABBR1 as ready
Genetic Epilepsy v0.1687 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1687 GABBR1 Zornitza Stark Classified gene: GABBR1 as Green List (high evidence)
Genetic Epilepsy v0.1687 GABBR1 Zornitza Stark Gene: gabbr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1686 DEPDC5 Zornitza Stark Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1 MIM#604364 to Epilepsy, familial focal, with variable foci 1 MIM#604364; Neurodevelopmental disorder, DEPDC5-related, MONDO:0700092
Genetic Epilepsy v0.1685 DEPDC5 Zornitza Stark Mode of inheritance for gene: DEPDC5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1684 LETM1 Ee Ming Wong gene: LETM1 was added
gene: LETM1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214
Phenotypes for gene: LETM1 were set to Mitochondrial disease MONDO#0044970, LETM1-related
Review for gene: LETM1 was set to GREEN
gene: LETM1 was marked as current diagnostic
Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants
-Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation,
and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years
-Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect
-From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components
Sources: Literature
Genetic Epilepsy v0.1684 GABBR1 Karina Sandoval reviewed gene: GABBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36103875; Phenotypes: Neurodevelopmental disorder, GABBR1-related, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1684 GABBR1 Karina Sandoval gene: GABBR1 was added
gene: GABBR1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GABBR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABBR1 were set to PMID:36103875
Phenotypes for gene: GABBR1 were set to Neurodevelopmental disorder, GABBR1-related, MONDO:0700092
Genetic Epilepsy v0.1684 DEPDC5 Dean Phelan reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36067010, 32848577; Phenotypes: polymicrogyria, macrocephaly, epilepsy, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1684 MED11 Ain Roesley Classified gene: MED11 as Green List (high evidence)
Genetic Epilepsy v0.1684 MED11 Ain Roesley Gene: med11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1683 MED11 Ain Roesley Classified gene: MED11 as Green List (high evidence)
Genetic Epilepsy v0.1683 MED11 Ain Roesley Gene: med11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1682 MED11 Ain Roesley Marked gene: MED11 as ready
Genetic Epilepsy v0.1682 MED11 Ain Roesley Gene: med11 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1682 MED11 Ain Roesley gene: MED11 was added
gene: MED11 was added to Genetic Epilepsy. Sources: Literature
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 neurodevelopmental disorder MONDO#0700092, MED11-related
Review for gene: MED11 was set to GREEN
gene: MED11 was marked as current diagnostic
Added comment: 7 affected from 5 families (3x consang) with the same recurrent variant of p.(Arg109*).

Protein truncating, NOT NMD as proven by RT-PCR and western blot. Zebrafish knockout model recapitulates key clinical phenotypes

NO evidence of founder effect from haplotype analysis

7/7 cerebral dysgyria, cortical atrophy
5/7 limb contracture
4/7 epilepsy
3/7 families with IUGR
3/7 GDD
3/7 hearing loss
3/7 undescended testis
2/7 nystagmus
1/7 congenital cataract
Sources: Literature
Genetic Epilepsy v0.1681 SLC32A1 Lucy Spencer reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36073542; Phenotypes: developmental and epileptic encephalopathy MONDO:0100062, SLC32A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1681 GABRG1 Alison Yeung Marked gene: GABRG1 as ready
Genetic Epilepsy v0.1681 GABRG1 Alison Yeung Gene: gabrg1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1681 GABRG1 Alison Yeung Classified gene: GABRG1 as Red List (low evidence)
Genetic Epilepsy v0.1681 GABRG1 Alison Yeung Gene: gabrg1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1680 GABRG1 Anna Ritchie gene: GABRG1 was added
gene: GABRG1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GABRG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRG1 were set to PMID: 36121006
Phenotypes for gene: GABRG1 were set to developmental and epileptic encephalopathy MONDO:0100062
Review for gene: GABRG1 was set to RED
Added comment: 2-year-old patient with epileptic encephalopathy, hypotonia, and global developmental delays. Clinical trio exome sequencing showed a novel, de novo missense variant in the GABRG1 gene.
Sources: Literature
Genetic Epilepsy v0.1680 ATP6V0C Alison Yeung Classified gene: ATP6V0C as Green List (high evidence)
Genetic Epilepsy v0.1680 ATP6V0C Alison Yeung Gene: atp6v0c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1679 ATP6V0C Alison Yeung Classified gene: ATP6V0C as Green List (high evidence)
Genetic Epilepsy v0.1679 ATP6V0C Alison Yeung Gene: atp6v0c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1678 NAPB Alison Yeung Marked gene: NAPB as ready
Genetic Epilepsy v0.1678 NAPB Alison Yeung Gene: napb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1678 NAPB Alison Yeung Classified gene: NAPB as Green List (high evidence)
Genetic Epilepsy v0.1678 NAPB Alison Yeung Gene: napb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1677 ATP6V0C Naomi Baker reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36074901; Phenotypes: neurodevelopmental disorder (MONDO:0700092), ATP6V0C-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1677 GCSH Ain Roesley Classified gene: GCSH as Green List (high evidence)
Genetic Epilepsy v0.1677 GCSH Ain Roesley Gene: gcsh has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1677 GCSH Ain Roesley Classified gene: GCSH as Green List (high evidence)
Genetic Epilepsy v0.1677 GCSH Ain Roesley Gene: gcsh has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1676 GCSH Ain Roesley Marked gene: GCSH as ready
Genetic Epilepsy v0.1676 GCSH Ain Roesley Gene: gcsh has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1676 GCSH Ain Roesley gene: GCSH was added
gene: GCSH was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GCSH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GCSH were set to 36190515
Phenotypes for gene: GCSH were set to Glycine encephalopathy MIM#605899; neurodevelopmental disorder MONDO#0700092, GCHS-related
Penetrance for gene: GCSH were set to Complete
Review for gene: GCSH was set to GREEN
gene: GCSH was marked as current diagnostic
Added comment: 6x individuals, 3x with severe fatal glycine encephalopathy and 3x attenuated phenotype of developmental delay, behavioural problems, limited epilepsy, and variable movement problems

Severe fatal variants: 2x start loss and 1x missense
Attenuated variants : 2x missense and 1x exon 4-5 dup
Sources: Literature
Genetic Epilepsy v0.1675 NAPB Paul De Fazio gene: NAPB was added
gene: NAPB was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 26235277; 28097321; 33189936
Phenotypes for gene: NAPB were set to Developmental and epileptic encephalopathy 107 MIM#620033
Review for gene: NAPB was set to GREEN
gene: NAPB was marked as current diagnostic
Added comment: PMID 26235277: homozygous nonsense variant identified in a 6 year old girl by trio WES with early-onset epileptic encephalopathy characterised by multifocal seizures and profound GDD

PMID 28097321: exome sequencing in 152 consanguineous families with at least one member affected with ID. Homozygous nonsense variant identified in a patient with profound ID, seizures, feeding difficulties in infancy, muscularhypotonia, microcephaly, and impaired vision

PMID 33189936: homozygous canonical splice variant identified by trio exome sequencing in two siblings with seizures, intellectual disability and global developmental delay, microcephaly (<-3SD), and muscular hypotonia.
Sources: Literature
Genetic Epilepsy v0.1675 MOCS1 Zornitza Stark Tag treatable tag was added to gene: MOCS1.
Genetic Epilepsy v0.1675 COQ4 Zornitza Stark Tag treatable tag was added to gene: COQ4.
Genetic Epilepsy v0.1675 ARG1 Zornitza Stark Tag treatable tag was added to gene: ARG1.
Genetic Epilepsy v0.1675 PCCB Zornitza Stark Tag review tag was added to gene: PCCB.
Genetic Epilepsy v0.1675 PCCA Zornitza Stark Tag treatable tag was added to gene: PCCA.
Genetic Epilepsy v0.1675 QDPR Zornitza Stark Tag treatable tag was added to gene: QDPR.
Genetic Epilepsy v0.1675 PTS Zornitza Stark Tag treatable tag was added to gene: PTS.
Genetic Epilepsy v0.1675 PAH Zornitza Stark Marked gene: PAH as ready
Genetic Epilepsy v0.1675 PAH Zornitza Stark Gene: pah has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1675 PAH Zornitza Stark Phenotypes for gene: PAH were changed from Phenylketonuria, MIM#261600 to Phenylketonuria, MIM#261600
Genetic Epilepsy v0.1674 PAH Zornitza Stark Phenotypes for gene: PAH were changed from to Phenylketonuria, MIM#261600
Genetic Epilepsy v0.1673 PAH Zornitza Stark Mode of inheritance for gene: PAH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1672 PAH Zornitza Stark reviewed gene: PAH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Phenylketonuria, MIM#261600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1672 PAH Zornitza Stark Tag treatable tag was added to gene: PAH.
Genetic Epilepsy v0.1672 BTD Zornitza Stark Tag treatable tag was added to gene: BTD.
Genetic Epilepsy v0.1672 HLCS Zornitza Stark Tag treatable tag was added to gene: HLCS.
Genetic Epilepsy v0.1672 MMADHC Zornitza Stark Tag treatable tag was added to gene: MMADHC.
Genetic Epilepsy v0.1672 MMACHC Zornitza Stark Tag treatable tag was added to gene: MMACHC.
Genetic Epilepsy v0.1672 BCKDHB Zornitza Stark Tag treatable tag was added to gene: BCKDHB.
Genetic Epilepsy v0.1672 BCKDHA Zornitza Stark Tag treatable tag was added to gene: BCKDHA.
Genetic Epilepsy v0.1672 DBT Zornitza Stark Marked gene: DBT as ready
Genetic Epilepsy v0.1672 DBT Zornitza Stark Gene: dbt has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1672 DBT Zornitza Stark Mode of inheritance for gene: DBT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1671 DBT Zornitza Stark Phenotypes for gene: DBT were changed from to Maple syrup urine disease, type II (MIM#248600)
Genetic Epilepsy v0.1670 DBT Zornitza Stark Tag treatable tag was added to gene: DBT.
Genetic Epilepsy v0.1670 HMGCL Zornitza Stark Tag treatable tag was added to gene: HMGCL.
Genetic Epilepsy v0.1670 ATP7A Zornitza Stark Marked gene: ATP7A as ready
Genetic Epilepsy v0.1670 ATP7A Zornitza Stark Gene: atp7a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1670 ATP7A Zornitza Stark Phenotypes for gene: ATP7A were changed from to Menkes disease MIM#309400
Genetic Epilepsy v0.1669 ATP7A Zornitza Stark Mode of inheritance for gene: ATP7A was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1668 ATP7A Zornitza Stark reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Menkes disease MIM#309400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1668 ATP7A Zornitza Stark Tag treatable tag was added to gene: ATP7A.
Genetic Epilepsy v0.1668 ALDH7A1 Zornitza Stark Marked gene: ALDH7A1 as ready
Genetic Epilepsy v0.1668 ALDH7A1 Zornitza Stark Gene: aldh7a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1668 ALDH7A1 Zornitza Stark Phenotypes for gene: ALDH7A1 were changed from to Epilepsy, pyridoxine-dependent, MIM# 266100
Genetic Epilepsy v0.1667 ALDH7A1 Zornitza Stark Publications for gene: ALDH7A1 were set to 33200442
Genetic Epilepsy v0.1666 ALDH7A1 Zornitza Stark Publications for gene: ALDH7A1 were set to
Genetic Epilepsy v0.1665 ALDH7A1 Zornitza Stark Mode of inheritance for gene: ALDH7A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1664 ALDH7A1 Zornitza Stark Tag treatable tag was added to gene: ALDH7A1.
Genetic Epilepsy v0.1664 ALDH7A1 Zornitza Stark reviewed gene: ALDH7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33200442; Phenotypes: Epilepsy, pyridoxine-dependent, MIM# 266100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1664 CACNA1C Zornitza Stark Phenotypes for gene: CACNA1C were changed from Neurodevelopmental abnormalities and epilepsy, no OMIM# to Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, MIM# 620029
Genetic Epilepsy v0.1663 CACNA1C Zornitza Stark edited their review of gene: CACNA1C: Changed phenotypes: Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, MIM# 620029
Genetic Epilepsy v0.1663 UFSP2 Zornitza Stark Phenotypes for gene: UFSP2 were changed from Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus to Developmental and epileptic encephalopathy 106, MIM# 620028; Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Genetic Epilepsy v0.1662 UFSP2 Zornitza Stark edited their review of gene: UFSP2: Changed phenotypes: Developmental and epileptic encephalopathy 106, MIM# 620028, Abnormal muscle tone, Seizures, Global developmental delay, Delayed speech and language development, Intellectual disability, Strabismus
Genetic Epilepsy v0.1662 TRAPPC10 Zornitza Stark Phenotypes for gene: TRAPPC10 were changed from neurodevelopmental disorder (MONDO:0700092), TRAPPC10-related to Neurodevelopmental disorder with microcephaly, short stature, and speech delay, MIM# 620027
Genetic Epilepsy v0.1661 TRAPPC10 Zornitza Stark reviewed gene: TRAPPC10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, short stature, and speech delay, MIM# 620027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1661 CAPRIN1 Zornitza Stark Publications for gene: CAPRIN1 were set to 35979925
Genetic Epilepsy v0.1660 UBAP2L Zornitza Stark Phenotypes for gene: UBAP2L were changed from Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related; 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, MONDO:0700092, UBAP2L-related; 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
Genetic Epilepsy v0.1660 UBAP2L Zornitza Stark Marked gene: UBAP2L as ready
Genetic Epilepsy v0.1660 UBAP2L Zornitza Stark Gene: ubap2l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1660 UBAP2L Zornitza Stark 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, MONDO:0700092, UBAP2L-related; 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
Genetic Epilepsy v0.1659 UBAP2L Zornitza Stark Classified gene: UBAP2L as Green List (high evidence)
Genetic Epilepsy v0.1659 UBAP2L Zornitza Stark Gene: ubap2l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1658 UBAP2L Zornitza Stark reviewed gene: UBAP2L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1658 CHKA Zornitza Stark Phenotypes for gene: CHKA were changed from Neurodevelopmental disorder, MONDO:0700092; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature to Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, MIM#620023
Genetic Epilepsy v0.1657 CHKA Zornitza Stark reviewed gene: CHKA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, MIM#620023; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1657 CAPRIN1 Konstantinos Varvagiannis reviewed gene: CAPRIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35979925, 35977029, 28135719, 31398340, https://doi.org/10.1101/2021.12.20.21267194; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Autistic behavior, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic Epilepsy v0.1657 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to AMBER
Added comment: Seizures have been reported in several individuals although a formal diagnosis of epilepsy was retained in ~30% in a small cohort discussed below. Consider inclusion with amber rating.

-----

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

Details provided below.

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

--------

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

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

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

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

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

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

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Genetic Epilepsy v0.1657 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Genetic Epilepsy v0.1657 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1657 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Red List (low evidence)
Genetic Epilepsy v0.1657 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1656 PPFIBP1 Zornitza Stark Phenotypes for gene: PPFIBP1 were changed from Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024 to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024
Genetic Epilepsy v0.1655 PPFIBP1 Zornitza Stark Phenotypes for gene: PPFIBP1 were changed from Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024
Genetic Epilepsy v0.1654 PPFIBP1 Zornitza Stark edited their review of gene: PPFIBP1: Changed phenotypes: Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, MIM# 620024
Genetic Epilepsy v0.1654 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to RED
Added comment: SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Genetic Epilepsy v0.1654 TMEM163 Zornitza Stark Marked gene: TMEM163 as ready
Genetic Epilepsy v0.1654 TMEM163 Zornitza Stark Gene: tmem163 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1654 TMEM163 Zornitza Stark Phenotypes for gene: TMEM163 were changed from Hypomyelinating leukodystrophy, MONDO:0019046 to Hypomyelinating leukodystrophy, MONDO:0019046
Genetic Epilepsy v0.1654 TMEM163 Zornitza Stark Phenotypes for gene: TMEM163 were changed from Hypomyelinating leukodystrophy to Hypomyelinating leukodystrophy, MONDO:0019046
Genetic Epilepsy v0.1653 TMEM163 Zornitza Stark Classified gene: TMEM163 as Green List (high evidence)
Genetic Epilepsy v0.1653 TMEM163 Zornitza Stark Gene: tmem163 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1652 COX11 Zornitza Stark Marked gene: COX11 as ready
Genetic Epilepsy v0.1652 COX11 Zornitza Stark Gene: cox11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1652 COX11 Zornitza Stark Classified gene: COX11 as Green List (high evidence)
Genetic Epilepsy v0.1652 COX11 Zornitza Stark Gene: cox11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1651 COX11 Zornitza Stark Classified gene: COX11 as Green List (high evidence)
Genetic Epilepsy v0.1651 COX11 Zornitza Stark Gene: cox11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1650 CAPRIN1 Zornitza Stark Marked gene: CAPRIN1 as ready
Genetic Epilepsy v0.1650 CAPRIN1 Zornitza Stark Gene: caprin1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1650 CAPRIN1 Zornitza Stark Classified gene: CAPRIN1 as Green List (high evidence)
Genetic Epilepsy v0.1650 CAPRIN1 Zornitza Stark Gene: caprin1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1649 COX11 Chern Lim gene: COX11 was added
gene: COX11 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551
Phenotypes for gene: COX11 were set to Mitochondrial disease (MONDO:0044970), COX11-related
Review for gene: COX11 was set to GREEN
gene: COX11 was marked as current diagnostic
Added comment: PMID: 36030551
- Biallelic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated consanguineous families, one with homozygous missense variant, another with homozygous frameshift variant.
- Functional studies supported pathogenicity of the missense variant, and showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10.
- RNA studies suggested the mutant transcript with p.(Val12Glyfs*21) is not degraded by nonsense mediated decay.
Sources: Literature
Genetic Epilepsy v0.1649 TMEM163 Teresa Zhao gene: TMEM163 was added
gene: TMEM163 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TMEM163 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM163 were set to PMID: 35953447
Phenotypes for gene: TMEM163 were set to Hypomyelinating leukodystrophy
Review for gene: TMEM163 was set to GREEN
Added comment: Four unrelated families with a hypomyelinating leukodystrophy phenotype. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant.

All have global developmental delay, three of them have seizures.
Sources: Literature
Genetic Epilepsy v0.1649 CAPRIN1 Paul De Fazio gene: CAPRIN1 was added
gene: CAPRIN1 was added to Genetic Epilepsy. 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
Phenotypes for gene: CAPRIN1 were set to Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092
Review for gene: CAPRIN1 was set to GREEN
gene: CAPRIN1 was marked as current diagnostic
Added comment: 12 individuals reported with ID and language impairment. Other features included seizures (4 individuals), hands and feet malformations (5 individuals), breathing problems (6 individuals), ocular problems (4 individuals) and hearing problems (3 individuals).

All of the variants were nonsense (NMD-predicted) or splicing variants. 10 were de novo, 1 was inherited from an affected father. Functional studies supported pathogenicity.
Sources: Literature
Genetic Epilepsy v0.1649 GRIN2A Zornitza Stark Publications for gene: GRIN2A were set to 30544257
Genetic Epilepsy v0.1648 GRIN2A Zornitza Stark Mode of inheritance for gene: GRIN2A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1647 GRIN2A Zornitza Stark Mode of inheritance for gene: GRIN2A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1646 GRIN2A Teresa Zhao reviewed gene: GRIN2A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35983985; Phenotypes: Epilepsy, focal, with speech disorder and with or without impaired intellectual development (MIM#245570); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1646 Zornitza Stark HPO terms changed from to Seizure, HP:0001250
Genetic Epilepsy v0.1645 LNPK Chirag Patel Classified gene: LNPK as Green List (high evidence)
Genetic Epilepsy v0.1645 LNPK Chirag Patel Gene: lnpk has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1644 LNPK Chirag Patel reviewed gene: LNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35599435; Phenotypes: Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, MIM# 618090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1644 ZMYND8 Zornitza Stark Marked gene: ZMYND8 as ready
Genetic Epilepsy v0.1644 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1644 ZMYND8 Zornitza Stark Classified gene: ZMYND8 as Green List (high evidence)
Genetic Epilepsy v0.1644 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1643 ZMYND8 Zornitza Stark gene: ZMYND8 was added
gene: ZMYND8 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Expert Review
Genetic Epilepsy v0.1642 SLITRK2 Zornitza Stark Marked gene: SLITRK2 as ready
Genetic Epilepsy v0.1642 SLITRK2 Zornitza Stark Gene: slitrk2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1642 SLITRK2 Zornitza Stark Classified gene: SLITRK2 as Green List (high evidence)
Genetic Epilepsy v0.1642 SLITRK2 Zornitza Stark Gene: slitrk2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1641 RAC3 Zornitza Stark Marked gene: RAC3 as ready
Genetic Epilepsy v0.1641 RAC3 Zornitza Stark Gene: rac3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1641 RAC3 Zornitza Stark Classified gene: RAC3 as Green List (high evidence)
Genetic Epilepsy v0.1641 RAC3 Zornitza Stark Gene: rac3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1640 SLITRK2 Paul De Fazio edited their review of gene: SLITRK2: Changed rating: GREEN
Genetic Epilepsy v0.1640 SLITRK2 Paul De Fazio gene: SLITRK2 was added
gene: SLITRK2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SLITRK2 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: SLITRK2 were set to 35840571
Phenotypes for gene: SLITRK2 were set to Neurodevelopmental disorder, SLITRK2-related MONDO:0700092
gene: SLITRK2 was marked as current diagnostic
Added comment: 6 missense variants and 1 nonsense variant (NOT NMD-predicted, single-exon gene) reported in 7 males and 1 female with neurodevelopmental disorders. Phenotypes included dev delay, mild to severe ID, delayed or absent speech, seizures and brain MRI anomalies (in some patients).

The nonsense variant was identified in two affected brothers but not in the mother, suggesting it was de novo in the maternal germline. The variant in the one affected female was de novo. All other variants in hemizygous males were inherited from an unaffected mother. In one case, the variant was also identified in the unaffected grandmother.

Functional studies showed some but not all variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Conditional knockout mice exhibited impaired long-term memory and abnormal gait.
Sources: Literature
Genetic Epilepsy v0.1640 RAC3 Alison Yeung gene: RAC3 was added
gene: RAC3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAC3 were set to 35851598
Phenotypes for gene: RAC3 were set to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, MIM#618577
Review for gene: RAC3 was set to GREEN
Added comment: Sources: Literature
Genetic Epilepsy v0.1640 RAC3 Alison Yeung gene: RAC3 was added
gene: RAC3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAC3 were set to 35851598
Phenotypes for gene: RAC3 were set to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, MIM#618577
Review for gene: RAC3 was set to GREEN
Added comment: Sources: Literature
Genetic Epilepsy v0.1639 PPFIBP1 Zornitza Stark Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Genetic Epilepsy v0.1638 ADGRL1 Elena Savva Classified gene: ADGRL1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1638 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1637 ADGRL1 Elena Savva Classified gene: ADGRL1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1637 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1637 ADGRL1 Elena Savva Classified gene: ADGRL1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1637 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1636 ADGRL1 Elena Savva Marked gene: ADGRL1 as ready
Genetic Epilepsy v0.1636 ADGRL1 Elena Savva Gene: adgrl1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1636 PPFIBP1 Ee Ming Wong reviewed gene: PPFIBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35830857; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v0.1636 ADGRL1 Elena Savva gene: ADGRL1 was added
gene: ADGRL1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ADGRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ADGRL1 were set to PMID: 35907405
Phenotypes for gene: ADGRL1 were set to Neurodevelopmental disorder, ADGRL1-related (MONDO#0700092)
Review for gene: ADGRL1 was set to AMBER
Added comment: PMID: 35907405 - 9 patients, only had epilepsy (2/9).

Het null mouse model shows neurological and developmental abnormalities, with hom null mice non-viable.
Sources: Literature
Genetic Epilepsy v0.1635 TAF8 Zornitza Stark Phenotypes for gene: TAF8 were changed from Neurodevelopmental disorder, MONDO:0700092, TAF8-related to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972
Genetic Epilepsy v0.1634 TAF8 Zornitza Stark edited their review of gene: TAF8: Changed phenotypes: Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, MIM# 619972
Genetic Epilepsy v0.1634 ARFGEF1 Zornitza Stark Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Genetic Epilepsy v0.1633 ARFGEF1 Zornitza Stark edited their review of gene: ARFGEF1: Changed phenotypes: Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619964
Genetic Epilepsy v0.1633 PLXNA1 Zornitza Stark Phenotypes for gene: PLXNA1 were changed from Neurodevelopmental disorder with cerebral and eye anomalies to Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Genetic Epilepsy v0.1632 PLXNA1 Zornitza Stark edited their review of gene: PLXNA1: Changed phenotypes: Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Genetic Epilepsy v0.1632 PIK3C2B Zornitza Stark Marked gene: PIK3C2B as ready
Genetic Epilepsy v0.1632 PIK3C2B Zornitza Stark Gene: pik3c2b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1632 PIK3C2B Zornitza Stark Classified gene: PIK3C2B as Amber List (moderate evidence)
Genetic Epilepsy v0.1632 PIK3C2B Zornitza Stark Gene: pik3c2b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1631 PIK3C2B Krithika Murali gene: PIK3C2B was added
gene: PIK3C2B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PIK3C2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3C2B were set to PMID: 35786744
Phenotypes for gene: PIK3C2B were set to familial partial epilepsy - MONDO#0017704
Review for gene: PIK3C2B was set to AMBER
Added comment: No OMIM gene disease association.

Gozzelino et al.(2022) Brain - report enrichment of ultra-rare PIK3C2B variants in focal epilepsy cohorts, including one variant shown to be de novo (G1294Q). Segregation data not provided for all cases. The p.G1345S variant was inherited from an affected father. The p.K584* variant was inherited from an unaffected father suggesting incomplete penetrance. Functional studies supported a LoF mechanism and mouse model studies suggestive of mTORC1 pathway hyperactivation.
Sources: Literature
Genetic Epilepsy v0.1631 WNK3 Zornitza Stark Marked gene: WNK3 as ready
Genetic Epilepsy v0.1631 WNK3 Zornitza Stark Gene: wnk3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1631 WNK3 Zornitza Stark Classified gene: WNK3 as Green List (high evidence)
Genetic Epilepsy v0.1631 WNK3 Zornitza Stark Gene: wnk3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1630 WNK3 Lucy Spencer gene: WNK3 was added
gene: WNK3 was added to Genetic Epilepsy. Sources: Literature
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 35678782
Phenotypes for gene: WNK3 were set to Neurodevelopmental disorder, WNK3-related (MONDO#0700092)
Review for gene: WNK3 was set to GREEN
Added comment: 6 maternally inherited hemizygous variants, 3 missense and 3 LOF. Seen in 14 individuals from 6 families. The variants cosegregated with disease in 3 families with multiple affected individuals. Phenotype described as intellectual disability, with the variable presence of seizures and structural brain defects. One family previously had a clinical diagnosis of X-linked Prieto syndrome.
Sources: Literature
Genetic Epilepsy v0.1630 TAF8 Zornitza Stark changed review comment from: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. This is likely to be a founder variant. One family with different compound heterozygous variants.
Sources: Literature; to: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. Unclear if this is a founder variant, families were of different ethnicities. One family with different compound heterozygous variants.
Sources: Literature
Genetic Epilepsy v0.1630 TAF8 Zornitza Stark Tag founder was removed from gene: TAF8.
Genetic Epilepsy v0.1630 TAF8 Zornitza Stark Marked gene: TAF8 as ready
Genetic Epilepsy v0.1630 TAF8 Zornitza Stark Gene: taf8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1630 TAF8 Zornitza Stark Classified gene: TAF8 as Green List (high evidence)
Genetic Epilepsy v0.1630 TAF8 Zornitza Stark Gene: taf8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1629 TAF8 Zornitza Stark gene: TAF8 was added
gene: TAF8 was added to Genetic Epilepsy. Sources: Literature
founder 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, MONDO:0700092, TAF8-related
Review for gene: TAF8 was set to GREEN
Added comment: 8 individuals reported from 5 families, four of which were consanguineous. Clinical features included severe psychomotor retardation with almost absent development, feeding problems, microcephaly, growth retardation, spasticity and epilepsy. Six had the c.781-1G > A variant in homozygous state. This is likely to be a founder variant. One family with different compound heterozygous variants.
Sources: Literature
Genetic Epilepsy v0.1628 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Intellectual disability; epilepsy to Neurodevelopmental disorder, MONDO:0700092, TRPM3-related
Genetic Epilepsy v0.1627 NR4A2 Zornitza Stark 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, MIM# 619911
Genetic Epilepsy v0.1626 NR4A2 Zornitza Stark edited their review of gene: NR4A2: Changed phenotypes: Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, MIM# 619911
Genetic Epilepsy v0.1626 KCNC2 Zornitza Stark Phenotypes for gene: KCNC2 were changed from Developmental and epileptic encephalopathy 103, MIM# 619913 to Developmental and epileptic encephalopathy 103, MIM# 619913
Genetic Epilepsy v0.1625 KCNC2 Zornitza Stark Phenotypes for gene: KCNC2 were changed from epileptic encephalopathy; spastic tetraplegia; opisthotonos attacks; intellectual disability; West syndrome to Developmental and epileptic encephalopathy 103, MIM# 619913
Genetic Epilepsy v0.1624 KCNC2 Zornitza Stark Publications for gene: KCNC2 were set to PMID:32392612; 31972370
Genetic Epilepsy v0.1623 KCNC2 Zornitza Stark Classified gene: KCNC2 as Green List (high evidence)
Genetic Epilepsy v0.1623 KCNC2 Zornitza Stark Gene: kcnc2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1622 KCNC2 Zornitza Stark reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35314505; Phenotypes: Developmental and epileptic encephalopathy 103, MIM# 619913; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1622 ATP2B1 Zornitza Stark Phenotypes for gene: ATP2B1 were changed from Neurodevelopmental disorder, MONDO:0700092, ATP2B1-related to Intellectual developmental disorder, autosomal dominant 66, MIM# 619910
Genetic Epilepsy v0.1621 ATP2B1 Zornitza Stark reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 66, MIM# 619910; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1621 TIAM1 Zornitza Stark Phenotypes for gene: TIAM1 were changed from Neurodevelopmental disorder, TIAM1-related, MONDO:0700092 to Neurodevelopmental disorder with language delay and seizures, MIM# 619908
Genetic Epilepsy v0.1620 DLG4 Zornitza Stark Marked gene: DLG4 as ready
Genetic Epilepsy v0.1620 DLG4 Zornitza Stark Gene: dlg4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1620 DLG4 Zornitza Stark Mode of inheritance for gene: DLG4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1619 DLG4 Zornitza Stark Classified gene: DLG4 as Green List (high evidence)
Genetic Epilepsy v0.1619 DLG4 Zornitza Stark Gene: dlg4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1618 DLG4 Lucy Spencer gene: DLG4 was added
gene: DLG4 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: DLG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLG4 were set to 33597769
Phenotypes for gene: DLG4 were set to Intellectual developmental disorder, autosomal dominant 62 MIM#618793
Review for gene: DLG4 was set to GREEN
Added comment: PMID: 33597769- A cohort of 53 individuals with DLG4 variants 24 of whom had epilepsy or some form of seizures including focal or febrile seizures along with ID and other features.
Sources: Literature
Genetic Epilepsy v0.1618 RMND1 Zornitza Stark Marked gene: RMND1 as ready
Genetic Epilepsy v0.1618 RMND1 Zornitza Stark Gene: rmnd1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1618 RMND1 Zornitza Stark Phenotypes for gene: RMND1 were changed from to Combined oxidative phosphorylation deficiency 11 MIM#614922
Genetic Epilepsy v0.1617 RMND1 Zornitza Stark Publications for gene: RMND1 were set to
Genetic Epilepsy v0.1616 RMND1 Zornitza Stark Mode of inheritance for gene: RMND1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1615 RMND1 Belinda Chong reviewed gene: RMND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23022098, 25604853, 26395190; Phenotypes: Combined oxidative phosphorylation deficiency 11 MIM#614922; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v0.1615 PRPF8 Zornitza Stark Marked gene: PRPF8 as ready
Genetic Epilepsy v0.1615 PRPF8 Zornitza Stark Gene: prpf8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1615 PRPF8 Zornitza Stark Phenotypes for gene: PRPF8 were changed from Neurodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059 to Neurodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059
Genetic Epilepsy v0.1614 PRPF8 Zornitza Stark Phenotypes for gene: PRPF8 were changed from urodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059 to Neurodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059
Genetic Epilepsy v0.1614 PRPF8 Zornitza Stark Phenotypes for gene: PRPF8 were changed from urodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059 to urodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059
Genetic Epilepsy v0.1614 PRPF8 Zornitza Stark Phenotypes for gene: PRPF8 were changed from Epilepsy; intellectual disability; Retinitis pigmentosa 13 - MIM#600059 to urodevelopmental disorder MONDO:0700092, PRPF8-related; Retinitis pigmentosa 13 - MIM#600059
Genetic Epilepsy v0.1613 PRPF8 Zornitza Stark Classified gene: PRPF8 as Green List (high evidence)
Genetic Epilepsy v0.1613 PRPF8 Zornitza Stark Gene: prpf8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1612 PRPF8 Krithika Murali changed review comment from: PMID 35543142 O'Grady et al 2022 report 14 unrelated individuals with heterozygous PRPF8 variants and ID, dymorphic features and epilepsy (7/14). Short stature, abnormal gait and cardiac anomalies also reported. 11 variants identified were de novo, 1 variant - maternal mosaicism, 1 variant - duo sequencing (not identified in mother, father could not be sequenced). 1 individual did not have parental testing. Cardiac anomalies varied and included benign cardiac tumour, dilated cardiomyopathy, dilated aortic root (COL5A2 VUS also identified), bicuspid aortic valve, cardiac arrest, self-resolving ASD/VSD.

Heterozygous PRPF8 variants previously associated with retinitis pigmentosa. 1 out of the 14 individuals in this cohort had a diagnosis of RP. RP variants noted to cluster in the C'terminal MPN domain. The individual with RP in this paper had a variant in the preceding RNAase H homology domain near the C-terminus. Not all of the individuals in this paper had formal ophthalmological examination.
Sources: Literature; to: PMID 35543142 O'Grady et al 2022 report 14 unrelated individuals with heterozygous PRPF8 variants and ID, dev delay, dymorphic features and epilepsy (7/14). Short stature, abnormal gait and cardiac anomalies also reported. 11 variants identified were de novo, 1 variant - maternal mosaicism, 1 variant - duo sequencing (not identified in mother, father could not be sequenced). 1 individual did not have parental testing. Cardiac anomalies varied and included benign cardiac tumour, dilated cardiomyopathy, dilated aortic root (COL5A2 VUS also identified), bicuspid aortic valve, cardiac arrest, self-resolving ASD/VSD.

Heterozygous PRPF8 variants previously associated with retinitis pigmentosa. 1 out of the 14 individuals in this cohort had a diagnosis of RP. RP variants noted to cluster in the C'terminal MPN domain. The individual with RP in this paper had a variant in the preceding RNAase H homology domain near the C-terminus. Not all of the individuals in this paper had formal ophthalmological examination.
Sources: Literature
Genetic Epilepsy v0.1612 PRPF8 Krithika Murali gene: PRPF8 was added
gene: PRPF8 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRPF8 were set to 35543142
Phenotypes for gene: PRPF8 were set to Epilepsy; intellectual disability; Retinitis pigmentosa 13 - MIM#600059
Review for gene: PRPF8 was set to GREEN
Added comment: PMID 35543142 O'Grady et al 2022 report 14 unrelated individuals with heterozygous PRPF8 variants and ID, dymorphic features and epilepsy (7/14). Short stature, abnormal gait and cardiac anomalies also reported. 11 variants identified were de novo, 1 variant - maternal mosaicism, 1 variant - duo sequencing (not identified in mother, father could not be sequenced). 1 individual did not have parental testing. Cardiac anomalies varied and included benign cardiac tumour, dilated cardiomyopathy, dilated aortic root (COL5A2 VUS also identified), bicuspid aortic valve, cardiac arrest, self-resolving ASD/VSD.

Heterozygous PRPF8 variants previously associated with retinitis pigmentosa. 1 out of the 14 individuals in this cohort had a diagnosis of RP. RP variants noted to cluster in the C'terminal MPN domain. The individual with RP in this paper had a variant in the preceding RNAase H homology domain near the C-terminus. Not all of the individuals in this paper had formal ophthalmological examination.
Sources: Literature
Genetic Epilepsy v0.1612 NOVA2 Seb Lunke Publications for gene: NOVA2 were set to 32197073
Genetic Epilepsy v0.1611 NOVA2 Seb Lunke Classified gene: NOVA2 as Green List (high evidence)
Genetic Epilepsy v0.1611 NOVA2 Seb Lunke Gene: nova2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1610 NOVA2 Seb Lunke reviewed gene: NOVA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35607920; Phenotypes: Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities, MIM# 618859; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Genetic Epilepsy v0.1610 U2AF2 Zornitza Stark Phenotypes for gene: U2AF2 were changed from Epilepsy; Developmental Delay; Intellectual Disability to Neurodevelopmental disorder MONDO:0700092, MMGT1-related
Genetic Epilepsy v0.1609 SLC38A3 Zornitza Stark Phenotypes for gene: SLC38A3 were changed from Developmental epileptic encephalopathy MONDO:0100062, SLC38A3-related to Developmental and epileptic encephalopathy 102, MIM# 619881
Genetic Epilepsy v0.1608 SLC38A3 Zornitza Stark reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, MIM# 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1608 PCDHGC4 Zornitza Stark Phenotypes for gene: PCDHGC4 were changed from Neurodevelopmental disorder with poor growth and skeletal anomalies, MIM# 619880 to Neurodevelopmental disorder with poor growth and skeletal anomalies, MIM# 619880
Genetic Epilepsy v0.1607 PCDHGC4 Zornitza Stark Phenotypes for gene: PCDHGC4 were changed from Intellectual disability; Seizures to Neurodevelopmental disorder with poor growth and skeletal anomalies, MIM# 619880
Genetic Epilepsy v0.1606 PCDHGC4 Zornitza Stark edited their review of gene: PCDHGC4: Changed phenotypes: Neurodevelopmental disorder with poor growth and skeletal anomalies, MIM# 619880
Genetic Epilepsy v0.1606 ZNF526 Zornitza Stark Phenotypes for gene: ZNF526 were changed from Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia to Dentici-Novelli neurodevelopmental syndrome, MIM# 619877
Genetic Epilepsy v0.1605 ZNF526 Zornitza Stark edited their review of gene: ZNF526: Changed phenotypes: Dentici-Novelli neurodevelopmental syndrome, MIM# 619877
Genetic Epilepsy v0.1605 CPSF3 Zornitza Stark Phenotypes for gene: CPSF3 were changed from Neurodevelopmental disorder, CPSF3-related, MONDO:0700092 to Neurodevelopmental disorder with microcephaly, hypotonia, and seizures (NEDMHS), MIM#619876
Genetic Epilepsy v0.1604 CPSF3 Zornitza Stark reviewed gene: CPSF3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and seizures (NEDMHS), MIM#619876; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1604 ATP6V0A1 Bryony Thompson Marked gene: ATP6V0A1 as ready
Genetic Epilepsy v0.1604 ATP6V0A1 Bryony Thompson Gene: atp6v0a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1604 ATP6V0A1 Bryony Thompson Classified gene: ATP6V0A1 as Green List (high evidence)
Genetic Epilepsy v0.1604 ATP6V0A1 Bryony Thompson Gene: atp6v0a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1603 GRIA4 Ain Roesley Phenotypes for gene: GRIA4 were changed from Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864 to Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864
Genetic Epilepsy v0.1603 GRIA4 Ain Roesley Phenotypes for gene: GRIA4 were changed from Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864 to Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864
Genetic Epilepsy v0.1603 GRIA4 Ain Roesley Publications for gene: GRIA4 were set to 35518358; 29220673
Genetic Epilepsy v0.1603 GRIA4 Ain Roesley Phenotypes for gene: GRIA4 were changed from Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864 to Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864
Genetic Epilepsy v0.1603 GRIA4 Ain Roesley Publications for gene: GRIA4 were set to 35518358; 29220673
Genetic Epilepsy v0.1603 GRIA4 Ain Roesley Phenotypes for gene: GRIA4 were changed from Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864 to Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864
Genetic Epilepsy v0.1602 GRIA4 Ain Roesley Phenotypes for gene: GRIA4 were changed from to Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864
Genetic Epilepsy v0.1602 GRIA4 Ain Roesley Publications for gene: GRIA4 were set to
Genetic Epilepsy v0.1602 GRIA4 Ain Roesley Marked gene: GRIA4 as ready
Genetic Epilepsy v0.1602 GRIA4 Ain Roesley Gene: gria4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1602 GRIA4 Ain Roesley Mode of inheritance for gene: GRIA4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1601 GRIA4 Ain Roesley reviewed gene: GRIA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35518358, 29220673; Phenotypes: Neurodevelopmental disorder with or without seizures and gait abnormalities MIM#617864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Genetic Epilepsy v0.1601 SLC1A2 Zornitza Stark Marked gene: SLC1A2 as ready
Genetic Epilepsy v0.1601 SLC1A2 Zornitza Stark Gene: slc1a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1601 SLC1A2 Zornitza Stark Publications for gene: SLC1A2 were set to 27476654; 28777935; 30937933; 23934111
Genetic Epilepsy v0.1600 SLC1A2 Zornitza Stark Phenotypes for gene: SLC1A2 were changed from Developmental and epileptic encephalopathy 41, MIM# 617105 to Developmental and epileptic encephalopathy 41, MIM# 617105
Genetic Epilepsy v0.1599 SLC1A2 Zornitza Stark Phenotypes for gene: SLC1A2 were changed from to Developmental and epileptic encephalopathy 41, MIM# 617105
Genetic Epilepsy v0.1598 SLC1A2 Zornitza Stark Publications for gene: SLC1A2 were set to
Genetic Epilepsy v0.1597 SLC1A2 Zornitza Stark Mode of pathogenicity for gene: SLC1A2 was changed from to Other
Genetic Epilepsy v0.1596 SLC1A2 Zornitza Stark Mode of inheritance for gene: SLC1A2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1595 SLC1A2 Zornitza Stark reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27476654, 28777935, 30937933, 23934111; Phenotypes: Developmental and epileptic encephalopathy 41, MIM# 617105; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1595 DEPDC5 Zornitza Stark Marked gene: DEPDC5 as ready
Genetic Epilepsy v0.1595 DEPDC5 Zornitza Stark Gene: depdc5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1595 DEPDC5 Zornitza Stark Phenotypes for gene: DEPDC5 were changed from to Epilepsy, familial focal, with variable foci 1 MIM#604364
Genetic Epilepsy v0.1594 DEPDC5 Zornitza Stark Publications for gene: DEPDC5 were set to
Genetic Epilepsy v0.1593 DEPDC5 Zornitza Stark Mode of inheritance for gene: DEPDC5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1592 DEPDC5 Zornitza Stark reviewed gene: DEPDC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31444548, 23542697, 23542701; Phenotypes: Epilepsy, familial focal, with variable foci 1 MIM#604364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1592 ACTL6B Zornitza Stark Mode of inheritance for gene: ACTL6B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1591 ACTL6B Zornitza Stark edited their review of gene: ACTL6B: Changed phenotypes: Epileptic encephalopathy, early infantile, 76, MIM# 618468, Intellectual developmental disorder with severe speech and ambulation defects, MIM# 618470; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1591 DNAH14 Zornitza Stark Marked gene: DNAH14 as ready
Genetic Epilepsy v0.1591 DNAH14 Zornitza Stark Gene: dnah14 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1591 DNAH14 Zornitza Stark Phenotypes for gene: DNAH14 were changed from Neurodevelopmental disorder, DNAH14-related (MONDO#0700092) to Neurodevelopmental disorder (MONDO#0700092), DNAH14-related
Genetic Epilepsy v0.1590 DNAH14 Zornitza Stark Classified gene: DNAH14 as Green List (high evidence)
Genetic Epilepsy v0.1590 DNAH14 Zornitza Stark Gene: dnah14 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1589 DNAH14 Chern Lim gene: DNAH14 was added
gene: DNAH14 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to PMID: 35438214
Phenotypes for gene: DNAH14 were set to Neurodevelopmental disorder, DNAH14-related (MONDO#0700092)
Review for gene: DNAH14 was set to GREEN
gene: DNAH14 was marked as current diagnostic
Added comment: PMID: 35438214:
- Three previously unreported patients with compound heterozygous DNAH14 variants, including one nonsense, one frameshift, and four missense variants. A spectrum of neurological and developmental phenotypes was observed, including seizures, global developmental delay, microcephaly, and hypotonia.
Sources: Literature
Genetic Epilepsy v0.1589 DROSHA Zornitza Stark Marked gene: DROSHA as ready
Genetic Epilepsy v0.1589 DROSHA Zornitza Stark Gene: drosha has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1589 DROSHA Zornitza Stark Classified gene: DROSHA as Amber List (moderate evidence)
Genetic Epilepsy v0.1589 DROSHA Zornitza Stark Gene: drosha has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1588 DROSHA Lucy Spencer gene: DROSHA was added
gene: DROSHA was added to Genetic Epilepsy. 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 Neurodevelopmental disorder (MONDO#0700092), DROSHA-related
Review for gene: DROSHA was set to AMBER
Added comment: 2 individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly, and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. Both variants are missense, absent from gnomad. Both individuals noted to have Rett-like features.

Functional studies in patient fibroblasts showed one of the missense altered the expression of mature miRNA. Fruit fly models with homozygous LOF variants die during larval stages. introduction of the missense seen in the patients was able to partially rescue this phenotype suggesting LOF is not the mechanism.
Sources: Literature
Genetic Epilepsy v0.1588 KCNH5 Elena Savva Classified gene: KCNH5 as Green List (high evidence)
Genetic Epilepsy v0.1588 KCNH5 Elena Savva Gene: kcnh5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1587 KCNH5 Elena Savva Marked gene: KCNH5 as ready
Genetic Epilepsy v0.1587 KCNH5 Elena Savva Gene: kcnh5 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1587 STX1A Ain Roesley Marked gene: STX1A as ready
Genetic Epilepsy v0.1587 STX1A Ain Roesley Gene: stx1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1587 STX1A Ain Roesley Classified gene: STX1A as Green List (high evidence)
Genetic Epilepsy v0.1587 STX1A Ain Roesley Gene: stx1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1586 STX1A Ain Roesley gene: STX1A was added
gene: STX1A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: STX1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: STX1A were set to neurodevelopmental disorder MONDO#0700092, STX1A-related
Review for gene: STX1A was set to GREEN
gene: STX1A was marked as current diagnostic
Added comment: Preprint: https://www.medrxiv.org/content/10.1101/2022.04.20.22274073v1
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature
Genetic Epilepsy v0.1585 PPFIBP1 Zornitza Stark Marked gene: PPFIBP1 as ready
Genetic Epilepsy v0.1585 PPFIBP1 Zornitza Stark Gene: ppfibp1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1585 KCNH5 Elena Savva gene: KCNH5 was added
gene: KCNH5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNH5 were set to https://www.medrxiv.org/content/10.1101/2022.04.26.22274147v1
Phenotypes for gene: KCNH5 were set to Neurodevelopmental disorder MONDO#0700092, KCNH5-related
Mode of pathogenicity for gene: KCNH5 was set to Other
Review for gene: KCNH5 was set to GREEN
Added comment: Happ (2022), preprint: Screen of 893 patients with DEE found 17 patients with missense variants (16/17 de novo, 1/17 inherited). GOF mechanism suggested.
Patient phenotypes included focal/generalized seizures, Cognitive outcome for the ten individuals >5 years ranged from normal (3/10) to mild (3/10), moderate (2/10), severe (1/10) and profound (1/10) intellectual disability (ID)

p.Arg327His (7 probands), p.Arg333His (4 probands) were recurring
Sources: Literature
Genetic Epilepsy v0.1585 PPFIBP1 Zornitza Stark Classified gene: PPFIBP1 as Green List (high evidence)
Genetic Epilepsy v0.1585 PPFIBP1 Zornitza Stark Gene: ppfibp1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1584 PPFIBP1 Zornitza Stark gene: PPFIBP1 was added
gene: PPFIBP1 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to https://www.medrxiv.org/content/10.1101/2022.04.04.22273309v1
Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder, MONDO:0700092, PPFIBP1-related
Review for gene: PPFIBP1 was set to GREEN
Added comment: 16 individuals from 10 unrelated families reported with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Drosophila model.
Sources: Expert Review
Genetic Epilepsy v0.1583 GNAI1 Zornitza Stark Phenotypes for gene: GNAI1 were changed from Intellectual disability; seizures; hypotonia to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, MIM# 619854
Genetic Epilepsy v0.1582 GNAI1 Zornitza Stark edited their review of gene: GNAI1: Changed phenotypes: Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, MIM# 619854
Genetic Epilepsy v0.1582 SIK1 Zornitza Stark Marked gene: SIK1 as ready
Genetic Epilepsy v0.1582 SIK1 Zornitza Stark Gene: sik1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1582 SIK1 Zornitza Stark Phenotypes for gene: SIK1 were changed from to Developmental and epileptic encephalopathy 30, MIM#616341; developmental and epileptic encephalopathy, MONDO#0100062
Genetic Epilepsy v0.1581 SIK1 Zornitza Stark Publications for gene: SIK1 were set to
Genetic Epilepsy v0.1580 SIK1 Zornitza Stark Mode of inheritance for gene: SIK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1579 SIK1 Zornitza Stark reviewed gene: SIK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25839329, 27966542, 35267137; Phenotypes: Developmental and epileptic encephalopathy 30, MIM#616341, developmental and epileptic encephalopathy, MONDO#0100062; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1579 HCN1 Zornitza Stark Marked gene: HCN1 as ready
Genetic Epilepsy v0.1579 HCN1 Zornitza Stark Gene: hcn1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1579 HCN1 Zornitza Stark Phenotypes for gene: HCN1 were changed from to Developmental and epileptic encephalopathy 24, MIM# 615871; Generalized epilepsy with febrile seizures plus, type 10, MIM# 618482
Genetic Epilepsy v0.1578 HCN1 Zornitza Stark Publications for gene: HCN1 were set to
Genetic Epilepsy v0.1577 HCN1 Zornitza Stark Mode of inheritance for gene: HCN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1576 HCN1 Zornitza Stark reviewed gene: HCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24747641, 30351409, 30351409; Phenotypes: Developmental and epileptic encephalopathy 24, MIM# 615871, Generalized epilepsy with febrile seizures plus, type 10, MIM# 618482; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1576 CDC42BPB Zornitza Stark Phenotypes for gene: CDC42BPB were changed from Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to Chilton-Okur-Chung neurodevelopmental syndrome, MIM# 619841
Genetic Epilepsy v0.1575 CDC42BPB Zornitza Stark edited their review of gene: CDC42BPB: Changed rating: AMBER; Changed phenotypes: Chilton-Okur-Chung neurodevelopmental syndrome, MIM# 619841; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1575 BSCL2 Zornitza Stark changed review comment from: Bi-allelic variants: multiple families reported with syndromic lipodystrophy including EE.

Mono-allelic variants: Two families reported with de novo variants in PMIDs 31369919 and 35290466. We are aware of further three individuals identified as a result of clinical testing, so a total of 4 with a change at position p.Pro149; to: Bi-allelic variants: multiple families reported with syndromic lipodystrophy including EE.

Mono-allelic variants: Two families reported with de novo variants in PMIDs 31369919 and 35290466. We are aware of further three individuals identified as a result of clinical testing, so a total of 4 with a change at position p.Pro149
Genetic Epilepsy v0.1575 BSCL2 Zornitza Stark Marked gene: BSCL2 as ready
Genetic Epilepsy v0.1575 BSCL2 Zornitza Stark Gene: bscl2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1575 BSCL2 Zornitza Stark Phenotypes for gene: BSCL2 were changed from to Encephalopathy, progressive, with or without lipodystrophy, MIM#615924; Developmental and epileptic encephalopathy, BSCL2-related, dominant, MONDO:0100062
Genetic Epilepsy v0.1574 BSCL2 Zornitza Stark Publications for gene: BSCL2 were set to
Genetic Epilepsy v0.1573 BSCL2 Zornitza Stark Mode of inheritance for gene: BSCL2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1572 BSCL2 Zornitza Stark reviewed gene: BSCL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11479539, 15181077, 15126564, 23564749, 31369919, 35290466; Phenotypes: Encephalopathy, progressive, with or without lipodystrophy, MIM#615924, Developmental and epileptic encephalopathy, BSCL2-related, dominant, MONDO:0100062; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1572 CNNM2 Ain Roesley Phenotypes for gene: CNNM2 were changed from Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418 to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418
Genetic Epilepsy v0.1572 CNNM2 Ain Roesley Phenotypes for gene: CNNM2 were changed from Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418 to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418
Genetic Epilepsy v0.1572 CNNM2 Ain Roesley Publications for gene: CNNM2 were set to 34604137; 35170241
Genetic Epilepsy v0.1572 CNNM2 Ain Roesley Publications for gene: CNNM2 were set to 34604137; 35170241
Genetic Epilepsy v0.1572 CNNM2 Ain Roesley Mode of inheritance for gene: CNNM2 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Genetic Epilepsy v0.1572 CNNM2 Ain Roesley Phenotypes for gene: CNNM2 were changed from Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418 to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418
Genetic Epilepsy v0.1572 CNNM2 Ain Roesley Mode of inheritance for gene: CNNM2 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Genetic Epilepsy v0.1571 CNNM2 Ain Roesley Phenotypes for gene: CNNM2 were changed from to Hypomagnesemia 6, renal MIM#613882; Hypomagnesemia, seizures, and mental retardation MIM#616418
Genetic Epilepsy v0.1571 CNNM2 Ain Roesley Publications for gene: CNNM2 were set to
Genetic Epilepsy v0.1571 CNNM2 Ain Roesley Mode of inheritance for gene: CNNM2 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Genetic Epilepsy v0.1570 CNNM2 Ain Roesley Marked gene: CNNM2 as ready
Genetic Epilepsy v0.1570 CNNM2 Ain Roesley Gene: cnnm2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1570 CNNM2 Ain Roesley Marked gene: CNNM2 as ready
Genetic Epilepsy v0.1570 CNNM2 Ain Roesley Gene: cnnm2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1570 CNNM2 Ain Roesley reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34604137, 35170241; Phenotypes: Hypomagnesemia 6, renal MIM#613882, Hypomagnesemia, seizures, and mental retardation MIM#616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v0.1570 PIGW Zornitza Stark Marked gene: PIGW as ready
Genetic Epilepsy v0.1570 PIGW Zornitza Stark Gene: pigw has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1570 PIGW Zornitza Stark Phenotypes for gene: PIGW were changed from to Glycosylphosphatidylinositol biosynthesis defect 11, MIM# 616025
Genetic Epilepsy v0.1569 PIGW Zornitza Stark Publications for gene: PIGW were set to
Genetic Epilepsy v0.1568 PIGW Zornitza Stark Mode of inheritance for gene: PIGW was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1567 PIGW Zornitza Stark reviewed gene: PIGW: Rating: GREEN; Mode of pathogenicity: None; Publications: 24367057, 27626616, 30813920, 32198969; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 11, MIM# 616025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1567 CHRNA2 Ain Roesley Publications for gene: CHRNA2 were set to 16826524; 25770198; 30809122; 25847220
Genetic Epilepsy v0.1567 CHRNA2 Ain Roesley Phenotypes for gene: CHRNA2 were changed from Epilepsy, nocturnal frontal lobe, type 4 MIM#610353 to Epilepsy, nocturnal frontal lobe, type 4 MIM#610353
Genetic Epilepsy v0.1566 CHRNA2 Ain Roesley Phenotypes for gene: CHRNA2 were changed from to Epilepsy, nocturnal frontal lobe, type 4 MIM#610353
Genetic Epilepsy v0.1566 CHRNA2 Ain Roesley Publications for gene: CHRNA2 were set to
Genetic Epilepsy v0.1566 CHRNA2 Ain Roesley Marked gene: CHRNA2 as ready
Genetic Epilepsy v0.1566 CHRNA2 Ain Roesley Gene: chrna2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1566 CHRNA2 Ain Roesley Mode of inheritance for gene: CHRNA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1565 CHRNA2 Ain Roesley reviewed gene: CHRNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826524, 25770198, 30809122, 25847220; Phenotypes: Epilepsy, nocturnal frontal lobe, type 4 MIM#610353; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Genetic Epilepsy v0.1565 PIDD1 Zornitza Stark reviewed gene: PIDD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1565 PIDD1 Zornitza Stark Phenotypes for gene: PIDD1 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum to Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, MIM# 619827
Genetic Epilepsy v0.1564 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835
Genetic Epilepsy v0.1563 CLPB Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, 3-methylglutaconic aciduria, type VIIA, autosomal dominant, MIM# 619835
Genetic Epilepsy v0.1563 FASTKD2 Bryony Thompson Publications for gene: FASTKD2 were set to 18771761; 28499982
Genetic Epilepsy v0.1562 FASTKD2 Bryony Thompson Classified gene: FASTKD2 as Green List (high evidence)
Genetic Epilepsy v0.1562 FASTKD2 Bryony Thompson Gene: fastkd2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1561 FASTKD2 Bryony Thompson reviewed gene: FASTKD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18771761, 28499982, 31944455, 34234304; Phenotypes: FASTKD2-related infantile mitochondrial encephalomyopathy MONDO:0015632; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1561 PRMT7 Zornitza Stark Marked gene: PRMT7 as ready
Genetic Epilepsy v0.1561 PRMT7 Zornitza Stark Gene: prmt7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1561 PRMT7 Zornitza Stark Phenotypes for gene: PRMT7 were changed from to Short stature, brachydactyly, intellectual developmental disability, and seizures, MIM# 617157
Genetic Epilepsy v0.1560 PRMT7 Zornitza Stark Publications for gene: PRMT7 were set to
Genetic Epilepsy v0.1559 PRMT7 Zornitza Stark Mode of inheritance for gene: PRMT7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1558 PRMT7 Zornitza Stark reviewed gene: PRMT7: Rating: GREEN; Mode of pathogenicity: None; Publications: 26437029, 27718516, 30513135; Phenotypes: Short stature, brachydactyly, intellectual developmental disability, and seizures, MIM# 617157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1558 CLPB Zornitza Stark Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Genetic Epilepsy v0.1557 CLPB Zornitza Stark edited their review of gene: CLPB: Changed phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271, Neutropenia, severe congenital, 9, autosomal dominant, MIM# 619813
Genetic Epilepsy v0.1557 NOVA2 Zornitza Stark Marked gene: NOVA2 as ready
Genetic Epilepsy v0.1557 NOVA2 Zornitza Stark Gene: nova2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1557 NOVA2 Zornitza Stark Phenotypes for gene: NOVA2 were changed from intellectual disability (ID), motor and speech delay; autistic features; hypotonia; feeding difficulties; spasticity; ataxia; epilepsy to Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities, MIM# 618859
Genetic Epilepsy v0.1556 NOVA2 Zornitza Stark Classified gene: NOVA2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1556 NOVA2 Zornitza Stark Gene: nova2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1555 NOVA2 Zornitza Stark reviewed gene: NOVA2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities, MIM# 618859; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1555 SLC25A12 Zornitza Stark Marked gene: SLC25A12 as ready
Genetic Epilepsy v0.1555 SLC25A12 Zornitza Stark Gene: slc25a12 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1555 SLC25A12 Zornitza Stark Phenotypes for gene: SLC25A12 were changed from to Developmental and epileptic encephalopathy 39, MIM# 612949
Genetic Epilepsy v0.1554 SLC25A12 Zornitza Stark Publications for gene: SLC25A12 were set to
Genetic Epilepsy v0.1553 SLC25A12 Zornitza Stark Mode of inheritance for gene: SLC25A12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1552 SLC25A12 Zornitza Stark reviewed gene: SLC25A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 19641205, 24515575, 35008954, 32700846, 31766059, 31514314; Phenotypes: Developmental and epileptic encephalopathy 39, MIM# 612949; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1552 SLC25A22 Zornitza Stark Marked gene: SLC25A22 as ready
Genetic Epilepsy v0.1552 SLC25A22 Zornitza Stark Gene: slc25a22 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1552 SLC25A22 Zornitza Stark Phenotypes for gene: SLC25A22 were changed from to Developmental and epileptic encephalopathy 3, MIM# 609304
Genetic Epilepsy v0.1551 SLC25A22 Zornitza Stark Publications for gene: SLC25A22 were set to
Genetic Epilepsy v0.1550 SLC25A22 Zornitza Stark Mode of inheritance for gene: SLC25A22 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1549 SLC25A22 Zornitza Stark reviewed gene: SLC25A22: Rating: GREEN; Mode of pathogenicity: None; Publications: 15592994, 19780765, 24596948, 33821742, 33342683, 31285529; Phenotypes: Developmental and epileptic encephalopathy 3, MIM# 609304; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1549 TRAK1 Zornitza Stark Marked gene: TRAK1 as ready
Genetic Epilepsy v0.1549 TRAK1 Zornitza Stark Gene: trak1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1549 TRAK1 Zornitza Stark Phenotypes for gene: TRAK1 were changed from to Developmental and epileptic encephalopathy 68, MIM# 618201
Genetic Epilepsy v0.1548 TRAK1 Zornitza Stark Publications for gene: TRAK1 were set to
Genetic Epilepsy v0.1547 TRAK1 Zornitza Stark Mode of inheritance for gene: TRAK1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1546 NOVA2 Shekeeb Mohammad gene: NOVA2 was added
gene: NOVA2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NOVA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOVA2 were set to 32197073
Phenotypes for gene: NOVA2 were set to intellectual disability (ID), motor and speech delay; autistic features; hypotonia; feeding difficulties; spasticity; ataxia; epilepsy
Penetrance for gene: NOVA2 were set to unknown
Review for gene: NOVA2 was set to GREEN
Added comment: Sources: Literature
Genetic Epilepsy v0.1546 PIGA Zornitza Stark Phenotypes for gene: PIGA were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM#300868 to Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466; Neurodevelopmental disorder with epilepsy and haemochromatosis, MIM# 301072
Genetic Epilepsy v0.1545 PIGA Zornitza Stark Publications for gene: PIGA were set to 24706016; 24259184; 29159939
Genetic Epilepsy v0.1544 PIGA Zornitza Stark reviewed gene: PIGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22305531, 24357517, 24706016, 26545172, 33333793, 32694024, 34875027; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466, Neurodevelopmental disorder with epilepsy and haemochromatosis, MIM# 301072; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1544 TRAPPC10 Zornitza Stark Marked gene: TRAPPC10 as ready
Genetic Epilepsy v0.1544 TRAPPC10 Zornitza Stark Gene: trappc10 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1544 TRAPPC10 Zornitza Stark Classified gene: TRAPPC10 as Green List (high evidence)
Genetic Epilepsy v0.1544 TRAPPC10 Zornitza Stark Gene: trappc10 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1543 ATP2B1 Zornitza Stark Marked gene: ATP2B1 as ready
Genetic Epilepsy v0.1543 ATP2B1 Zornitza Stark Gene: atp2b1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1543 ATP2B1 Zornitza Stark Classified gene: ATP2B1 as Green List (high evidence)
Genetic Epilepsy v0.1543 ATP2B1 Zornitza Stark Gene: atp2b1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1542 TRAPPC10 Naomi Baker gene: TRAPPC10 was added
gene: TRAPPC10 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC10 were set to PMID: 35298461; 30167849
Phenotypes for gene: TRAPPC10 were set to neurodevelopmental disorder (MONDO:0700092), TRAPPC10-related
Review for gene: TRAPPC10 was set to GREEN
Added comment: PMID: 35298461 – two Pakistani families reported with homozygous variants. Family 1 has frameshift variant in 8 affected individual and family 2 has missense variant in 2 affected individuals. Patients present with microcephaly, short stature, hypotonia, severe ID and behavioural abnormalities. Seizures also reported in 4/10 individuals. Paper also reported brain abnormalities in null mouse model and other functional in transfected cell lines.

PMID: 30167849 – initial report of family 2 above.
Sources: Literature
Genetic Epilepsy v0.1542 CACNA2D1 Alison Yeung Phenotypes for gene: CACNA2D1 were changed from Developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related to Developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related
Genetic Epilepsy v0.1542 CACNA2D1 Alison Yeung Phenotypes for gene: CACNA2D1 were changed from Developmental and pileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related to Developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related
Genetic Epilepsy v0.1541 CACNA2D1 Alison Yeung Phenotypes for gene: CACNA2D1 were changed from to Developmental and pileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related
Genetic Epilepsy v0.1540 CACNA2D1 Alison Yeung Classified gene: CACNA2D1 as Green List (high evidence)
Genetic Epilepsy v0.1540 CACNA2D1 Alison Yeung Added comment: Comment on list classification: Two affected individuals with very similar and specific phenotypes. Functional studies in patient cells showed reduced protein expression. Two variants are frameshift, one missense variant shown to affect channel function.
Genetic Epilepsy v0.1540 CACNA2D1 Alison Yeung Gene: cacna2d1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1539 ATP2B1 Daniel Flanagan gene: ATP2B1 was added
gene: ATP2B1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP2B1 were set to PMID: 35358416
Phenotypes for gene: ATP2B1 were set to Neurodevelopmental disorder, MONDO:0700092, ATP2B1-related
Review for gene: ATP2B1 was set to GREEN
Added comment: 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism (5), dissimilar forms of seizures (6), and distal limb abnormalities (4). 9 variants proven to be de novo, other 3 variants had unknown inheritance. 9 missense and 3 nonsense reported. Supporting functional analysis for missense.
Sources: Expert list
Genetic Epilepsy v0.1539 CACNA2D1 Michelle Torres changed review comment from: PMID 35293990: WES of 2x unrelated individuals with early-onset developmental epileptic encephalopathy, microcephaly, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia, and 2 cortical visual impairment, corpus callosum hypoplasia and progressive volume loss. Patient 2 also had a tiny patent foramen ovale.

Patient 1 is homozygous for p.(Ser275Asnfs*13). mRNA and protein expression were reduced to ~10% of WT in fibroblasts.

Patient 2 is cHet for p.(Leu9Alafs*5) and p.(Gly209Asp). mRNA expression in patients fibroblasts was similar to controls, and protein expression reduced to 31-38%. Functional of the p.(Gly209Asp) showed it affects channel function due to impaired localisation.
Sources: Literature; to: PMID 35293990: WES of 2x unrelated individuals with early-onset developmental epileptic encephalopathy, microcephaly, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia, and 2 cortical visual impairment, corpus callosum hypoplasia and progressive volume loss. Patient 2 also had a tiny patent foramen ovale.

Patient 1 is homozygous for p.(Ser275Asnfs*13). mRNA and protein expression were reduced to ~10% of WT in fibroblasts.

Patient 2 is cHet for p.(Leu9Alafs*5) and p.(Gly209Asp). mRNA expression in patients fibroblasts was similar to controls, and protein expression reduced to 31-38%. Mutagenesis of the p.(Gly209Asp) showed it affects channel function due to impaired localisation.
Sources: Literature
Genetic Epilepsy v0.1539 ADAM22 Alison Yeung Phenotypes for gene: ADAM22 were changed from Developmental and epileptic encephalopathy 61 (MIM#617933) to Developmental and epileptic encephalopathy 61 (MIM#617933)
Genetic Epilepsy v0.1538 ADAM22 Alison Yeung Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, MIM# 617933 to Developmental and epileptic encephalopathy 61 (MIM#617933)
Genetic Epilepsy v0.1537 ADAM22 Alison Yeung Publications for gene: ADAM22 were set to 27066583; 30237576
Genetic Epilepsy v0.1536 ADAM22 Alison Yeung Classified gene: ADAM22 as Green List (high evidence)
Genetic Epilepsy v0.1536 ADAM22 Alison Yeung Gene: adam22 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1535 ADAM22 Lucy Spencer reviewed gene: ADAM22: Rating: GREEN; Mode of pathogenicity: None; Publications: 35373813; Phenotypes: Developmental and epileptic encephalopathy 61 (MIM#617933); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1535 CACNA2D1 Michelle Torres edited their review of gene: CACNA2D1: Changed phenotypes: developmental and epileptic encephalopathy disorder MONDO:0100062 CACNA2D1-related
Genetic Epilepsy v0.1535 CACNA2D1 Michelle Torres gene: CACNA2D1 was added
gene: CACNA2D1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990
Review for gene: CACNA2D1 was set to GREEN
Added comment: PMID 35293990: WES of 2x unrelated individuals with early-onset developmental epileptic encephalopathy, microcephaly, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia, and 2 cortical visual impairment, corpus callosum hypoplasia and progressive volume loss. Patient 2 also had a tiny patent foramen ovale.

Patient 1 is homozygous for p.(Ser275Asnfs*13). mRNA and protein expression were reduced to ~10% of WT in fibroblasts.

Patient 2 is cHet for p.(Leu9Alafs*5) and p.(Gly209Asp). mRNA expression in patients fibroblasts was similar to controls, and protein expression reduced to 31-38%. Functional of the p.(Gly209Asp) showed it affects channel function due to impaired localisation.
Sources: Literature
Genetic Epilepsy v0.1535 LIG3 Zornitza Stark Phenotypes for gene: LIG3 were changed from mitochondrial neurogastrointestinal encephalomyopathy to Mitochondrial DNA depletion syndrome 20 (MNGIE type), MIM# 619780
Genetic Epilepsy v0.1534 LIG3 Zornitza Stark reviewed gene: LIG3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 20 (MNGIE type), MIM# 619780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1534 PACS2 Zornitza Stark Marked gene: PACS2 as ready
Genetic Epilepsy v0.1534 PACS2 Zornitza Stark Gene: pacs2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1534 PACS2 Zornitza Stark Phenotypes for gene: PACS2 were changed from to Developmental and epileptic encephalopathy 66 - MIM#618067
Genetic Epilepsy v0.1533 PACS2 Zornitza Stark Publications for gene: PACS2 were set to
Genetic Epilepsy v0.1532 PACS2 Zornitza Stark Mode of inheritance for gene: PACS2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1531 PACS2 Zornitza Stark reviewed gene: PACS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29656858, 34894068, 34859793; Phenotypes: Developmental and epileptic encephalopathy 66 - MIM#618067; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1531 CACNA2D2 Zornitza Stark changed review comment from: Multiple affected individuals reported; DD/ID is variable but present in most.; to: Multiple affected individuals reported; seizures are part of the phenotype.
Genetic Epilepsy v0.1531 CACNA2D2 Zornitza Stark Marked gene: CACNA2D2 as ready
Genetic Epilepsy v0.1531 CACNA2D2 Zornitza Stark Gene: cacna2d2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1531 CACNA2D2 Zornitza Stark Phenotypes for gene: CACNA2D2 were changed from to Cerebellar atrophy with seizures and variable developmental delay MIM#618501
Genetic Epilepsy v0.1530 CACNA2D2 Zornitza Stark Publications for gene: CACNA2D2 were set to
Genetic Epilepsy v0.1529 CACNA2D2 Zornitza Stark Mode of inheritance for gene: CACNA2D2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1528 CACNA2D2 Zornitza Stark reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Phenotypes: Cerebellar atrophy with seizures and variable developmental delay MIM#618501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1528 LGI1 Zornitza Stark Marked gene: LGI1 as ready
Genetic Epilepsy v0.1528 LGI1 Zornitza Stark Gene: lgi1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1528 LGI1 Zornitza Stark Phenotypes for gene: LGI1 were changed from to Epilepsy, familial temporal lobe, 1, MIM# 6000512
Genetic Epilepsy v0.1527 LGI1 Zornitza Stark Publications for gene: LGI1 were set to
Genetic Epilepsy v0.1526 LGI1 Zornitza Stark Mode of inheritance for gene: LGI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1526 LGI1 Zornitza Stark Mode of inheritance for gene: LGI1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1525 LGI1 Zornitza Stark reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18711109, 12205652, 15079010, 22496201; Phenotypes: Epilepsy, familial temporal lobe, 1, MIM# 6000512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1525 NRXN1 Zornitza Stark Phenotypes for gene: NRXN1 were changed from Pitt-Hopkins-like syndrome 2 - MIM#614325 to Pitt-Hopkins-like syndrome 2 - MIM#614325
Genetic Epilepsy v0.1525 NRXN1 Zornitza Stark Marked gene: NRXN1 as ready
Genetic Epilepsy v0.1525 NRXN1 Zornitza Stark Gene: nrxn1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1525 NRXN1 Zornitza Stark Phenotypes for gene: NRXN1 were changed from to Pitt-Hopkins-like syndrome 2 - MIM#614325
Genetic Epilepsy v0.1524 NRXN1 Zornitza Stark Publications for gene: NRXN1 were set to
Genetic Epilepsy v0.1523 NRXN1 Zornitza Stark Mode of inheritance for gene: NRXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1522 NRXN1 Zornitza Stark Mode of inheritance for gene: NRXN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1521 SCARB2 Zornitza Stark Marked gene: SCARB2 as ready
Genetic Epilepsy v0.1521 SCARB2 Zornitza Stark Gene: scarb2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1521 SCARB2 Zornitza Stark Phenotypes for gene: SCARB2 were changed from Progressive Myoclonus Epilepsy, MONDO:0020074; Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900 to Progressive Myoclonus Epilepsy, MONDO:0020074; Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900
Genetic Epilepsy v0.1520 SCARB2 Zornitza Stark Phenotypes for gene: SCARB2 were changed from Progressive Myoclonus Epilepsy, MONDO:0020074; Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900 to Progressive Myoclonus Epilepsy, MONDO:0020074; Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900
Genetic Epilepsy v0.1520 SCARB2 Zornitza Stark Phenotypes for gene: SCARB2 were changed from to Progressive Myoclonus Epilepsy, MONDO:0020074; Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900
Genetic Epilepsy v0.1519 SCARB2 Zornitza Stark Publications for gene: SCARB2 were set to
Genetic Epilepsy v0.1518 SCARB2 Zornitza Stark Mode of inheritance for gene: SCARB2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1517 SCARB2 Zornitza Stark reviewed gene: SCARB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18308289, 18424452, 23659519, 19847901, 18022370, 19933215; Phenotypes: Progressive Myoclonus Epilepsy, MONDO:0020074, Epilepsy, progressive myoclonic 4, with or without renal failure, MIM #254900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1517 LIAS Alison Yeung Phenotypes for gene: LIAS were changed from Hyperglycinemia, lactic acidosis, and seizures, MIM# 614462 to Hyperglycinemia, lactic acidosis, and seizures, MIM# 614462
Genetic Epilepsy v0.1517 LIAS Alison Yeung Marked gene: LIAS as ready
Genetic Epilepsy v0.1517 LIAS Alison Yeung Gene: lias has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1517 LIAS Alison Yeung Phenotypes for gene: LIAS were changed from Hyperglycinemia, lactic acidosis, and seizures, MIM# 614462 to Hyperglycinemia, lactic acidosis, and seizures, MIM# 614462
Genetic Epilepsy v0.1517 LIAS Alison Yeung Phenotypes for gene: LIAS were changed from to Hyperglycinemia, lactic acidosis, and seizures, MIM# 614462
Genetic Epilepsy v0.1516 LIAS Alison Yeung Publications for gene: LIAS were set to 22152680; 24334290; 26108146
Genetic Epilepsy v0.1516 LIAS Alison Yeung Mode of inheritance for gene: LIAS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1515 LIAS Alison Yeung Publications for gene: LIAS were set to
Genetic Epilepsy v0.1515 LIAS Alison Yeung Mode of inheritance for gene: LIAS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1514 NRXN1 Krithika Murali reviewed gene: NRXN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25486015, 19896112, 21964664, 30873608, 35101781, 22337556, 22670139; Phenotypes: Pitt-Hopkins-like syndrome 2 - MIM#614325; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1514 GRIN1 Zornitza Stark Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254 to Developmental and epileptic encephalopathy 101, MIM# 619814; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Genetic Epilepsy v0.1513 GRIN1 Zornitza Stark Publications for gene: GRIN1 were set to 29365063; 27164704
Genetic Epilepsy v0.1512 GRIN1 Zornitza Stark Mode of inheritance for gene: GRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1511 GRIN1 Zornitza Stark edited their review of gene: GRIN1: Added comment: Note also families reported with bi-allelic LoF variants and DEE phenotype, PMIDs 34611970 and 27164704; Changed publications: 29365063, 27164704, 27164704, 28051072, 34611970; Changed phenotypes: Developmental and epileptic encephalopathy 101 , MIM#619814, Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1511 TBCK Zornitza Stark Marked gene: TBCK as ready
Genetic Epilepsy v0.1511 TBCK Zornitza Stark Gene: tbck has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1511 TBCK Zornitza Stark Phenotypes for gene: TBCK were changed from to Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900
Genetic Epilepsy v0.1510 TBCK Zornitza Stark Publications for gene: TBCK were set to
Genetic Epilepsy v0.1509 TBCK Zornitza Stark Mode of inheritance for gene: TBCK was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1508 TBCK Zornitza Stark reviewed gene: TBCK: Rating: GREEN; Mode of pathogenicity: None; Publications: 27040692, 30103036, 27040691; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 3, MIM# 616900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1508 LAMC3 Zornitza Stark Marked gene: LAMC3 as ready
Genetic Epilepsy v0.1508 LAMC3 Zornitza Stark Gene: lamc3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1508 LAMC3 Zornitza Stark Classified gene: LAMC3 as Green List (high evidence)
Genetic Epilepsy v0.1508 LAMC3 Zornitza Stark Gene: lamc3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1507 NPRL3 Zornitza Stark Marked gene: NPRL3 as ready
Genetic Epilepsy v0.1507 NPRL3 Zornitza Stark Gene: nprl3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1507 NPRL3 Zornitza Stark Phenotypes for gene: NPRL3 were changed from to Epilepsy, familial focal, with variable foci 3- MIM#617118
Genetic Epilepsy v0.1506 NPRL3 Zornitza Stark Publications for gene: NPRL3 were set to
Genetic Epilepsy v0.1505 NPRL3 Zornitza Stark Mode of inheritance for gene: NPRL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1504 POU3F3 Zornitza Stark Marked gene: POU3F3 as ready
Genetic Epilepsy v0.1504 POU3F3 Zornitza Stark Gene: pou3f3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1504 POU3F3 Zornitza Stark Classified gene: POU3F3 as Amber List (moderate evidence)
Genetic Epilepsy v0.1504 POU3F3 Zornitza Stark Gene: pou3f3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1503 NPRL3 Krithika Murali reviewed gene: NPRL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27173016, 26285051, 33461085; Phenotypes: Epilepsy, familial focal, with variable foci 3- MIM#617118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1503 STX1B Zornitza Stark Marked gene: STX1B as ready
Genetic Epilepsy v0.1503 STX1B Zornitza Stark Gene: stx1b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1503 STX1B Zornitza Stark Phenotypes for gene: STX1B were changed from to Generalized epilepsy with febrile seizures plus, type 9, MIM# 616172
Genetic Epilepsy v0.1502 STX1B Zornitza Stark Publications for gene: STX1B were set to
Genetic Epilepsy v0.1501 STX1B Zornitza Stark Mode of inheritance for gene: STX1B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1500 STX1B Zornitza Stark reviewed gene: STX1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25362483, 33677401; Phenotypes: Generalized epilepsy with febrile seizures plus, type 9, MIM# 616172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1500 NDUFV2 Zornitza Stark Marked gene: NDUFV2 as ready
Genetic Epilepsy v0.1500 NDUFV2 Zornitza Stark Gene: ndufv2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1500 NDUFV2 Zornitza Stark Classified gene: NDUFV2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1500 NDUFV2 Zornitza Stark Gene: ndufv2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1499 SYNJ1 Zornitza Stark Phenotypes for gene: SYNJ1 were changed from to Developmental and epileptic encephalopathy 53, MIM# 617389; Parkinson disease 20, early-onset, MIM# 615530
Genetic Epilepsy v0.1498 SYNJ1 Zornitza Stark Publications for gene: SYNJ1 were set to
Genetic Epilepsy v0.1497 SYNJ1 Zornitza Stark Mode of inheritance for gene: SYNJ1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1496 SYNJ1 Zornitza Stark reviewed gene: SYNJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32435303, 27435091, 23804563, 23804577, 27496670, 33841314; Phenotypes: Developmental and epileptic encephalopathy 53, MIM# 617389, Parkinson disease 20, early-onset, MIM# 615530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1496 SZT2 Zornitza Stark Marked gene: SZT2 as ready
Genetic Epilepsy v0.1496 SZT2 Zornitza Stark Gene: szt2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1496 SZT2 Zornitza Stark Phenotypes for gene: SZT2 were changed from to Developmental and epileptic encephalopathy 18, OMIM #615476
Genetic Epilepsy v0.1495 SZT2 Zornitza Stark Publications for gene: SZT2 were set to 23932106; 30560016; 30359774; 28556953; 32402703
Genetic Epilepsy v0.1494 SZT2 Zornitza Stark Publications for gene: SZT2 were set to
Genetic Epilepsy v0.1493 SZT2 Zornitza Stark Mode of inheritance for gene: SZT2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1492 SZT2 Zornitza Stark reviewed gene: SZT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23932106, 30560016, 30359774, 28556953, 32402703; Phenotypes: Developmental and epileptic encephalopathy 18, OMIM #615476; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1492 NDUFV2 Krithika Murali gene: NDUFV2 was added
gene: NDUFV2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NDUFV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFV2 were set to 33811136; 34405929; 12754703; 26008862; 30770271; 19167255
Phenotypes for gene: NDUFV2 were set to Mitochondrial complex I deficiency, nuclear type 7 - MIM#618229
Review for gene: NDUFV2 was set to AMBER
Added comment: 2 siblings diagnosed with seizures age 3 and 9 months. Seizures not reported in other cases.

--

PMID 33811136 Liu et al 2021 - describe 4 individuals from 2 unrelated families with progressive cavitating leukoencephalopathy, recurring episodes of acute/subacute developmental regression in the first years
of life, followed by gradual remissions and prolonged periods of stability. Variant specific supportive functional evidence provided. MRI brain features - cystic changes in cerebral white matter, with corpus callosum involvement reported in 2 siblings.

PMID 34405929 Kishita et al 2021 - report two unrelated individuals with biallelic variants

PMID 12754703 Benit et al 2003 - report homozygous NDUFV2 4-bp deletion in intron 2 (IVS2+5_+8delGTAA) of the associated with early onset hypertrophic cardiomyopathy with trunk hypotonia in three affected sibs of a consanguineous family

PMID 26008862 Cameron et al 2015 report 5 affected individuals from 2 unrelated families
- Family 1 - intronic mutation (c.IVS2 þ 1delGTAA) + (c.669_670insG, p.Ser224Valfs*3) (hypertrophic cardiomyopathy, brain atrophy)
- Family 2 - homozygous intronic c.IVS2 þ 1delGTAA mutation (proband - seizures started at 2-3 months of age. Regression with progressive spasticity, nystagmus, optic atrophy and microcephaly was noted at 10 months of age. Repeat CT scans showed progressive caudate and putaminal cavitation, brain atrophy. Sibling - FTT, progressive microcephaly, spasticity, cerebral atrophy, still alive at 32 years. Affected male sibling - seizures age 9 months.

PMID 30770271 - Zhang et al 2019 - report 2 unrelated individuals with biallelic variants and progressive cavitating leukoencephalopathy

PMID 19167255 Pagniez-Mammeri et al 2009 - limited clinical information, x1 individual homozygous for splice site variant
Sources: Literature
Genetic Epilepsy v0.1492 NDUFA2 Zornitza Stark Phenotypes for gene: NDUFA2 were changed from Leigh syndrome due to mitochondrial complex I deficiency, MIM#256000; Mitochondrial complex I deficiency, nuclear type 13 - MIM#618235 to Mitochondrial complex I deficiency, nuclear type 13 - MIM#618235; Leigh syndrome due to mitochondrial complex I deficiency, MIM#256000
Genetic Epilepsy v0.1491 NDUFA2 Zornitza Stark Phenotypes for gene: NDUFA2 were changed from Leigh syndrome due to mitochondrial complex I deficiency, MIM#256000 to Leigh syndrome due to mitochondrial complex I deficiency, MIM#256000; Mitochondrial complex I deficiency, nuclear type 13 - MIM#618235
Genetic Epilepsy v0.1491 NDUFA2 Zornitza Stark Publications for gene: NDUFA2 were set to 28857146; 18513682
Genetic Epilepsy v0.1490 NDUFA2 Krithika Murali reviewed gene: NDUFA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28857146, 32154054, 18513682; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13 - MIM#618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1490 NDUFAF2 Zornitza Stark Marked gene: NDUFAF2 as ready
Genetic Epilepsy v0.1490 NDUFAF2 Zornitza Stark Gene: ndufaf2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1490 NDUFAF2 Zornitza Stark Phenotypes for gene: NDUFAF2 were changed from to Mitochondrial complex I deficiency, nuclear type 10 - MIM#618233
Genetic Epilepsy v0.1489 NDUFAF2 Zornitza Stark Publications for gene: NDUFAF2 were set to
Genetic Epilepsy v0.1488 NDUFAF2 Zornitza Stark Mode of inheritance for gene: NDUFAF2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1487 NDUFAF2 Zornitza Stark reviewed gene: NDUFAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33528536, 34364746, 16200211, 19384974, 20571988; Phenotypes: Mitochondrial complex I deficiency, nuclear type 10 - MIM#618233; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1487 NDUFAF2 Krithika Murali reviewed gene: NDUFAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1487 NDUFA10 Zornitza Stark Marked gene: NDUFA10 as ready
Genetic Epilepsy v0.1487 NDUFA10 Zornitza Stark Gene: ndufa10 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1487 NDUFA10 Zornitza Stark Phenotypes for gene: NDUFA10 were changed from to Mitochondrial complex I deficiency, nuclear type 22 - MIM#618243
Genetic Epilepsy v0.1486 NDUFA10 Zornitza Stark Publications for gene: NDUFA10 were set to
Genetic Epilepsy v0.1485 NDUFA10 Zornitza Stark Mode of inheritance for gene: NDUFA10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1484 NDUFA10 Zornitza Stark Classified gene: NDUFA10 as Red List (low evidence)
Genetic Epilepsy v0.1484 NDUFA10 Zornitza Stark Gene: ndufa10 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1483 NDUFA10 Zornitza Stark reviewed gene: NDUFA10: Rating: RED; Mode of pathogenicity: None; Publications: 21150889, 26741492, 28247337; Phenotypes: Mitochondrial complex I deficiency, nuclear type 22 - MIM#618243; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1483 NDST1 Zornitza Stark Marked gene: NDST1 as ready
Genetic Epilepsy v0.1483 NDST1 Zornitza Stark Gene: ndst1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1483 NDST1 Zornitza Stark Classified gene: NDST1 as Green List (high evidence)
Genetic Epilepsy v0.1483 NDST1 Zornitza Stark Gene: ndst1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1482 NDST1 Zornitza Stark Classified gene: NDST1 as Green List (high evidence)
Genetic Epilepsy v0.1482 NDST1 Zornitza Stark Gene: ndst1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1481 NDUFA10 Krithika Murali reviewed gene: NDUFA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 26741492, 21150889; Phenotypes: Mitochondrial complex I deficiency, nuclear type 22 - MIM#618243; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1481 NDST1 Krithika Murali gene: NDST1 was added
gene: NDST1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NDST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDST1 were set to 25125150; 21937992; 32878022; 28211985
Phenotypes for gene: NDST1 were set to Mental retardation, autosomal recessive 46 - MIM#616116
Review for gene: NDST1 was set to GREEN
Added comment: At least 8 unrelated families reported. Biallelic NDST1 variants associated with intellectual disability, muscular hypotonia, epilepsy (feature noted in majority of published individuals, onset in infancy/childhood), and postnatal growth deficiency
Sources: Literature
Genetic Epilepsy v0.1481 KCND3 Zornitza Stark Marked gene: KCND3 as ready
Genetic Epilepsy v0.1481 KCND3 Zornitza Stark Gene: kcnd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1481 KCND3 Zornitza Stark Classified gene: KCND3 as Green List (high evidence)
Genetic Epilepsy v0.1481 KCND3 Zornitza Stark Gene: kcnd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1480 KCND3 Zornitza Stark gene: KCND3 was added
gene: KCND3 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: KCND3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND3 were set to 32823520
Phenotypes for gene: KCND3 were set to Spinocerebellar ataxia 19, MIM#607346
Review for gene: KCND3 was set to GREEN
Added comment: Over 60 individuals reported with neurological disorders and variants in KCND3. Two broad clinical groups in terms of presentation: neurodevelopmental disorder with epilepsy and/or movement disorders with ataxia later in the disease course characterized the early onset forms, while a prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy were observed in the late onset forms.
Sources: Expert Review
Genetic Epilepsy v0.1479 KCNJ10 Zornitza Stark Marked gene: KCNJ10 as ready
Genetic Epilepsy v0.1479 KCNJ10 Zornitza Stark Gene: kcnj10 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1479 KCNJ10 Zornitza Stark Phenotypes for gene: KCNJ10 were changed from SESAME syndrome, MIM# 612780 to SESAME syndrome, MIM# 612780
Genetic Epilepsy v0.1478 KCNJ10 Zornitza Stark Phenotypes for gene: KCNJ10 were changed from to SESAME syndrome, MIM# 612780
Genetic Epilepsy v0.1477 KCNJ10 Zornitza Stark Publications for gene: KCNJ10 were set to
Genetic Epilepsy v0.1476 KCNJ10 Zornitza Stark Mode of inheritance for gene: KCNJ10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1475 KCNJ10 Zornitza Stark reviewed gene: KCNJ10: Rating: GREEN; Mode of pathogenicity: None; Publications: 19289823, 19420365, 21849804, 11466414; Phenotypes: SESAME syndrome, MIM# 612780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1475 KCNMA1 Zornitza Stark Marked gene: KCNMA1 as ready
Genetic Epilepsy v0.1475 KCNMA1 Zornitza Stark Gene: kcnma1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1475 KCNMA1 Zornitza Stark Phenotypes for gene: KCNMA1 were changed from to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446; Cerebellar atrophy, developmental delay, and seizures, MIM# 617643; Liang-Wang syndrome, MIM# 618729
Genetic Epilepsy v0.1474 KCNMA1 Zornitza Stark Publications for gene: KCNMA1 were set to
Genetic Epilepsy v0.1473 KCNMA1 Zornitza Stark Mode of inheritance for gene: KCNMA1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1472 KCNMA1 Zornitza Stark reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15937479, 26195193, 27567911, 29545233, 31427379, 31152168; Phenotypes: Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446, Cerebellar atrophy, developmental delay, and seizures, MIM# 617643, Liang-Wang syndrome, MIM# 618729; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1472 NAT8L Zornitza Stark Marked gene: NAT8L as ready
Genetic Epilepsy v0.1472 NAT8L Zornitza Stark Gene: nat8l has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1472 NAT8L Zornitza Stark Phenotypes for gene: NAT8L were changed from ?N-acetylaspartate deficiency - MIM#614063 to N-acetylaspartate deficiency - MIM#614063
Genetic Epilepsy v0.1471 NAT8L Zornitza Stark Classified gene: NAT8L as Red List (low evidence)
Genetic Epilepsy v0.1471 NAT8L Zornitza Stark Gene: nat8l has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1470 NAT8L Zornitza Stark reviewed gene: NAT8L: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: N-acetylaspartate deficiency - MIM#614063; Mode of inheritance: None
Genetic Epilepsy v0.1470 FBXO28 Zornitza Stark Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 100, MIM# 619777
Genetic Epilepsy v0.1469 FBXO28 Zornitza Stark edited their review of gene: FBXO28: Changed phenotypes: Developmental and epileptic encephalopathy 100, MIM# 619777
Genetic Epilepsy v0.1469 NAT8L Krithika Murali gene: NAT8L was added
gene: NAT8L was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NAT8L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAT8L were set to 11310630; 19807691; 32275776
Phenotypes for gene: NAT8L were set to ?N-acetylaspartate deficiency - MIM#614063
Review for gene: NAT8L was set to AMBER
Added comment: Absence of brain N-acetylaspartate, has been described in only one patient, with truncal ataxia, marked developmental delay, seizures and secondary microcephaly (first described by - PMID: 11310630 Martin et al 2001). PMID: 19807691 - Wiame et al 2009 identified in this patient a homozygous 19 bp NAT8L gene deletion, resulting in a change in reading frame and the absence of production of a functional protein. The affected individual is adopted and testing of the biological parents was not possible. The authors provide supportive functional studies.
Sources: Literature
Genetic Epilepsy v0.1469 NARS2 Zornitza Stark Marked gene: NARS2 as ready
Genetic Epilepsy v0.1469 NARS2 Zornitza Stark Added comment: Comment when marking as ready: Refractory seizures are part of the phenotype.
Genetic Epilepsy v0.1469 NARS2 Zornitza Stark Gene: nars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1469 NARS2 Zornitza Stark Phenotypes for gene: NARS2 were changed from to Combined oxidative phosphorylation deficiency 24 - MIM#616239
Genetic Epilepsy v0.1468 NARS2 Zornitza Stark Publications for gene: NARS2 were set to
Genetic Epilepsy v0.1467 NARS2 Zornitza Stark Mode of inheritance for gene: NARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1466 NACC1 Zornitza Stark Marked gene: NACC1 as ready
Genetic Epilepsy v0.1466 NACC1 Zornitza Stark Gene: nacc1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1466 NACC1 Zornitza Stark Phenotypes for gene: NACC1 were changed from to Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination - MIM#617393
Genetic Epilepsy v0.1465 NACC1 Zornitza Stark Publications for gene: NACC1 were set to
Genetic Epilepsy v0.1464 NACC1 Zornitza Stark Mode of inheritance for gene: NACC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1463 NACC1 Zornitza Stark reviewed gene: NACC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28132692; Phenotypes: Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination - MIM#617393; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1463 NARS2 Krithika Murali reviewed gene: NARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25385316, 25807530, 30327238, 28077841; Phenotypes: Combined oxidative phosphorylation deficiency 24 - MIM#616239, ?Deafness, autosomal recessive 94 - MIM#618434; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1463 EARS2 Bryony Thompson Marked gene: EARS2 as ready
Genetic Epilepsy v0.1463 EARS2 Bryony Thompson Gene: ears2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1463 EARS2 Bryony Thompson Phenotypes for gene: EARS2 were changed from to Leigh syndrome MONDO:0009723; Combined oxidative phosphorylation deficiency 12 MIM#614924; leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome MONDO:0013971
Genetic Epilepsy v0.1462 EARS2 Bryony Thompson Publications for gene: EARS2 were set to
Genetic Epilepsy v0.1461 EARS2 Bryony Thompson Mode of inheritance for gene: EARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1460 EARS2 Bryony Thompson reviewed gene: EARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22492562, 23008233, 25854774, 26619324, 26893310, 27206875, 27571996, 27117034; Phenotypes: Leigh syndrome MONDO:0009723, Combined oxidative phosphorylation deficiency 12 MIM#614924, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome MONDO:0013971; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v0.1460 CPSF3 Alison Yeung Classified gene: CPSF3 as Green List (high evidence)
Genetic Epilepsy v0.1460 CPSF3 Alison Yeung Gene: cpsf3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1461 CPSF3 Alison Yeung Phenotypes for gene: CPSF3 were changed from Neurodevelopmental disorder, CPSF3-related, MONDO:0700092 to Neurodevelopmental disorder, CPSF3-related, MONDO:0700092
Genetic Epilepsy v0.1461 CPSF3 Alison Yeung Phenotypes for gene: CPSF3 were changed from Neurodevelopmental disorder, CPSF3-related, MONDO:0700092 to Neurodevelopmental disorder, CPSF3-related, MONDO:0700092
Genetic Epilepsy v0.1460 CPSF3 Alison Yeung Phenotypes for gene: CPSF3 were changed from Intellectual disability syndrome to Neurodevelopmental disorder, CPSF3-related, MONDO:0700092
Genetic Epilepsy v0.1460 CPSF3 Alison Yeung Classified gene: CPSF3 as Green List (high evidence)
Genetic Epilepsy v0.1460 CPSF3 Alison Yeung Gene: cpsf3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1459 CPSF3 Alison Yeung Marked gene: CPSF3 as ready
Genetic Epilepsy v0.1459 CPSF3 Alison Yeung Gene: cpsf3 has been removed from the panel.
Genetic Epilepsy v0.1459 CPSF3 Belinda Chong gene: CPSF3 was added
gene: CPSF3 was added to Genetic Epilepsy. 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 Intellectual disability syndrome
Review for gene: CPSF3 was set to GREEN
gene: CPSF3 was marked as current diagnostic
Added comment: Study of a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes

Six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone.

- Four identified through Icelandic geneology (p.Gly468Glu), three carrier couples total of four children who had died prematurely. Tested archival samples for two of these children, and confirm a homozygous genotype.
- Two of Mexican descent (p.Ile354Thr), first-degree cousins
Sources: Literature
Genetic Epilepsy v0.1459 TIAM1 Alison Yeung Classified gene: TIAM1 as Green List (high evidence)
Genetic Epilepsy v0.1459 TIAM1 Alison Yeung Gene: tiam1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1458 TIAM1 Alison Yeung Classified gene: TIAM1 as Green List (high evidence)
Genetic Epilepsy v0.1458 TIAM1 Alison Yeung Gene: tiam1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1458 TIAM1 Alison Yeung Classified gene: TIAM1 as Green List (high evidence)
Genetic Epilepsy v0.1458 TIAM1 Alison Yeung Gene: tiam1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1457 TIAM1 Alison Yeung Marked gene: TIAM1 as ready
Genetic Epilepsy v0.1457 TIAM1 Alison Yeung Gene: tiam1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1457 TIAM1 Alison Yeung gene: TIAM1 was added
gene: TIAM1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TIAM1 were set to Neurodevelopmental disorder, TIAM1-related, MONDO:0700092
Review for gene: TIAM1 was set to GREEN
Added comment: Reported in 4 unrelated individuals. Phenotype of developmental delay/intellectual disability and seizures. Loss of ortholog in Drosophila reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. Functional studies in 3 variants from two probands showed loss of function.
Sources: Literature
Genetic Epilepsy v0.1456 ATP6V0A1 Chern Lim gene: ATP6V0A1 was added
gene: ATP6V0A1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ATP6V0A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATP6V0A1 were set to PMID:34909687
Phenotypes for gene: ATP6V0A1 were set to Neurodevelopmental disorder, MONDO:0700092, ATP6V0A1-associated
Review for gene: ATP6V0A1 was set to GREEN
gene: ATP6V0A1 was marked as current diagnostic
Added comment: PMID: 34909687
- 17 individuals from 14 unrelated families: 5 affected individuals with biallelic variants, presented with early-onset progressive myoclonus epilepsy with ataxia; 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy.
- The mean age of onset was 11.8+/-7.5 years for individuals carrying the compound heterozygous variants and 5.8+/-4.2 months for individuals with the de novo variants.
Sources: Literature
Genetic Epilepsy v0.1456 BAP1 Zornitza Stark Phenotypes for gene: BAP1 were changed from Kury-Isidor syndrome , MIM#619762 to Kury-Isidor syndrome , MIM#619762
Genetic Epilepsy v0.1455 BAP1 Zornitza Stark Phenotypes for gene: BAP1 were changed from syndromic intellectual disability MONDO:0000508 to Kury-Isidor syndrome , MIM#619762
Genetic Epilepsy v0.1454 BAP1 Zornitza Stark reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Kury-Isidor syndrome, MIM# 619762; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1454 CHKA Zornitza Stark Marked gene: CHKA as ready
Genetic Epilepsy v0.1454 CHKA Zornitza Stark Gene: chka has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1454 CHKA Zornitza Stark Phenotypes for gene: CHKA were changed from Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature to Neurodevelopmental disorder, MONDO:0700092; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Genetic Epilepsy v0.1453 CHKA Zornitza Stark Classified gene: CHKA as Green List (high evidence)
Genetic Epilepsy v0.1453 CHKA Zornitza Stark Gene: chka has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1452 CHKA Zornitza Stark Classified gene: CHKA as Green List (high evidence)
Genetic Epilepsy v0.1452 CHKA Zornitza Stark Gene: chka has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1451 CHKA Konstantinos Varvagiannis gene: CHKA was added
gene: CHKA was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.1451 AGO1 Zornitza Stark Marked gene: AGO1 as ready
Genetic Epilepsy v0.1451 AGO1 Zornitza Stark Gene: ago1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1451 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from focal epilepsy; intellectual disability; global developmental delay to Neurodevelopmental disorder MONDO:0700092, AGO1-related; non-syndromic ID and seizures
Genetic Epilepsy v0.1450 AGO1 Zornitza Stark Classified gene: AGO1 as Green List (high evidence)
Genetic Epilepsy v0.1450 AGO1 Zornitza Stark Gene: ago1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1449 AGO1 Zornitza Stark reviewed gene: AGO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder MONDO:0700092, AGO1-related, non-syndromic ID and seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1449 AGO1 Krithika Murali changed review comment from: PMID 35060114 Niu et al 2022 - 4 additional individuals reported with ID/GDD associated with heterozygous de novo AGO1 variants. Authors provide a review of 14 individuals reported in the literature. 5 out of 14 from 3 different studies noted to have epilepsy, predominantly focal seizures.
Sources: Literature; to: PMID 35060114 Niu et al 2022 - 4 additional individuals reported with ID/GDD associated with heterozygous de novo AGO1 variants. Authors provide a review of the 18 individuals reported in the literature. 5 out of 18 from 3 different studies noted to have epilepsy, predominantly focal seizures.
Sources: Literature
Genetic Epilepsy v0.1449 AGO1 Krithika Murali gene: AGO1 was added
gene: AGO1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: AGO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO1 were set to 35060114; 30213762; 25356899
Phenotypes for gene: AGO1 were set to focal epilepsy; intellectual disability; global developmental delay
Review for gene: AGO1 was set to GREEN
Added comment: PMID 35060114 Niu et al 2022 - 4 additional individuals reported with ID/GDD associated with heterozygous de novo AGO1 variants. Authors provide a review of 14 individuals reported in the literature. 5 out of 14 from 3 different studies noted to have epilepsy, predominantly focal seizures.
Sources: Literature
Genetic Epilepsy v0.1449 EEF1B2 Zornitza Stark Marked gene: EEF1B2 as ready
Genetic Epilepsy v0.1449 EEF1B2 Zornitza Stark Gene: eef1b2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1449 EEF1B2 Zornitza Stark Classified gene: EEF1B2 as Green List (high evidence)
Genetic Epilepsy v0.1449 EEF1B2 Zornitza Stark Gene: eef1b2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1448 EEF1B2 Zornitza Stark gene: EEF1B2 was added
gene: EEF1B2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: EEF1B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEF1B2 were set to 31845318; 21937992; 35015920
Phenotypes for gene: EEF1B2 were set to Neurodevelopmental disorder MONDO:0700092; non-syndromic ID and seizures
Review for gene: EEF1B2 was set to GREEN
Added comment: Now 7 individuals in 3 unrelated families with a phenotype of non-syndromic ID and fever-sensitive seizures. Knockout zebrafish model demonstrated abnormal development and a photosensitive seizure-like behavioural phenotype.
Sources: Literature
Genetic Epilepsy v0.1447 BAP1 Zornitza Stark Marked gene: BAP1 as ready
Genetic Epilepsy v0.1447 BAP1 Zornitza Stark Gene: bap1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1447 BAP1 Zornitza Stark Classified gene: BAP1 as Green List (high evidence)
Genetic Epilepsy v0.1447 BAP1 Zornitza Stark Gene: bap1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1446 FZR1 Alison Yeung Marked gene: FZR1 as ready
Genetic Epilepsy v0.1446 FZR1 Alison Yeung Gene: fzr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1446 FZR1 Alison Yeung Classified gene: FZR1 as Green List (high evidence)
Genetic Epilepsy v0.1446 FZR1 Alison Yeung Gene: fzr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1445 RBL2 Zornitza Stark Marked gene: RBL2 as ready
Genetic Epilepsy v0.1445 RBL2 Zornitza Stark Gene: rbl2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1445 RBL2 Zornitza Stark Phenotypes for gene: RBL2 were changed from PMID: 33980986; 32105419; 9806916 to Brunet-Wagner neurodevelopmental syndrome, MIM# 619690
Genetic Epilepsy v0.1444 RBL2 Zornitza Stark Classified gene: RBL2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1444 RBL2 Zornitza Stark Gene: rbl2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1443 RBL2 Zornitza Stark Classified gene: RBL2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1443 RBL2 Zornitza Stark Gene: rbl2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1442 RBL2 Elena Savva gene: RBL2 was added
gene: RBL2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RBL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBL2 were set to PMID: 33980986; 32105419; 9806916
Phenotypes for gene: RBL2 were set to PMID: 33980986; 32105419; 9806916
Review for gene: RBL2 was set to AMBER
Added comment: PMID: 33980986: 2 unrelated patients (3 total) with infantile hypotonia, severe developmental delay and microcephaly. Functional studies on patient fibroblasts supports loss of protein and mRNA expression. Patients were homozygous for a PTC, and a CNV (exon 4-5 del)

PMID: 32105419: affecting siblings with severe intellectual disability, stereotypies and dysmorphic features. Chet PTC/CNV (exon 13-17 del).

3 unrelated families - 2/3 corpus callosum hypoplasia/cerebral atrophy, 2/3 epilepsy, 2/3 microcephaly

PMID: 9806916: mouse model in support
Sources: Literature
Genetic Epilepsy v0.1442 BAP1 Anna Ritchie gene: BAP1 was added
gene: BAP1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAP1 were set to PMID: 35051358
Phenotypes for gene: BAP1 were set to syndromic intellectual disability MONDO:0000508
Penetrance for gene: BAP1 were set to unknown
Review for gene: BAP1 was set to GREEN
Added comment: 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. All affected individuals harboring a de novo BAP1 variant had DD or ID (11/11) characterized notably by speech (11/ 11) and motor delay (6/11). Most of them had hypotonia (7/11), seizures (6/11), and abnormal behavior (8/10), including autism spectrum disorder, attention deficit hyperactivity disorder, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations (involving the hands [4/11], feet [3/11], or spine [2/11]). Most of the individuals had growth failure (9/11), including four individuals with a very short stature.
Sources: Literature
Genetic Epilepsy v0.1442 SLC38A3 Zornitza Stark Phenotypes for gene: SLC38A3 were changed from developmental epileptic encephalopathy, SLC38A3-related MONDO:0100062 to Developmental epileptic encephalopathy MONDO:0100062, SLC38A3-related
Genetic Epilepsy v0.1441 SLC38A3 Zornitza Stark Marked gene: SLC38A3 as ready
Genetic Epilepsy v0.1441 SLC38A3 Zornitza Stark Gene: slc38a3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1441 SLC38A3 Zornitza Stark Classified gene: SLC38A3 as Green List (high evidence)
Genetic Epilepsy v0.1441 SLC38A3 Zornitza Stark Gene: slc38a3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1440 FZR1 Alison Yeung gene: FZR1 was added
gene: FZR1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: FZR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FZR1 were set to 34788397
Phenotypes for gene: FZR1 were set to Developmental and epileptic encephalopathy, FZR1-related, MONDO:0100062
Review for gene: FZR1 was set to GREEN
Added comment: >3 unrelated individuals reported with de novo missense variants. Functional studies in Drosophila demonstrate missense variants cause LOF.
Sources: Literature
Genetic Epilepsy v0.1439 SLC38A3 Ain Roesley gene: SLC38A3 was added
gene: SLC38A3 was added to Genetic Epilepsy. Sources: Literature
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 developmental epileptic encephalopathy, SLC38A3-related MONDO:0100062
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
gene: SLC38A3 was marked as current diagnostic
Added comment: 7 families 6 of whom are consanguineous but unique variants in all of them

8/10 with seizures
Sources: Literature
Genetic Epilepsy v0.1439 PLAA Zornitza Stark Marked gene: PLAA as ready
Genetic Epilepsy v0.1439 PLAA Zornitza Stark Gene: plaa has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1439 PLAA Zornitza Stark Phenotypes for gene: PLAA were changed from to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, MIM# 617527
Genetic Epilepsy v0.1438 PLAA Zornitza Stark Publications for gene: PLAA were set to
Genetic Epilepsy v0.1437 PLAA Zornitza Stark Mode of inheritance for gene: PLAA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1436 PLAA Zornitza Stark reviewed gene: PLAA: Rating: GREEN; Mode of pathogenicity: None; Publications: 28007986, 28413018, 31322726; Phenotypes: Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, MIM# 617527; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1436 KCNN2 Zornitza Stark Phenotypes for gene: KCNN2 were changed from Neurological Disorder; Developmental Delay; Seizures to Neurodevelopmental disorder with or without variable movement or behavioural abnormalities, MIM#619725
Genetic Epilepsy v0.1435 KCNN2 Zornitza Stark Mode of inheritance for gene: KCNN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1434 KCNN2 Zornitza Stark reviewed gene: KCNN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with or without variable movement or behavioural abnormalities, MIM#619725; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1434 SLC45A1 Zornitza Stark Marked gene: SLC45A1 as ready
Genetic Epilepsy v0.1434 SLC45A1 Zornitza Stark Gene: slc45a1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1434 SLC45A1 Zornitza Stark Phenotypes for gene: SLC45A1 were changed from to Intellectual developmental disorder with neuropsychiatric features, MIM# 617532
Genetic Epilepsy v0.1433 SLC45A1 Zornitza Stark Publications for gene: SLC45A1 were set to
Genetic Epilepsy v0.1432 SLC45A1 Zornitza Stark Mode of inheritance for gene: SLC45A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1431 SLC45A1 Zornitza Stark Classified gene: SLC45A1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1431 SLC45A1 Zornitza Stark Gene: slc45a1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1430 CSNK2B Zornitza Stark Marked gene: CSNK2B as ready
Genetic Epilepsy v0.1430 CSNK2B Zornitza Stark Gene: csnk2b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1430 CSNK2B Zornitza Stark Phenotypes for gene: CSNK2B were changed from to Poirier-Bienvenu neurodevelopmental syndrome , MIM#618732
Genetic Epilepsy v0.1429 CSNK2B Zornitza Stark Publications for gene: CSNK2B were set to
Genetic Epilepsy v0.1428 CSNK2B Zornitza Stark Mode of inheritance for gene: CSNK2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1427 CSNK2B Zornitza Stark reviewed gene: CSNK2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28585349, 28762608; Phenotypes: Poirier-Bienvenu neurodevelopmental syndrome , MIM#618732; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1427 BET1 Zornitza Stark Marked gene: BET1 as ready
Genetic Epilepsy v0.1427 BET1 Zornitza Stark Gene: bet1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1427 BET1 Zornitza Stark Classified gene: BET1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1427 BET1 Zornitza Stark Gene: bet1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1426 BET1 Zornitza Stark gene: BET1 was added
gene: BET1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BET1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BET1 were set to 34779586
Phenotypes for gene: BET1 were set to Muscular dystrophy; Epilepsy
Review for gene: BET1 was set to AMBER
Added comment: Three individuals from 2 unrelated families reported.
Sources: Literature
Genetic Epilepsy v0.1425 MDH2 Zornitza Stark Marked gene: MDH2 as ready
Genetic Epilepsy v0.1425 MDH2 Zornitza Stark Gene: mdh2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1425 MDH2 Zornitza Stark Phenotypes for gene: MDH2 were changed from to Developmental and epileptic encephalopathy 51 MIM#617339
Genetic Epilepsy v0.1424 MDH2 Zornitza Stark Publications for gene: MDH2 were set to
Genetic Epilepsy v0.1423 MDH2 Zornitza Stark Mode of inheritance for gene: MDH2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1422 MDH2 Zornitza Stark reviewed gene: MDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27989324, 34766628; Phenotypes: Developmental and epileptic encephalopathy 51 MIM#617339; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1422 LMBRD2 Zornitza Stark Phenotypes for gene: LMBRD2 were changed from Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye to Developmental delay with variable neurologic and brain abnormalities, MIM# 619694; Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Genetic Epilepsy v0.1421 LMBRD2 Zornitza Stark edited their review of gene: LMBRD2: Changed phenotypes: Developmental delay with variable neurologic and brain abnormalities, MIM# 619694, Global developmental delay, Intellectual disability, Microcephaly, Seizures, Abnormality of nervous system morphology, Abnormality of the eye
Genetic Epilepsy v0.1421 OGDHL Zornitza Stark Phenotypes for gene: OGDHL were changed from Neurodevelopmental disorder featuring epilepsy, hearing loss, visual impairment, and ataxia to Yoon-Bellen neurodevelopmental syndrome, MIM# 619701; Neurodevelopmental disorder featuring epilepsy, hearing loss, visual impairment, and ataxia
Genetic Epilepsy v0.1420 OGDHL Zornitza Stark edited their review of gene: OGDHL: Changed phenotypes: Yoon-Bellen neurodevelopmental syndrome, MIM# 619701, Neurodevelopmental disorder featuring epilepsy, hearing loss, visual impairment, and ataxia
Genetic Epilepsy v0.1420 HNRNPH2 Zornitza Stark Marked gene: HNRNPH2 as ready
Genetic Epilepsy v0.1420 HNRNPH2 Zornitza Stark Gene: hnrnph2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1420 HNRNPH2 Zornitza Stark Phenotypes for gene: HNRNPH2 were changed from to Intellectual developmental disorder, X-linked, syndromic, Bain type MIM#300986
Genetic Epilepsy v0.1419 HNRNPH2 Zornitza Stark Publications for gene: HNRNPH2 were set to
Genetic Epilepsy v0.1418 HNRNPH2 Zornitza Stark Mode of inheritance for gene: HNRNPH2 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1417 HNRNPH2 Zornitza Stark reviewed gene: HNRNPH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34907471, 33728377, 31670473, 31236915, 30887513; Phenotypes: Intellectual developmental disorder, X-linked, syndromic, Bain type MIM#300986; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1417 KCNT1 Zornitza Stark Deleted their comment
Genetic Epilepsy v0.1417 KCNT1 Zornitza Stark commented on gene: KCNT1: Multiple families reported.
Genetic Epilepsy v0.1417 VPS50 Zornitza Stark Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685; Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Genetic Epilepsy v0.1416 VPS50 Zornitza Stark reviewed gene: VPS50: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685, Neonatal cholestatic liver disease, Failure to thrive, Profound global developmental delay, Postnatal microcephaly, Seizures, Abnormality of the corpus callosum; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1416 KCNC1 Zornitza Stark Marked gene: KCNC1 as ready
Genetic Epilepsy v0.1416 KCNC1 Zornitza Stark Gene: kcnc1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1416 KCNC1 Zornitza Stark Phenotypes for gene: KCNC1 were changed from to Epilepsy, progressive myoclonic 7 (MIM#616187); Intellectual disability; Movement disorders
Genetic Epilepsy v0.1415 KCNC1 Zornitza Stark Publications for gene: KCNC1 were set to 28145425; 31353862; 25401298
Genetic Epilepsy v0.1415 KCNC1 Zornitza Stark Publications for gene: KCNC1 were set to
Genetic Epilepsy v0.1414 KCNC1 Zornitza Stark Mode of inheritance for gene: KCNC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1413 KCNC1 Zornitza Stark reviewed gene: KCNC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28145425, 31353862, 25401298; Phenotypes: Epilepsy, progressive myoclonic 7 (MIM#616187), Intellectual disability, Movement disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1413 CSNK2B Emma Goss reviewed gene: CSNK2B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34041744 DOI: 10.1111/epi.16931; Phenotypes: genetic epilepsy, developmental delay, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1413 ZBTB18 Zornitza Stark Marked gene: ZBTB18 as ready
Genetic Epilepsy v0.1413 ZBTB18 Zornitza Stark Gene: zbtb18 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1413 ZBTB18 Zornitza Stark Phenotypes for gene: ZBTB18 were changed from to Mental retardation, autosomal dominant 22, MIM# 612337
Genetic Epilepsy v0.1412 ZBTB18 Zornitza Stark Publications for gene: ZBTB18 were set to
Genetic Epilepsy v0.1411 ZBTB18 Zornitza Stark Mode of inheritance for gene: ZBTB18 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1410 ZBTB18 Zornitza Stark reviewed gene: ZBTB18: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573576; Phenotypes: Mental retardation, autosomal dominant 22, MIM# 612337; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1410 KCND2 Zornitza Stark Marked gene: KCND2 as ready
Genetic Epilepsy v0.1410 KCND2 Zornitza Stark Gene: kcnd2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1410 KCND2 Zornitza Stark Classified gene: KCND2 as Green List (high evidence)
Genetic Epilepsy v0.1410 KCND2 Zornitza Stark Gene: kcnd2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1409 KCND2 Zornitza Stark gene: KCND2 was added
gene: KCND2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND2 were set to 24501278; 16934482; 29581270; 34245260
Phenotypes for gene: KCND2 were set to Neurodevelopmental disorder MONDO:0700092; global developmental delay, HP:0001263; seizure, HP:0001250
Review for gene: KCND2 was set to GREEN
Added comment: 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.
Sources: Literature
Genetic Epilepsy v0.1408 CHRNB2 Zornitza Stark Marked gene: CHRNB2 as ready
Genetic Epilepsy v0.1408 CHRNB2 Zornitza Stark Gene: chrnb2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1408 CHRNB2 Zornitza Stark Phenotypes for gene: CHRNB2 were changed from to Epilepsy, nocturnal frontal lobe, 3, MIM# 605375
Genetic Epilepsy v0.1407 CHRNB2 Zornitza Stark Publications for gene: CHRNB2 were set to
Genetic Epilepsy v0.1406 CHRNB2 Zornitza Stark Mode of inheritance for gene: CHRNB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1405 CHRNB2 Zornitza Stark reviewed gene: CHRNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11062464, 11104662, 19153075, 32536355, 25770198, 23032131; Phenotypes: Epilepsy, nocturnal frontal lobe, 3, MIM# 605375; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1405 BCAS3 Zornitza Stark Phenotypes for gene: BCAS3 were changed from Syndromic neurodevelopmental disorder to Hengel-Maroofian-Schols syndrome, MIM# 619641
Genetic Epilepsy v0.1404 BCAS3 Zornitza Stark reviewed gene: BCAS3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hengel-Maroofian-Schols syndrome, MIM# 619641; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1404 GNB1 Zornitza Stark Marked gene: GNB1 as ready
Genetic Epilepsy v0.1404 GNB1 Zornitza Stark Gene: gnb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1404 GNB1 Zornitza Stark Phenotypes for gene: GNB1 were changed from to Intellectual developmental disorder, autosomal dominant 42, MIM# 616973
Genetic Epilepsy v0.1403 GNB1 Zornitza Stark Publications for gene: GNB1 were set to 32134617
Genetic Epilepsy v0.1403 GNB1 Zornitza Stark Publications for gene: GNB1 were set to
Genetic Epilepsy v0.1402 GNB1 Zornitza Stark Mode of inheritance for gene: GNB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1401 GNB1 Zornitza Stark reviewed gene: GNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32134617; Phenotypes: Intellectual developmental disorder, autosomal dominant 42, MIM# 616973; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1401 SNIP1 Zornitza Stark Marked gene: SNIP1 as ready
Genetic Epilepsy v0.1401 SNIP1 Zornitza Stark Gene: snip1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1401 SNIP1 Zornitza Stark Classified gene: SNIP1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1401 SNIP1 Zornitza Stark Gene: snip1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1400 SNIP1 Zornitza Stark gene: SNIP1 was added
gene: SNIP1 was added to Genetic Epilepsy. Sources: Expert Review
founder tags were added to gene: SNIP1.
Mode of inheritance for gene: SNIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNIP1 were set to 22279524; 34570759
Phenotypes for gene: SNIP1 were set to Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501
Review for gene: SNIP1 was set to AMBER
Added comment: 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.
Sources: Expert Review
Genetic Epilepsy v0.1399 PLK1 Zornitza Stark Marked gene: PLK1 as ready
Genetic Epilepsy v0.1399 PLK1 Zornitza Stark Gene: plk1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1399 PLK1 Zornitza Stark Classified gene: PLK1 as Green List (high evidence)
Genetic Epilepsy v0.1399 PLK1 Zornitza Stark Gene: plk1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1398 PLK1 Zornitza Stark gene: PLK1 was added
gene: PLK1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK1 were set to 33875846
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: More than 5 individuals reported.
Sources: Literature
Genetic Epilepsy v0.1397 OGDHL Zornitza Stark Marked gene: OGDHL as ready
Genetic Epilepsy v0.1397 OGDHL Zornitza Stark Gene: ogdhl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1397 OGDHL Zornitza Stark Classified gene: OGDHL as Green List (high evidence)
Genetic Epilepsy v0.1397 OGDHL Zornitza Stark Gene: ogdhl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1396 OGDHL Zornitza Stark gene: OGDHL was added
gene: OGDHL was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 34800363
Phenotypes for gene: OGDHL were set to Neurodevelopmental disorder featuring epilepsy, hearing loss, visual impairment, and ataxia
Review for gene: OGDHL was set to GREEN
Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Four individuals had seizures.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Genetic Epilepsy v0.1395 SPATA5L1 Zornitza Stark Phenotypes for gene: SPATA5L1 were changed from Intellectual disability; spastic-dystonic cerebral palsy; epilepsy; hearing loss to Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616
Genetic Epilepsy v0.1394 SPATA5L1 Zornitza Stark reviewed gene: SPATA5L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1394 ATP1A2 Zornitza Stark Phenotypes for gene: ATP1A2 were changed from developmental and epileptic encephalopathy; early or neonatal onset seizures, polymicrogyria to Developmental and epileptic encephalopathy 98, MIM# 619605
Genetic Epilepsy v0.1393 ATP1A2 Zornitza Stark reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 98, MIM# 619605; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1393 CDKL5 Zornitza Stark Marked gene: CDKL5 as ready
Genetic Epilepsy v0.1393 CDKL5 Zornitza Stark Gene: cdkl5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1393 CDKL5 Zornitza Stark Phenotypes for gene: CDKL5 were changed from to Developmental and epileptic encephalopathy 2, MIM# 300672
Genetic Epilepsy v0.1392 CDKL5 Zornitza Stark Publications for gene: CDKL5 were set to
Genetic Epilepsy v0.1391 CDKL5 Zornitza Stark Mode of inheritance for gene: CDKL5 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1390 CDKL5 Zornitza Stark reviewed gene: CDKL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 19793311; Phenotypes: Developmental and epileptic encephalopathy 2, MIM# 300672; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1390 EFHC1 Zornitza Stark Tag disputed tag was added to gene: EFHC1.
Genetic Epilepsy v0.1390 CPA6 Zornitza Stark Tag refuted tag was added to gene: CPA6.
Tag disputed tag was added to gene: CPA6.
Genetic Epilepsy v0.1390 SCN9A Zornitza Stark Publications for gene: SCN9A were set to 19763161; 29500686; 30834459; 23895530
Genetic Epilepsy v0.1389 RYR3 Zornitza Stark Marked gene: RYR3 as ready
Genetic Epilepsy v0.1389 RYR3 Zornitza Stark Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1389 SLC46A1 Bryony Thompson Marked gene: SLC46A1 as ready
Genetic Epilepsy v0.1389 SLC46A1 Bryony Thompson Gene: slc46a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1389 SLC46A1 Bryony Thompson Classified gene: SLC46A1 as Green List (high evidence)
Genetic Epilepsy v0.1389 SLC46A1 Bryony Thompson Gene: slc46a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1388 RYR3 Bryony Thompson Classified gene: RYR3 as Amber List (moderate evidence)
Genetic Epilepsy v0.1388 RYR3 Bryony Thompson Gene: ryr3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1387 RYR3 Bryony Thompson gene: RYR3 was added
gene: RYR3 was added to Genetic Epilepsy. Sources: ClinGen
Mode of inheritance for gene: RYR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYR3 were set to 25262651
Phenotypes for gene: RYR3 were set to undetermined early-onset epileptic encephalopathy (MONDO:0018614)
Review for gene: RYR3 was set to AMBER
Added comment: 2 probands with different de novo missense variants in a single publication. Classified as Limited by ClinGen Epilepsy GCEP - Classification - 06/19/2018.
Sources: ClinGen
Genetic Epilepsy v0.1386 EFHC1 Bryony Thompson Classified gene: EFHC1 as Red List (low evidence)
Genetic Epilepsy v0.1386 EFHC1 Bryony Thompson Added comment: Comment on list classification: ClinGen Epilepsy GCEP gene-disease association curation: Disputed - We have disregarded the very limited functional evidence in light of the complete lack of genetic evidence connecting EFHC1 and epilepsy. In summary, there is convincing evidence disputing the association between EFHC1 and epilepsy. All variants in EFHC1 associated with epilepsy have contradictory evidence for disease association (too common in ExAC/gnomAD, with minor allele frequencies (MAF) of 2.857e-5 to 0.05973). More evidence is needed to either support or refute the role EFHC1 plays in this disease. Classification - 07/27/2018, reviewed Sept 2021
Genetic Epilepsy v0.1386 EFHC1 Bryony Thompson Gene: efhc1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1385 DNAJC5 Bryony Thompson Marked gene: DNAJC5 as ready
Genetic Epilepsy v0.1385 DNAJC5 Bryony Thompson Gene: dnajc5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1385 DNAJC5 Bryony Thompson Classified gene: DNAJC5 as Green List (high evidence)
Genetic Epilepsy v0.1385 DNAJC5 Bryony Thompson Gene: dnajc5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1384 DNAJC5 Bryony Thompson gene: DNAJC5 was added
gene: DNAJC5 was added to Genetic Epilepsy. Sources: ClinGen
Mode of inheritance for gene: DNAJC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNAJC5 were set to 22978711; 21820099; 22235333; 31919451; 26659577
Phenotypes for gene: DNAJC5 were set to adult neuronal ceroid lipofuscinosis (MONDO:0019260)
Review for gene: DNAJC5 was set to GREEN
Added comment: ClinGen Epilepsy GCEP gene-disease curation: Moderate, >3 families reported. Classification - 07/30/2021
Sources: ClinGen
Genetic Epilepsy v0.1383 MICAL1 Bryony Thompson Marked gene: MICAL1 as ready
Genetic Epilepsy v0.1383 MICAL1 Bryony Thompson Gene: mical1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1383 MICAL1 Bryony Thompson Classified gene: MICAL1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1383 MICAL1 Bryony Thompson Gene: mical1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1382 MICAL1 Bryony Thompson Classified gene: MICAL1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1382 MICAL1 Bryony Thompson Gene: mical1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1381 MICAL1 Bryony Thompson gene: MICAL1 was added
gene: MICAL1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: MICAL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MICAL1 were set to 29394500; 21638339
Phenotypes for gene: MICAL1 were set to Autosomal dominant epilepsy with auditory features (ADEAF)
Review for gene: MICAL1 was set to AMBER
Added comment: Two families with supporting in vitro functional assays. Assessment of expression pattern of Mical-1 in the temporal neocortex of patients with intractable temporal epilepsy and pilocarpine-induced rat model, suggests Mical-1 may associate with inner pathophysiological modulation in epilepsy.
Sources: Expert list
Genetic Epilepsy v0.1380 SCN9A Bryony Thompson Classified gene: SCN9A as Red List (low evidence)
Genetic Epilepsy v0.1380 SCN9A Bryony Thompson Added comment: Comment on list classification: ClinGen Epilepsy GCEP curated gene-disease association with epilepsy: A novel publication provides evidence against pathogenicity for a previously reported variant providing the primary evidence for an association with epilepsy. Classification - 03/09/2021
Genetic Epilepsy v0.1380 SCN9A Bryony Thompson Gene: scn9a has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1379 CPA6 Bryony Thompson Classified gene: CPA6 as Red List (low evidence)
Genetic Epilepsy v0.1379 CPA6 Bryony Thompson Added comment: Comment on list classification: ClinGen Epilepsy GCEP has reviewed both inheritances for gene-disease associations with epilepsy: AR disease is Disputed - There is contradictory case level and experimental data regarding any association between CPA6 and autosomal recessive epilepsy. Classification - 07/29/2021 AD disease is Refuted- There is very limited evidence supporting a gene-disease association. Many of the reported pathogenic variants have been subsequently identified as having a high minor allele frequency in population databases. Classification - 07/29/2021
Genetic Epilepsy v0.1379 CPA6 Bryony Thompson Gene: cpa6 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1378 CNTN2 Bryony Thompson Marked gene: CNTN2 as ready
Genetic Epilepsy v0.1378 CNTN2 Bryony Thompson Gene: cntn2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1378 CNTN2 Bryony Thompson Classified gene: CNTN2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1378 CNTN2 Bryony Thompson Gene: cntn2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1377 CNTN2 Bryony Thompson reviewed gene: CNTN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 23518707, 34120799, 34691156; Phenotypes: Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1377 LAMC3 Daniel Flanagan gene: LAMC3 was added
gene: LAMC3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: LAMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMC3 were set to 33639934; 21572413; 34354730
Phenotypes for gene: LAMC3 were set to Cortical malformations, occipital, MIM#614115
Review for gene: LAMC3 was set to GREEN
Added comment: Biallelic LAMC3 variants cause occipital cortical malformation with 6 unrelated families reported. Childhood-onset seizures is the most common clinical manifestation, usually occurring around age 10.
Sources: Literature
Genetic Epilepsy v0.1377 OTUD7A Zornitza Stark Phenotypes for gene: OTUD7A were changed from Epileptic encephalopathy, no OMIM# yet to Intellectual disability; Epilepsy
Genetic Epilepsy v0.1376 OTUD7A Zornitza Stark Publications for gene: OTUD7A were set to PMID: 31997314
Genetic Epilepsy v0.1375 OTUD7A Zornitza Stark Classified gene: OTUD7A as Amber List (moderate evidence)
Genetic Epilepsy v0.1375 OTUD7A Zornitza Stark Gene: otud7a has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1374 OTUD7A Zornitza Stark reviewed gene: OTUD7A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31997314, 29395075, 29395074, 33381903; Phenotypes: Intellectual disability, Epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1374 ALG1 Zornitza Stark Marked gene: ALG1 as ready
Genetic Epilepsy v0.1374 ALG1 Zornitza Stark Gene: alg1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1374 ALG1 Zornitza Stark Phenotypes for gene: ALG1 were changed from to Congenital disorder of glycosylation, type Ik, MIM# 608540
Genetic Epilepsy v0.1373 ALG1 Zornitza Stark Publications for gene: ALG1 were set to
Genetic Epilepsy v0.1372 ALG1 Zornitza Stark Mode of inheritance for gene: ALG1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1371 ALG1 Zornitza Stark reviewed gene: ALG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26931382; Phenotypes: Congenital disorder of glycosylation, type Ik, MIM# 608540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1371 SPATA5L1 Zornitza Stark Marked gene: SPATA5L1 as ready
Genetic Epilepsy v0.1371 SPATA5L1 Zornitza Stark Gene: spata5l1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1371 SPATA5L1 Zornitza Stark Classified gene: SPATA5L1 as Green List (high evidence)
Genetic Epilepsy v0.1371 SPATA5L1 Zornitza Stark Gene: spata5l1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1370 SPATA5L1 Paul De Fazio changed review comment from: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

In 25 patients for whom full phenotype datasets were available, 13 had epilepsy.
Sources: Literature; to: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

~64% of patients had epilepsy.
Sources: Literature
Genetic Epilepsy v0.1370 SPATA5L1 Paul De Fazio gene: SPATA5L1 was added
gene: SPATA5L1 was added to Genetic Epilepsy. Sources: Literature
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 Intellectual disability; spastic-dystonic cerebral palsy; epilepsy; hearing loss
Review for gene: SPATA5L1 was set to GREEN
gene: SPATA5L1 was marked as current diagnostic
Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

In 25 patients for whom full phenotype datasets were available, 13 had epilepsy.
Sources: Literature
Genetic Epilepsy v0.1370 GRIK2 Zornitza Stark Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6 MIM# 611092; nonsyndromic neurodevelopmental disorder (NDD) to Mental retardation, autosomal recessive, 6 MIM# 611092; Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580
Genetic Epilepsy v0.1369 GRIK2 Zornitza Stark reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with impaired language and ataxia and with or without seizures, MIM# 619580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1369 TFE3 Zornitza Stark Phenotypes for gene: TFE3 were changed from TFE3-associated neurodevelopmental disorder; Intellectual disability; Epilepsy; Coarse facial features to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, MIM# 301066; Intellectual disability; Epilepsy; Coarse facial features
Genetic Epilepsy v0.1368 TFE3 Zornitza Stark edited their review of gene: TFE3: Changed phenotypes: Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, MIM# 301066, Intellectual disability, Epilepsy, Coarse facial features
Genetic Epilepsy v0.1368 ETHE1 Zornitza Stark Marked gene: ETHE1 as ready
Genetic Epilepsy v0.1368 ETHE1 Zornitza Stark Gene: ethe1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1368 ETHE1 Zornitza Stark Phenotypes for gene: ETHE1 were changed from to Ethylmalonic encephalopathy , MIM#602473
Genetic Epilepsy v0.1367 ETHE1 Zornitza Stark Publications for gene: ETHE1 were set to
Genetic Epilepsy v0.1366 ETHE1 Zornitza Stark Mode of inheritance for gene: ETHE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1365 ETHE1 Zornitza Stark reviewed gene: ETHE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 14732903, 28933811; Phenotypes: Ethylmalonic encephalopathy , MIM#602473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1365 ZNHIT3 Zornitza Stark Marked gene: ZNHIT3 as ready
Genetic Epilepsy v0.1365 ZNHIT3 Zornitza Stark Gene: znhit3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1365 ZNHIT3 Zornitza Stark Classified gene: ZNHIT3 as Green List (high evidence)
Genetic Epilepsy v0.1365 ZNHIT3 Zornitza Stark Gene: znhit3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1364 ZNHIT3 Zornitza Stark gene: ZNHIT3 was added
gene: ZNHIT3 was added to Genetic Epilepsy. Sources: Expert Review
founder tags were added to gene: ZNHIT3.
Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNHIT3 were set to 28335020; 28335020; 31048081
Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, MIM# 260565
Review for gene: ZNHIT3 was set to GREEN
Added comment: PEHO is a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy due to almost total loss of granule neurons. Affected individuals present in early infancy with hypotonia, profoundly delayed psychomotor development, optic atrophy, progressive atrophy of the cerebellum and brainstem, and dysmyelination. Most patients also develop infantile seizures that are often associated with hypsarrhythmia on EEG, and many have peripheral oedema. More than 20 affected individuals reported of Finnish origin, p.Ser31Leu is a founder variant. One compound het reported and supportive animal model.
Sources: Expert Review
Genetic Epilepsy v0.1363 ADGRG1 Zornitza Stark changed review comment from: 12 families reported in the original paper. ID and seizures are common features.; to: 12 families reported in the original paper. ID and seizures are common features.

Note promoter deletion is common.
Genetic Epilepsy v0.1363 ADGRG1 Zornitza Stark Tag 5'UTR tag was added to gene: ADGRG1.
Genetic Epilepsy v0.1363 ADGRG1 Zornitza Stark Marked gene: ADGRG1 as ready
Genetic Epilepsy v0.1363 ADGRG1 Zornitza Stark Gene: adgrg1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1363 ADGRG1 Zornitza Stark Phenotypes for gene: ADGRG1 were changed from to Polymicrogyria, bilateral frontoparietal, MIM#606854
Genetic Epilepsy v0.1362 ADGRG1 Zornitza Stark Publications for gene: ADGRG1 were set to
Genetic Epilepsy v0.1361 ADGRG1 Zornitza Stark Mode of inheritance for gene: ADGRG1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1360 ADGRG1 Zornitza Stark reviewed gene: ADGRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16240336, 33299078; Phenotypes: Polymicrogyria, bilateral frontoparietal, MIM#606854; Mode of inheritance: None
Genetic Epilepsy v0.1360 GATAD2B Zornitza Stark Marked gene: GATAD2B as ready
Genetic Epilepsy v0.1360 GATAD2B Zornitza Stark Gene: gatad2b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1360 GATAD2B Zornitza Stark Classified gene: GATAD2B as Amber List (moderate evidence)
Genetic Epilepsy v0.1360 GATAD2B Zornitza Stark Gene: gatad2b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1359 GATAD2B Zornitza Stark gene: GATAD2B was added
gene: GATAD2B was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: GATAD2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2B were set to 32688057
Phenotypes for gene: GATAD2B were set to Mental retardation, autosomal dominant 18, OMIM # 615074
Review for gene: GATAD2B was set to AMBER
Added comment: More than 70 patients reported: - loss-of-function and missense variants - clinical features of hypotonia, intellectual disability, strabismus, cardiac defects, characteristic facies, childhood apraxia of speech, and macrocephaly.

Seizures are a rare feature.
Sources: Expert Review
Genetic Epilepsy v0.1358 FGF12 Zornitza Stark Marked gene: FGF12 as ready
Genetic Epilepsy v0.1358 FGF12 Zornitza Stark Gene: fgf12 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1358 FGF12 Zornitza Stark Phenotypes for gene: FGF12 were changed from to Developmental and epileptic encephalopathy 47, MIM# 617166
Genetic Epilepsy v0.1357 FGF12 Zornitza Stark Publications for gene: FGF12 were set to
Genetic Epilepsy v0.1356 FGF12 Zornitza Stark Mode of inheritance for gene: FGF12 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1355 FGF12 Zornitza Stark reviewed gene: FGF12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32645220, 27164707, 27830185, 27872899; Phenotypes: Developmental and epileptic encephalopathy 47, MIM# 617166; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1355 KIF5A Zornitza Stark Marked gene: KIF5A as ready
Genetic Epilepsy v0.1355 KIF5A Zornitza Stark Gene: kif5a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1355 KIF5A Zornitza Stark Classified gene: KIF5A as Green List (high evidence)
Genetic Epilepsy v0.1355 KIF5A Zornitza Stark Gene: kif5a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1354 MED27 Zornitza Stark Marked gene: MED27 as ready
Genetic Epilepsy v0.1354 MED27 Zornitza Stark Gene: med27 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1354 KPNA7 Zornitza Stark Marked gene: KPNA7 as ready
Genetic Epilepsy v0.1354 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1354 KPNA7 Zornitza Stark Classified gene: KPNA7 as Red List (low evidence)
Genetic Epilepsy v0.1354 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1353 KPNA7 Ain Roesley gene: KPNA7 was added
gene: KPNA7 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KPNA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KPNA7 were set to 24045845; 32179771
Phenotypes for gene: KPNA7 were set to severe neurodevelopmental defects; epilepsy
Penetrance for gene: KPNA7 were set to unknown
Review for gene: KPNA7 was set to RED
gene: KPNA7 was marked as current diagnostic
Added comment: 1 fam with 2 siblings. Functional showed disruptions to CTCF binding
Sources: Literature
Genetic Epilepsy v0.1353 KMT2D Zornitza Stark Marked gene: KMT2D as ready
Genetic Epilepsy v0.1353 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1353 KMT2D Zornitza Stark Publications for gene: KMT2D were set to 33552639; 28404210; 27922244
Genetic Epilepsy v0.1352 KMT2D Zornitza Stark Classified gene: KMT2D as Green List (high evidence)
Genetic Epilepsy v0.1352 KMT2D Zornitza Stark Gene: kmt2d has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1351 KMT2D Zornitza Stark reviewed gene: KMT2D: Rating: GREEN; Mode of pathogenicity: None; Publications: 21882399; Phenotypes: Kabuki syndrome 1 MIM#147920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1351 MED27 Zornitza Stark Classified gene: MED27 as Green List (high evidence)
Genetic Epilepsy v0.1351 MED27 Zornitza Stark Gene: med27 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1350 MED13L Zornitza Stark Marked gene: MED13L as ready
Genetic Epilepsy v0.1350 MED13L Zornitza Stark Gene: med13l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1350 MAP1B Zornitza Stark Marked gene: MAP1B as ready
Genetic Epilepsy v0.1350 MAP1B Zornitza Stark Gene: map1b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1350 MAP1B Zornitza Stark Phenotypes for gene: MAP1B were changed from febrile, fever-triggered and afebrile seizures to Intellectual disability; seizures; PVNH; dysmorphic features; Periventricular nodular heterotopia 9, MIM# 618918
Genetic Epilepsy v0.1350 MED13L Zornitza Stark Classified gene: MED13L as Green List (high evidence)
Genetic Epilepsy v0.1350 MED13L Zornitza Stark Gene: med13l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1349 MAP1B Zornitza Stark Classified gene: MAP1B as Green List (high evidence)
Genetic Epilepsy v0.1349 MAP1B Zornitza Stark Gene: map1b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1348 LIG3 Zornitza Stark Marked gene: LIG3 as ready
Genetic Epilepsy v0.1348 LIG3 Zornitza Stark Gene: lig3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1348 MAP1B Zornitza Stark reviewed gene: MAP1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31317654, 30150678, 30214071, 33772511; Phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features, Periventricular nodular heterotopia 9, MIM# 618918; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1348 LIG3 Zornitza Stark Classified gene: LIG3 as Green List (high evidence)
Genetic Epilepsy v0.1348 LIG3 Zornitza Stark Gene: lig3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1347 ODC1 Zornitza Stark Marked gene: ODC1 as ready
Genetic Epilepsy v0.1347 ODC1 Zornitza Stark Gene: odc1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1347 ODC1 Zornitza Stark Classified gene: ODC1 as Red List (low evidence)
Genetic Epilepsy v0.1347 ODC1 Zornitza Stark Gene: odc1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1346 NAA10 Zornitza Stark Phenotypes for gene: NAA10 were changed from Microphthalmia, syndromic 1, MIM# 309800 to Microphthalmia, syndromic 1, MIM# 309800; NAA10-related syndrome; Seizures
Genetic Epilepsy v0.1345 KCTD13 Zornitza Stark Marked gene: KCTD13 as ready
Genetic Epilepsy v0.1345 KCTD13 Zornitza Stark Gene: kctd13 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1345 NAA10 Zornitza Stark Classified gene: NAA10 as Amber List (moderate evidence)
Genetic Epilepsy v0.1345 NAA10 Zornitza Stark Gene: naa10 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1344 KCTD13 Zornitza Stark Classified gene: KCTD13 as Red List (low evidence)
Genetic Epilepsy v0.1344 KCTD13 Zornitza Stark Gene: kctd13 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1343 OGT Zornitza Stark Marked gene: OGT as ready
Genetic Epilepsy v0.1343 OGT Zornitza Stark Gene: ogt has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1343 OGT Zornitza Stark Classified gene: OGT as Red List (low evidence)
Genetic Epilepsy v0.1343 OGT Zornitza Stark Gene: ogt has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1342 KCNH1 Zornitza Stark Marked gene: KCNH1 as ready
Genetic Epilepsy v0.1342 KCNH1 Zornitza Stark Gene: kcnh1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1342 NAGLU Zornitza Stark reviewed gene: NAGLU: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis type IIIB (Sanfilippo B) - 252920, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1342 KCNH1 Zornitza Stark Phenotypes for gene: KCNH1 were changed from seizures; epilepsy; intellectual disability; hypotonia; skeletal abnormalities; nail abnormalities to Temple-Baraitser syndrome, OMIM:611816 Zimmermann-Laband syndrome 1, OMIM:135500 Intellectual disability Encephalopathy without features of TBS/ZLS
Genetic Epilepsy v0.1342 KCTD7 Ain Roesley reviewed gene: KCTD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33767931, 33970744, 22693283, 22748208; Phenotypes: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions MMI#611726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v0.1342 NAGLU Zornitza Stark Marked gene: NAGLU as ready
Genetic Epilepsy v0.1342 NAGLU Zornitza Stark Gene: naglu has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1342 NAGLU Zornitza Stark Phenotypes for gene: NAGLU were changed from Mucopolysaccharidosis type IIIB (Sanfilippo B) - 252920; ?Charcot-Marie-Tooth disease, axonal, type 2V - 616491; Seizures to Mucopolysaccharidosis type IIIB (Sanfilippo B) - 252920; Seizures
Genetic Epilepsy v0.1341 KCNH1 Zornitza Stark Classified gene: KCNH1 as Green List (high evidence)
Genetic Epilepsy v0.1341 KCNH1 Zornitza Stark Gene: kcnh1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1340 KCNH1 Zornitza Stark reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Temple-Baraitser syndrome, OMIM:611816 Zimmermann-Laband syndrome 1, OMIM:135500 Intellectual disability Encephalopathy without features of TBS/ZLS; Mode of inheritance: None
Genetic Epilepsy v0.1340 ODC1 Belinda Chong changed review comment from: Epilepsy appears to be a rare feature of this syndrome.
Sources: Literature; to: Epilepsy not reported.
Sources: Literature
Genetic Epilepsy v0.1340 NAGLU Zornitza Stark Mode of inheritance for gene: NAGLU was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1339 OSGEP Zornitza Stark Marked gene: OSGEP as ready
Genetic Epilepsy v0.1339 OSGEP Zornitza Stark Gene: osgep has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1339 NAGLU Zornitza Stark Classified gene: NAGLU as Green List (high evidence)
Genetic Epilepsy v0.1339 NAGLU Zornitza Stark Gene: naglu has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1338 OSGEP Zornitza Stark Classified gene: OSGEP as Green List (high evidence)
Genetic Epilepsy v0.1338 OSGEP Zornitza Stark Gene: osgep has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1337 OGT Belinda Chong changed review comment from: Epilepsy appears to be a rare feature of this disorder.
Sources: Literature; to: Epilepsy not reported
Sources: Literature
Genetic Epilepsy v0.1337 KCNN3 Zornitza Stark Marked gene: KCNN3 as ready
Genetic Epilepsy v0.1337 KCNN3 Zornitza Stark Gene: kcnn3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1337 KCNN3 Zornitza Stark Classified gene: KCNN3 as Red List (low evidence)
Genetic Epilepsy v0.1337 KCNN3 Zornitza Stark Gene: kcnn3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1336 OSTC Zornitza Stark Marked gene: OSTC as ready
Genetic Epilepsy v0.1336 OSTC Zornitza Stark Gene: ostc has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1336 OGT Belinda Chong changed review comment from: Epilepsy appears to be a rare feature of this syndrome.
Sources: Literature; to: Epilepsy appears to be a rare feature of this disorder.
Sources: Literature
Genetic Epilepsy v0.1336 OSTC Zornitza Stark Classified gene: OSTC as Red List (low evidence)
Genetic Epilepsy v0.1336 OSTC Zornitza Stark Gene: ostc has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1335 NDUFA8 Zornitza Stark Marked gene: NDUFA8 as ready
Genetic Epilepsy v0.1335 NDUFA8 Zornitza Stark Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1335 NDUFA8 Zornitza Stark Classified gene: NDUFA8 as Amber List (moderate evidence)
Genetic Epilepsy v0.1335 NDUFA8 Zornitza Stark Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1334 OTUD5 Zornitza Stark Marked gene: OTUD5 as ready
Genetic Epilepsy v0.1334 OTUD5 Zornitza Stark Gene: otud5 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1334 OTUD5 Zornitza Stark Phenotypes for gene: OTUD5 were changed from X-Linked Intellectual Disability and Congenital Malformation to Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056
Genetic Epilepsy v0.1333 KCNC2 Zornitza Stark Marked gene: KCNC2 as ready
Genetic Epilepsy v0.1333 KCNC2 Zornitza Stark Gene: kcnc2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1333 KCNC2 Zornitza Stark Classified gene: KCNC2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1333 KCNC2 Zornitza Stark Gene: kcnc2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1332 OTUD5 Zornitza Stark Classified gene: OTUD5 as Amber List (moderate evidence)
Genetic Epilepsy v0.1332 OTUD5 Zornitza Stark Gene: otud5 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1331 NOTCH3 Zornitza Stark Marked gene: NOTCH3 as ready
Genetic Epilepsy v0.1331 NOTCH3 Zornitza Stark Gene: notch3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1331 OTUD5 Zornitza Stark reviewed gene: OTUD5: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, MIM# 301056; Mode of inheritance: None
Genetic Epilepsy v0.1331 NOTCH3 Zornitza Stark Phenotypes for gene: NOTCH3 were changed from ?Myofibromatosis, infantile 2 - 615293; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 - 125310; Lateral meningocele syndrome - 130720 to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 - 125310
Genetic Epilepsy v0.1330 NOTCH3 Zornitza Stark Classified gene: NOTCH3 as Red List (low evidence)
Genetic Epilepsy v0.1330 NOTCH3 Zornitza Stark Gene: notch3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1329 KCNAB3 Zornitza Stark Marked gene: KCNAB3 as ready
Genetic Epilepsy v0.1329 KCNAB3 Zornitza Stark Gene: kcnab3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1329 KCNAB3 Zornitza Stark Classified gene: KCNAB3 as Red List (low evidence)
Genetic Epilepsy v0.1329 KCNAB3 Zornitza Stark Gene: kcnab3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1328 KCNA1 Zornitza Stark Marked gene: KCNA1 as ready
Genetic Epilepsy v0.1328 KCNA1 Zornitza Stark Gene: kcna1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1328 KCNA1 Zornitza Stark Classified gene: KCNA1 as Green List (high evidence)
Genetic Epilepsy v0.1328 KCNA1 Zornitza Stark Gene: kcna1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1327 DAB1 Zornitza Stark Marked gene: DAB1 as ready
Genetic Epilepsy v0.1327 DAB1 Zornitza Stark Gene: dab1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1327 DAB1 Zornitza Stark Classified gene: DAB1 as Red List (low evidence)
Genetic Epilepsy v0.1327 DAB1 Zornitza Stark Gene: dab1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1326 KIF5A Ain Roesley gene: KIF5A was added
gene: KIF5A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5A were set to 27414745; 33681666; 27463701
Phenotypes for gene: KIF5A were set to Myoclonus, intractable, neonatal MIM#617235
Penetrance for gene: KIF5A were set to Complete
Review for gene: KIF5A was set to GREEN
gene: KIF5A was marked as current diagnostic
Added comment: PMID: 27414745
1x de novo with myoclonic seizures

PMID: 33681666
1x de novo with epileptic spasm

PMID: 27463701
2 unrelated patients who presented shortly after birth with nearly continuous nonrhythmic large-amplitude myoclonic jerks associated with intermittent apnea
2x de novo fs
Sources: Literature
Genetic Epilepsy v0.1326 KMT2D Ain Roesley gene: KMT2D was added
gene: KMT2D was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KMT2D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KMT2D were set to 33552639; 28404210; 27922244
Phenotypes for gene: KMT2D were set to Kabuki syndrome 1 MIM#147920
Penetrance for gene: KMT2D were set to Complete
Review for gene: KMT2D was set to GREEN
Added comment: PMID:33552639
1x proband with focal epilepsy. Note: only KDM6A and KMT2D were analysed as Kabuki syndrome was suspected. Parental DNA unavailable for segregation

PMID:28404210
5 out of 14 reported to have epilepsy

PMID:27922244
1x individual
Sources: Literature
Genetic Epilepsy v0.1326 EXOSC8 Zornitza Stark Marked gene: EXOSC8 as ready
Genetic Epilepsy v0.1326 EXOSC8 Zornitza Stark Gene: exosc8 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1326 EXOSC8 Zornitza Stark gene: EXOSC8 was added
gene: EXOSC8 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC8 were set to 24989451; 29656927; 34210538
Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C, MIM#616081
Review for gene: EXOSC8 was set to RED
Added comment: Typical clinical presentation is with severe muscle weakness and failure to thrive apparent in the first months of life. Affected infants show delayed psychomotor development, often with visual and hearing impairment, and may die of respiratory failure. Brain imaging typically shows cerebellar hypoplasia, hypoplasia of the corpus callosum, and immature myelination.

Single family reported with seizures as part of the phenotype.
Sources: Literature
Genetic Epilepsy v0.1325 ELOVL4 Zornitza Stark changed review comment from: 5 unrelated families reported, seizures in at least 4 of the families.
Sources: Expert Review; to: 5 unrelated families reported, seizures in at least 4 of the families.

Note mono-allelic variants cause retinopathy/SCA.
Sources: Expert Review
Genetic Epilepsy v0.1325 ELOVL4 Zornitza Stark Marked gene: ELOVL4 as ready
Genetic Epilepsy v0.1325 ELOVL4 Zornitza Stark Gene: elovl4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1325 ELOVL4 Zornitza Stark Classified gene: ELOVL4 as Green List (high evidence)
Genetic Epilepsy v0.1325 ELOVL4 Zornitza Stark Gene: elovl4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1324 ELOVL4 Zornitza Stark gene: ELOVL4 was added
gene: ELOVL4 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: ELOVL4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ELOVL4 were set to 22100072; 24571530; 33652762
Phenotypes for gene: ELOVL4 were set to Ichthyosis, spastic quadriplegia, and mental retardation (MIM#614457)
Review for gene: ELOVL4 was set to GREEN
Added comment: 5 unrelated families reported, seizures in at least 4 of the families.
Sources: Expert Review
Genetic Epilepsy v0.1323 EFHC1 Zornitza Stark Publications for gene: EFHC1 were set to 31056551; 28370826; 29750216
Genetic Epilepsy v0.1322 EFHC1 Zornitza Stark edited their review of gene: EFHC1: Changed publications: 31056551, 28370826, 29750216, 33969125, 33181902
Genetic Epilepsy v0.1322 MED27 Ain Roesley gene: MED27 was added
gene: MED27 was added to Genetic Epilepsy. Sources: Literature
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 Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia MIM#619286
Penetrance for gene: MED27 were set to unknown
Review for gene: MED27 was set to GREEN
Added comment: 9 out of 15 reported to have epilepsy
Sources: Literature
Genetic Epilepsy v0.1322 MED13L Ain Roesley gene: MED13L was added
gene: MED13L was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: MED13L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MED13L were set to 32646507; 29511999; 25712080
Phenotypes for gene: MED13L were set to Impaired intellectual development and distinctive facial features with or without cardiac defects MIM#616789
Penetrance for gene: MED13L were set to unknown
Review for gene: MED13L was set to GREEN
gene: MED13L was marked as current diagnostic
Added comment: PMID:32646507;
8/18 individuals with missense variants reported to have epileptic seizures

PMID:29511999;
1x individual with fs variant

PMID: 25712080;
1x individual with nonsense variant
Sources: Literature
Genetic Epilepsy v0.1322 MAP1B Ain Roesley gene: MAP1B was added
gene: MAP1B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAP1B were set to 33772511
Phenotypes for gene: MAP1B were set to febrile, fever-triggered and afebrile seizures
Penetrance for gene: MAP1B were set to unknown
Review for gene: MAP1B was set to RED
Added comment: 4 affected family members had various combinations of: febrile, fever-triggered and afebrile seizures; photo-sensitivity; comorbid mild developmental delays; obsessive-compulsive behaviors; and poor attention span.
childhood onset, heterozygous fs variant
Sources: Literature
Genetic Epilepsy v0.1322 DNAJC6 Zornitza Stark Publications for gene: DNAJC6 were set to
Genetic Epilepsy v0.1321 DNAJC6 Zornitza Stark edited their review of gene: DNAJC6: Changed publications: 23211418
Genetic Epilepsy v0.1321 DENND5A Zornitza Stark Marked gene: DENND5A as ready
Genetic Epilepsy v0.1321 DENND5A Zornitza Stark Gene: dennd5a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1321 DENND5A Zornitza Stark Phenotypes for gene: DENND5A were changed from to Epileptic encephalopathy, early infantile, 49, MIM# 617281
Genetic Epilepsy v0.1320 DENND5A Zornitza Stark Publications for gene: DENND5A were set to
Genetic Epilepsy v0.1319 DENND5A Zornitza Stark Mode of inheritance for gene: DENND5A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1318 DENND5A Zornitza Stark reviewed gene: DENND5A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27431290, 27866705, 32705489; Phenotypes: Epileptic encephalopathy, early infantile, 49, MIM# 617281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1318 DARS2 Zornitza Stark Marked gene: DARS2 as ready
Genetic Epilepsy v0.1318 DARS2 Zornitza Stark Gene: dars2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1318 DARS2 Zornitza Stark gene: DARS2 was added
gene: DARS2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: DARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DARS2 were set to 17384640; 15002045; 16788019; 30352563
Phenotypes for gene: DARS2 were set to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105
Review for gene: DARS2 was set to RED
Added comment: Well established gene-disease association. Affected individuals typically present with slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. Single individual reported with seizures in PMID 30352563.
Sources: Literature
Genetic Epilepsy v0.1317 LIG3 Ain Roesley gene: LIG3 was added
gene: LIG3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to mitochondrial neurogastrointestinal encephalomyopathy
Penetrance for gene: LIG3 were set to Complete
Review for gene: LIG3 was set to GREEN
gene: LIG3 was marked as current diagnostic
Added comment: 7 affecteds from 3 families
All had severe dysmotility of the gut, leukoencephalopathy and/or progressive cortical atrophy and 1 family with cerebellar atrophy
All had epilepsy, stroke-like episodes, migraine and developmental delay, reminiscent of MELAS.

4 missense (K537N led to splicing defects) and 2 nonsense
molecular defects demonstrated on patients' fibroblasts
KO models done on zebrafish
Sources: Literature
Genetic Epilepsy v0.1317 ODC1 Belinda Chong gene: ODC1 was added
gene: ODC1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ODC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ODC1 were set to PMID:30475435; 30239107
Phenotypes for gene: ODC1 were set to Bachmann-Bupp syndrome 619075
Review for gene: ODC1 was set to RED
gene: ODC1 was marked as current diagnostic
Added comment: Epilepsy appears to be a rare feature of this syndrome.
Sources: Literature
Genetic Epilepsy v0.1317 NAA10 Krithika Murali reviewed gene: NAA10: Rating: AMBER; Mode of pathogenicity: None; Publications: 29957440, 34200686; Phenotypes: Microphthalmia, syndromic 1 - 309800, Ogden syndrome - 300855, Seizures; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1317 KCTD13 Daniel Flanagan gene: KCTD13 was added
gene: KCTD13 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: KCTD13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCTD13 were set to PMID: 33409479
Review for gene: KCTD13 was set to RED
Added comment: Mouse model and in vitro evidence suggesting the deletion of KCTD13 has a similar metabolic affect as adenylosuccinate lyase deficiency, which has seizures and autistic features.
Sources: Expert list
Genetic Epilepsy v0.1317 OGT Belinda Chong gene: OGT was added
gene: OGT was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OGT was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OGT were set to PMID: 28302723; 28584052; 31296563; 31627256; 29769320; 29606577
Phenotypes for gene: OGT were set to Intellectual developmental disorder, X-linked 106 MIM#300997
Review for gene: OGT was set to RED
gene: OGT was marked as current diagnostic
Added comment: Epilepsy appears to be a rare feature of this syndrome.
Sources: Literature
Genetic Epilepsy v0.1317 KCNH1 Daniel Flanagan gene: KCNH1 was added
gene: KCNH1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KCNH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH1 were set to PMID: 33594261
Phenotypes for gene: KCNH1 were set to seizures; epilepsy; intellectual disability; hypotonia; skeletal abnormalities; nail abnormalities
Added comment: 24/27 patients with KCNH1 variants have seizures/epilepsy. These patients also had intellectual disabilities, hypotonia, skeletal abnormalities and nail abnormalities.
Sources: Literature
Genetic Epilepsy v0.1317 NAGLU Krithika Murali gene: NAGLU was added
gene: NAGLU was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: NAGLU was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: NAGLU were set to 34396902; 25818867; 8650226
Phenotypes for gene: NAGLU were set to Mucopolysaccharidosis type IIIB (Sanfilippo B) - 252920; ?Charcot-Marie-Tooth disease, axonal, type 2V - 616491; Seizures
Review for gene: NAGLU was set to GREEN
Added comment: The association between bi-allelic variants and Sanfilippo B is well established. The disorder is characterized by the accumulation of heparan sulfate, resulting in progressive neurodegeneration, behavioural problems, mild skeletal changes, and shortened life span. The clinical severity ranges from mild to severe. Seizures have been reported in affected individuals.

Two families reported with mono-allelic variants and CMT.
Sources: Expert list, Literature
Genetic Epilepsy v0.1317 OSGEP Belinda Chong gene: OSGEP was added
gene: OSGEP was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OSGEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSGEP were set to PMID: 28805828; 33333793
Phenotypes for gene: OSGEP were set to Galloway-Mowat syndrome 3, MIM#617729
Review for gene: OSGEP was set to GREEN
gene: OSGEP was marked as current diagnostic
Added comment: Epilepsy reported in multiple individuals with Galloway-Mowat syndrome 3
Sources: Literature
Genetic Epilepsy v0.1317 KCNN3 Daniel Flanagan gene: KCNN3 was added
gene: KCNN3 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: KCNN3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNN3 were set to PMID: 33594261
Phenotypes for gene: KCNN3 were set to Zimmermann-Laband syndrome
Review for gene: KCNN3 was set to RED
Added comment: PMID: 33594261. 0/5 patients with KCNN3 variants had seizures or epilepsy. 1 patient had suspected but not confirmed seizures.
Sources: Expert list
Genetic Epilepsy v0.1317 OSTC Belinda Chong gene: OSTC was added
gene: OSTC was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OSTC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSTC were set to PMID: 32267060
Phenotypes for gene: OSTC were set to Oligosaccharyltransferase complex-congenital disorders of glycosylation
Review for gene: OSTC was set to RED
Added comment: A patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.
Patient was homozygous for a canonical splice variant (c.431 + 1G > A), mRNA from patient's fibroblast showed mRNA transcript reduced 80-90%/aberrant splicing - predicting NMD.
GnomAD - 10 hets, 0 hom
Sources: Literature
Genetic Epilepsy v0.1317 NDUFA8 Krithika Murali gene: NDUFA8 was added
gene: NDUFA8 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: NDUFA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA8 were set to 32385911; 33153867
Phenotypes for gene: NDUFA8 were set to Mitochondrial complex I deficiency, nuclear type 37 - 619272; Epilepsy; Microcephaly; Developmental Delay
Review for gene: NDUFA8 was set to AMBER
Added comment: Second family reported with pair of affected siblings and homozygous missense variant, some functional data. 1 sibling had seizures.

Single individual reported with homozygous variant, fibroblasts showed apparent biochemical defects in mitochondrial complex I. Seizures reported.
Sources: Expert list, Literature
Genetic Epilepsy v0.1317 KCNC2 Daniel Flanagan gene: KCNC2 was added
gene: KCNC2 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: KCNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNC2 were set to PMID:32392612; 31972370
Phenotypes for gene: KCNC2 were set to epileptic encephalopathy; spastic tetraplegia; opisthotonos 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: Expert list
Genetic Epilepsy v0.1317 OTUD5 Belinda Chong gene: OTUD5 was added
gene: OTUD5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to PMID:33748114
Phenotypes for gene: OTUD5 were set to X-Linked Intellectual Disability and Congenital Malformation
Review for gene: OTUD5 was set to AMBER
Added comment: A hemizygous OTUD5 missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in a family in two brothers with epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly.
Sources: Literature
Genetic Epilepsy v0.1317 NOTCH3 Krithika Murali gene: NOTCH3 was added
gene: NOTCH3 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 33020014; 30776699; 21414809; 30056822; 17675836
Phenotypes for gene: NOTCH3 were set to ?Myofibromatosis, infantile 2 - 615293; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 - 125310; Lateral meningocele syndrome - 130720
Review for gene: NOTCH3 was set to RED
Added comment: CADASIL typically presents with adult-onset migraine, TIA/stroke, cognitive disorders. Seizures noted in 5-10% of patients with CADASIL, usually preceded by stroke. Less than 5 cases described of adult-onset epilepsy as initial presenting symptom of CADASIL. All had characteristic MRI-B changes and review of cases shows that a number of them had preceding migraine or other symptoms.

Not suitable for inclusion in genetic epilepsy panel as seizures are adult-onset, rarely observed, and usually develop as a secondary phenomenon.
Sources: Expert list, Literature
Genetic Epilepsy v0.1317 KCNAB3 Daniel Flanagan gene: KCNAB3 was added
gene: KCNAB3 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: KCNAB3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNAB3 were set to PMID: 32990398
Phenotypes for gene: KCNAB3 were set to febrile seizures; afebrile seizure; genetic epilepsy with febrile seizures plus
Review for gene: KCNAB3 was set to RED
Added comment: Missense variant identified in a single Han Chinese family with febrile seizures plus. Three affected carriers and one unaffected carrier. Patch clamp functional studies indicates that the variant accelerates the inactivation of the potassium channels.
Sources: Expert list
Genetic Epilepsy v0.1317 KCNA1 Daniel Flanagan gene: KCNA1 was added
gene: KCNA1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: KCNA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA1 were set to PMID: 32316562
Phenotypes for gene: KCNA1 were set to Epilepsy; seizures; epileptic encephalopathies; episodic ataxia type 1 and epilepsy
Review for gene: KCNA1 was set to GREEN
Added comment: KCNA1 variants reported in patients with episodic ataxia type 1 with epilepsy and seizures. KCNA1 variants also reported in patients with epileptic encephalopathies alone. Epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.
Sources: Expert list
Genetic Epilepsy v0.1317 DAB1 Daniel Flanagan gene: DAB1 was added
gene: DAB1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: DAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAB1 were set to PMID: 33928188
Phenotypes for gene: DAB1 were set to epilepsy; developmental delay; cerebellar ataxia; structural brain abnormalities; oral motor difficulty
Review for gene: DAB1 was set to RED
Added comment: WES trio analysis identified compound heterozygous DAB1 canonical splice variants in a child with epilepsy (onset 6 years), developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities. RT-PCR confirms that the first variant (c.307-2A>T) causes a in-frame deletion of 3 amino acids. The second variant (c.67+1G>T) is reported to causes an in-frame deletion of exon 4 (first coding exon) and loss of the ATG initiation site.

New LoF mechanism suggested. Repeat expansion in this gene is known to be associated with disease.
Sources: Expert list
Genetic Epilepsy v0.1317 NSRP1 Zornitza Stark Marked gene: NSRP1 as ready
Genetic Epilepsy v0.1317 NSRP1 Zornitza Stark Gene: nsrp1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1317 NSRP1 Zornitza Stark Classified gene: NSRP1 as Green List (high evidence)
Genetic Epilepsy v0.1317 NSRP1 Zornitza Stark Gene: nsrp1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1316 NSRP1 Zornitza Stark reviewed gene: NSRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1316 NSRP1 Krithika Murali gene: NSRP1 was added
gene: NSRP1 was added to Genetic Epilepsy. Sources: Expert list,Literature
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 Epilepsy; Cerebral palsy; microcephaly; Intellectual disability
Review for gene: NSRP1 was set to AMBER
Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
Sources: Expert list, Literature
Genetic Epilepsy v0.1316 GABRD Zornitza Stark Marked gene: GABRD as ready
Genetic Epilepsy v0.1316 GABRD Zornitza Stark Gene: gabrd has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1316 GABRD Zornitza Stark Classified gene: GABRD as Green List (high evidence)
Genetic Epilepsy v0.1316 GABRD Zornitza Stark Gene: gabrd has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1315 GABRD Zornitza Stark gene: GABRD was added
gene: GABRD was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRD were set to 15115768; 34633442
Phenotypes for gene: GABRD were set to Intellectual disability; Epilepsy; Susceptibility to epilepsy, MIM#613060
Review for gene: GABRD was set to GREEN
Added comment: Susceptibility to epilepsy, MIM#613060: Limited reports. The variant originally reported in PMID 15115768 in association with epilepsy is present in >4,000 hets in gnomad and 55 homs which is not consistent with a Mendelian disorder.

PMID 34633442: 10 individuals with 7 unique variants reported in individuals with neurodevelopmental disorders and epilepsy. Six of the variants were demonstrated to be GoF, and those individuals with neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. In contrast, the one individual carrying a loss-of-function variant had normal intelligence, no seizure history but has a diagnosis of autism spectrum disorder and suffering from elevated internalizing psychiatric symptoms.
Sources: Literature
Genetic Epilepsy v0.1314 CXorf56 Zornitza Stark Marked gene: CXorf56 as ready
Genetic Epilepsy v0.1314 CXorf56 Zornitza Stark Gene: cxorf56 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1314 CXorf56 Zornitza Stark Classified gene: CXorf56 as Green List (high evidence)
Genetic Epilepsy v0.1314 CXorf56 Zornitza Stark Gene: cxorf56 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1313 CXorf56 Zornitza Stark gene: CXorf56 was added
gene: CXorf56 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CXorf56 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CXorf56 were set to 29374277; 31822863
Phenotypes for gene: CXorf56 were set to Mental retardation, X-linked 107, MIM# 301013
Review for gene: CXorf56 was set to GREEN
Added comment: Four families reported, seizures in males, who tend to be more severe.
Sources: Literature
Genetic Epilepsy v0.1312 CWF19L1 Zornitza Stark Marked gene: CWF19L1 as ready
Genetic Epilepsy v0.1312 CWF19L1 Zornitza Stark Gene: cwf19l1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1312 CWF19L1 Zornitza Stark gene: CWF19L1 was added
gene: CWF19L1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CWF19L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CWF19L1 were set to 33012273
Phenotypes for gene: CWF19L1 were set to Spinocerebellar ataxia, autosomal recessive 17, MIM# 616127
Review for gene: CWF19L1 was set to RED
Added comment: Well established gene-disease association, but only single report of epilepsy.
Sources: Literature
Genetic Epilepsy v0.1311 TNPO2 Zornitza Stark Phenotypes for gene: TNPO2 were changed from Intellectual disability, neurologic deficits and dysmorphic features to Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies, MIM# 619556
Genetic Epilepsy v0.1310 TNPO2 Zornitza Stark edited their review of gene: TNPO2: Changed phenotypes: Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies, MIM# 619556
Genetic Epilepsy v0.1310 CPT1A Zornitza Stark Marked gene: CPT1A as ready
Genetic Epilepsy v0.1310 CPT1A Zornitza Stark Gene: cpt1a has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1310 CPT1A Zornitza Stark Classified gene: CPT1A as Amber List (moderate evidence)
Genetic Epilepsy v0.1310 CPT1A Zornitza Stark Gene: cpt1a has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1309 CPT1A Zornitza Stark gene: CPT1A was added
gene: CPT1A was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CPT1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPT1A were set to 12189492; 33565078
Phenotypes for gene: CPT1A were set to CPT deficiency, hepatic, type IA, MIM# 255120
Review for gene: CPT1A was set to AMBER
Added comment: Well established gene-disease association.

CPT I deficiency is an autosomal recessive metabolic disorder of long-chain fatty acid oxidation characterized by severe episodes of hypoketotic hypoglycaemia usually occurring after fasting or illness. Onset is in infancy or early childhood.

Case report of presentation with seizures.
Sources: Expert Review
Genetic Epilepsy v0.1308 KCTD3 Zornitza Stark Marked gene: KCTD3 as ready
Genetic Epilepsy v0.1308 KCTD3 Zornitza Stark Gene: kctd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1308 KCTD3 Zornitza Stark Phenotypes for gene: KCTD3 were changed from to Epilepsy; Intellectual disability; Posterior fossa abnormalities
Genetic Epilepsy v0.1307 KCTD3 Zornitza Stark Publications for gene: KCTD3 were set to
Genetic Epilepsy v0.1306 KCTD3 Zornitza Stark Mode of inheritance for gene: KCTD3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1305 KCTD3 Zornitza Stark reviewed gene: KCTD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29406573; Phenotypes: Epilepsy, Intellectual disability, Posterior fossa abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1305 POLR3B Zornitza Stark Marked gene: POLR3B as ready
Genetic Epilepsy v0.1305 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1305 POLR3B Zornitza Stark Classified gene: POLR3B as Green List (high evidence)
Genetic Epilepsy v0.1305 POLR3B Zornitza Stark Gene: polr3b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1304 PPP1CB Zornitza Stark Marked gene: PPP1CB as ready
Genetic Epilepsy v0.1304 PPP1CB Zornitza Stark Gene: ppp1cb has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1304 PPP1CB Zornitza Stark Classified gene: PPP1CB as Amber List (moderate evidence)
Genetic Epilepsy v0.1304 PPP1CB Zornitza Stark Gene: ppp1cb has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1303 SMARCB1 Zornitza Stark Phenotypes for gene: SMARCB1 were changed from Coffin-Siris syndrome and epilepsy to Coffin-Siris syndrome 3, MIM# 614608; Epilepsy
Genetic Epilepsy v0.1302 SMARCB1 Zornitza Stark Classified gene: SMARCB1 as Green List (high evidence)
Genetic Epilepsy v0.1302 SMARCB1 Zornitza Stark Gene: smarcb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1301 SMARCB1 Zornitza Stark Marked gene: SMARCB1 as ready
Genetic Epilepsy v0.1301 SMARCB1 Zornitza Stark Gene: smarcb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1301 SMARCB1 Zornitza Stark Publications for gene: SMARCB1 were set to PMID:33006724
Genetic Epilepsy v0.1300 SMARCB1 Zornitza Stark Classified gene: SMARCB1 as Green List (high evidence)
Genetic Epilepsy v0.1300 SMARCB1 Zornitza Stark Gene: smarcb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1299 SMARCB1 Zornitza Stark reviewed gene: SMARCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22426308, 23906836, 23929686; Phenotypes: Coffin-Siris syndrome 3, MIM# 614608; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1299 SMARCB1 Zornitza Stark Classified gene: SMARCB1 as Red List (low evidence)
Genetic Epilepsy v0.1299 SMARCB1 Zornitza Stark Gene: smarcb1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1298 SMARCA4 Zornitza Stark Marked gene: SMARCA4 as ready
Genetic Epilepsy v0.1298 SMARCA4 Zornitza Stark Gene: smarca4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1298 SMARCA4 Zornitza Stark Classified gene: SMARCA4 as Red List (low evidence)
Genetic Epilepsy v0.1298 SMARCA4 Zornitza Stark Gene: smarca4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1297 SMARCB1 Belinda Chong gene: SMARCB1 was added
gene: SMARCB1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCB1 were set to PMID:33006724
Phenotypes for gene: SMARCB1 were set to Coffin-Siris syndrome and epilepsy
Review for gene: SMARCB1 was set to RED
Added comment: A single 8-year-old male with a p.Arg366Cys mutation of the SMARCB1 gene. Speech impairment and intellectual disability were reported. At the age of 6.3 years, he experienced his first generalized seizure during sleep. CBZ (16 mg/kg/day) was started and later switched to VPA (22 mg/kg/day) that could exert an additional role as a mood stabilizer, from which the hyperactive patient could benefit. Since then, he has been seizure-free. Brain MRI was normal.
Sources: Literature
Genetic Epilepsy v0.1297 SMARCA4 Belinda Chong gene: SMARCA4 was added
gene: SMARCA4 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SMARCA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA4 were set to 33333793
Phenotypes for gene: SMARCA4 were set to Refractory seizures
Review for gene: SMARCA4 was set to RED
Added comment: A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: Single patient with seizure onset at 3months old (de novo variant c.3595G>A, p.Val199Met).
Sources: Literature
Genetic Epilepsy v0.1297 PPP1CB Ain Roesley gene: PPP1CB was added
gene: PPP1CB was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PPP1CB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP1CB were set to 33333793; 30236064
Phenotypes for gene: PPP1CB were set to Noonan syndrome-like disorder with loose anagen hair 2 MIM#617506
Penetrance for gene: PPP1CB were set to Complete
Review for gene: PPP1CB was set to AMBER
Added comment: PMID:33333793
1x de novo missense. Apnea, eye gazed deviation, myoclonic seizures

PMID:30236064
1x de novo missense. infant presented with severe intractable epileptic spasms

>20 individuals reported with this syndrome
Sources: Literature
Genetic Epilepsy v0.1297 POLR3B Ain Roesley gene: POLR3B was added
gene: POLR3B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: POLR3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR3B were set to 33417887
Phenotypes for gene: POLR3B were set to ataxia, spasticity, and demyelinating neuropathy
Penetrance for gene: POLR3B were set to unknown
Review for gene: POLR3B was set to GREEN
Added comment: 3/6 individuals with de novo missense presented with seizures
Sources: Literature
Genetic Epilepsy v0.1297 POU3F3 Ain Roesley gene: POU3F3 was added
gene: POU3F3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POU3F3 were set to 31303265; 33645921
Phenotypes for gene: POU3F3 were set to Snijders Blok-Fisher syndrome MIM#618604
Penetrance for gene: POU3F3 were set to unknown
Review for gene: POU3F3 was set to AMBER
Added comment: Seizures a rare feature. Only 3 out of 20 individuals presented with seizures.
Sources: Literature
Genetic Epilepsy v0.1297 U2AF2 Zornitza Stark Marked gene: U2AF2 as ready
Genetic Epilepsy v0.1297 U2AF2 Zornitza Stark Added comment: Comment when marking as ready: Note de novo variants in this gene were found to be enriched in the DDD study, however phenotypic information on the patients not presented.
Genetic Epilepsy v0.1297 U2AF2 Zornitza Stark Gene: u2af2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1297 U2AF2 Zornitza Stark Marked gene: U2AF2 as ready
Genetic Epilepsy v0.1297 U2AF2 Zornitza Stark Gene: u2af2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1297 U2AF2 Zornitza Stark Classified gene: U2AF2 as Red List (low evidence)
Genetic Epilepsy v0.1297 U2AF2 Zornitza Stark Gene: u2af2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1296 RARS2 Zornitza Stark Marked gene: RARS2 as ready
Genetic Epilepsy v0.1296 RARS2 Zornitza Stark Gene: rars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1296 SLC22A5 Zornitza Stark Marked gene: SLC22A5 as ready
Genetic Epilepsy v0.1296 SLC22A5 Zornitza Stark Gene: slc22a5 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1296 RARS2 Zornitza Stark Phenotypes for gene: RARS2 were changed from to Pontocerebellar hypoplasia, type 6 MIM#611523
Genetic Epilepsy v0.1295 RARS2 Zornitza Stark Publications for gene: RARS2 were set to
Genetic Epilepsy v0.1294 RARS2 Zornitza Stark Mode of inheritance for gene: RARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1293 SLC22A5 Zornitza Stark Classified gene: SLC22A5 as Red List (low evidence)
Genetic Epilepsy v0.1293 SLC22A5 Zornitza Stark Gene: slc22a5 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1292 PNPT1 Zornitza Stark Marked gene: PNPT1 as ready
Genetic Epilepsy v0.1292 PNPT1 Zornitza Stark Gene: pnpt1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1292 PNPT1 Zornitza Stark Phenotypes for gene: PNPT1 were changed from to Combined oxidative phosphorylation deficiency 13, MIM# 614932
Genetic Epilepsy v0.1291 PNPT1 Zornitza Stark Classified gene: PNPT1 as Green List (high evidence)
Genetic Epilepsy v0.1291 PNPT1 Zornitza Stark Gene: pnpt1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1290 SLC22A5 Belinda Chong gene: SLC22A5 was added
gene: SLC22A5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SLC22A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC22A5 were set to PMID: 33005244
Phenotypes for gene: SLC22A5 were set to Intractable epilepsy
Review for gene: SLC22A5 was set to RED
Added comment: Two sisters with intractable epilepsy and reversible metabolic cardiomyopathy. Potential mutations in the SLC22A5 gene were investigated within the family, and a nonsense mutation [c.760C>T (p.R254X)] was identified in four family members. The two sisters harboured homozygous mutations, whereas their parents presented heterozygous mutations.

Metabolic disease screening revealed low plasma free carnitine levels (<5 µmol/l) in the two sisters. The plasma free carnitine levels of their parents were normal, and they were asymptomatic. PCD in the two patients was managed using oral levocarnitine.
Sources: Literature
Genetic Epilepsy v0.1290 PNPT1 Zornitza Stark reviewed gene: PNPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency 13, MIM# 614932; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1290 PHF6 Zornitza Stark Marked gene: PHF6 as ready
Genetic Epilepsy v0.1290 PHF6 Zornitza Stark Gene: phf6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1290 PHF6 Zornitza Stark Classified gene: PHF6 as Green List (high evidence)
Genetic Epilepsy v0.1290 PHF6 Zornitza Stark Gene: phf6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1289 PGM3 Zornitza Stark Marked gene: PGM3 as ready
Genetic Epilepsy v0.1289 PGM3 Zornitza Stark Gene: pgm3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1289 PGM3 Zornitza Stark Classified gene: PGM3 as Amber List (moderate evidence)
Genetic Epilepsy v0.1289 PGM3 Zornitza Stark Gene: pgm3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1288 PGM3 Zornitza Stark reviewed gene: PGM3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1288 TARS2 Zornitza Stark Marked gene: TARS2 as ready
Genetic Epilepsy v0.1288 TARS2 Zornitza Stark Gene: tars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1288 TARS2 Zornitza Stark Classified gene: TARS2 as Green List (high evidence)
Genetic Epilepsy v0.1288 TARS2 Zornitza Stark Gene: tars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1287 TBX19 Zornitza Stark Marked gene: TBX19 as ready
Genetic Epilepsy v0.1287 TBX19 Zornitza Stark Gene: tbx19 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1287 TBX19 Zornitza Stark Classified gene: TBX19 as Green List (high evidence)
Genetic Epilepsy v0.1287 TBX19 Zornitza Stark Gene: tbx19 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1286 THG1L Zornitza Stark Marked gene: THG1L as ready
Genetic Epilepsy v0.1286 THG1L Zornitza Stark Gene: thg1l has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1286 TRAPPC12 Zornitza Stark Marked gene: TRAPPC12 as ready
Genetic Epilepsy v0.1286 TRAPPC12 Zornitza Stark Added comment: Comment when marking as ready: Three unrelated families with consistent phenotype including microcephaly and seizures.
Genetic Epilepsy v0.1286 TRAPPC12 Zornitza Stark Gene: trappc12 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1286 THG1L Zornitza Stark Phenotypes for gene: THG1L were changed from Spinocerebellar ataxia, autosomal recessive 28 - 618800; Epilepsy to Spinocerebellar ataxia, autosomal recessive 28 - 618800; Epilepsy; Intellectual disability
Genetic Epilepsy v0.1285 THG1L Zornitza Stark Classified gene: THG1L as Amber List (moderate evidence)
Genetic Epilepsy v0.1285 THG1L Zornitza Stark Gene: thg1l has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1284 TRAPPC12 Zornitza Stark Classified gene: TRAPPC12 as Green List (high evidence)
Genetic Epilepsy v0.1284 TRAPPC12 Zornitza Stark Gene: trappc12 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1283 TRPC3 Zornitza Stark Marked gene: TRPC3 as ready
Genetic Epilepsy v0.1283 TRPC3 Zornitza Stark Gene: trpc3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1283 TRPC3 Zornitza Stark Classified gene: TRPC3 as Red List (low evidence)
Genetic Epilepsy v0.1283 TRPC3 Zornitza Stark Gene: trpc3 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1282 RARS2 Ain Roesley reviewed gene: RARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31536827; Phenotypes: Pontocerebellar hypoplasia, type 6 MIM#611523; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1282 COLGALT1 Zornitza Stark Marked gene: COLGALT1 as ready
Genetic Epilepsy v0.1282 COLGALT1 Zornitza Stark Gene: colgalt1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1282 COLGALT1 Zornitza Stark Classified gene: COLGALT1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1282 COLGALT1 Zornitza Stark Gene: colgalt1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1281 COLGALT1 Zornitza Stark gene: COLGALT1 was added
gene: COLGALT1 was added to Genetic Epilepsy. Sources: Expert Review
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 MIM#618360
Review for gene: COLGALT1 was set to AMBER
Added comment: 3 unrelated families with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos.

Refractory seizures part of the presenting phenotype in one family.
Sources: Expert Review
Genetic Epilepsy v0.1280 CLPB Zornitza Stark Marked gene: CLPB as ready
Genetic Epilepsy v0.1280 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1280 CLPB Zornitza Stark Classified gene: CLPB as Green List (high evidence)
Genetic Epilepsy v0.1280 CLPB Zornitza Stark Gene: clpb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1279 CLPB Zornitza Stark gene: CLPB was added
gene: CLPB was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CLPB was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLPB were set to 25597510; 34140661
Phenotypes for gene: CLPB were set to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271
Review for gene: CLPB was set to GREEN
Added comment: Bi-allelic variants: 3-Methylglutaconic aciduria (MGCA7) is an autosomal recessive inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with neurologic deterioration and neutropenia. The phenotype is highly variable: most patients have infantile onset of a progressive encephalopathy with various movement abnormalities and delayed psychomotor development, although rare patients with normal neurologic development have been reported. Other common, but variable, features include cataracts, seizures, and recurrent infections. More than 10 unrelated families reported.

Mono-allelic variants: six unrelated individuals reported with de novo variants and neutropaenia, epilepsy, developmental issues, and 3-methylglutaconic aciduria.
Sources: Expert Review
Genetic Epilepsy v0.1278 CLN6 Zornitza Stark Marked gene: CLN6 as ready
Genetic Epilepsy v0.1278 CLN6 Zornitza Stark Gene: cln6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1278 CLN6 Zornitza Stark Classified gene: CLN6 as Green List (high evidence)
Genetic Epilepsy v0.1278 CLN6 Zornitza Stark Gene: cln6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1277 CLN6 Zornitza Stark gene: CLN6 was added
gene: CLN6 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CLN6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLN6 were set to 11791207; 11727201; 21549341; 33798445; 33024953
Phenotypes for gene: CLN6 were set to Ceroid lipofuscinosis, neuronal, 6, MIM# 601780; Ceroid lipofuscinosis, neuronal, Kufs type, adult onset, MIM# 204300
Review for gene: CLN6 was set to GREEN
Added comment: Well established gene-disease association, seizures are part of the phenotype.
Sources: Expert Review
Genetic Epilepsy v0.1276 PNPT1 Ain Roesley gene: PNPT1 was added
gene: PNPT1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PNPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPT1 were set to 33158637; 31752325
Penetrance for gene: PNPT1 were set to unknown
Review for gene: PNPT1 was set to GREEN
Added comment: PMID:33158637
1x homozygous (c.1399C > T, p.Pro467Ser) in an individual who presented with a phenotype similar to Aicardi-Goutieres Syndrome. She presented with feeding difficulties and vomiting, muscle weakness, and hyperexcitability, accompanied by a sterile febrile episode. Later developed refractory focal impaired awareness and pharmaco-refractory generalized seizures.

PMID: 31752325
7 presented with seizures (out of 21 for whom clinical info was available)
Sources: Literature
Genetic Epilepsy v0.1276 PHF6 Ain Roesley gene: PHF6 was added
gene: PHF6 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PHF6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PHF6 were set to 32399860
Phenotypes for gene: PHF6 were set to Borjeson-Forssman-Lehmann syndrome MIM#301900
Penetrance for gene: PHF6 were set to unknown
Review for gene: PHF6 was set to GREEN
Added comment: Epilepsy is part of the phenotypic spectrum for Borjeson-Forssman-Lehmann syndrome (OMIM). At least 18 mutations known to date.
Sources: Literature
Genetic Epilepsy v0.1276 PGM3 Ain Roesley gene: PGM3 was added
gene: PGM3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PGM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PGM3 were set to 33193641
Phenotypes for gene: PGM3 were set to Idiopathic focal epilepsy
Penetrance for gene: PGM3 were set to Incomplete
Review for gene: PGM3 was set to AMBER
Added comment: 4x unrelated families including 2x de novo +2x inherited from unaffected parents. Hence reduced penetrance suggested
3x missense, 1x protein truncating
both missense variants inherited from unaffected parents classified as VUS by ACMG guidelines

no functional studies done
Sources: Literature
Genetic Epilepsy v0.1276 TARS2 Krithika Murali gene: TARS2 was added
gene: TARS2 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: TARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS2 were set to 33153448; 24827421; 34508595
Phenotypes for gene: TARS2 were set to Combined oxidative phosphorylation deficiency 21 - 615918; Epilepsy
Review for gene: TARS2 was set to GREEN
Added comment: 8 cases from 7 unrelated families are reported in the literature with early-onset mitochondrial encephalomyopathy and a broad phenotypic spectrum that includes epilepsy.
Sources: Expert list, Literature
Genetic Epilepsy v0.1276 TBX19 Krithika Murali gene: TBX19 was added
gene: TBX19 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: TBX19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBX19 were set to 31998673
Phenotypes for gene: TBX19 were set to Adrenocorticotropic hormone deficiency - 201400
Review for gene: TBX19 was set to GREEN
Added comment: Well-established gene-disease association with congenital isolated ACTH deficiency. Affected individuals can present with seizures in conjunction with hypoglycaemia and cholestasis.

Although this gene is not associated with primary epilepsy and is a primary pituitary disorder, early detection and prompt institution of glucocorticoid treatment is vital to lower the risk of recurrent hypoglycemia and uncontrolled epilepsy. As patients can present with seizures, inclusion in this panel may aid timely diagnosis of this rare but treatable disorder.
Sources: Expert list, Literature
Genetic Epilepsy v0.1276 THG1L Krithika Murali gene: THG1L was added
gene: THG1L was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: THG1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THG1L were set to 33682303
Phenotypes for gene: THG1L were set to Spinocerebellar ataxia, autosomal recessive 28 - 618800; Epilepsy
Review for gene: THG1L was set to AMBER
Added comment: 3 individuals from 2 unrelated families of Ashkenazi Jewish descent with compound heterozygous variants ( p.Cys51Trp and p.Val55Ala) presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia.
Sources: Expert list, Literature
Genetic Epilepsy v0.1276 TRAPPC12 Krithika Murali reviewed gene: TRAPPC12: Rating: AMBER; Mode of pathogenicity: None; Publications: 28777934, 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity - 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1276 TRPC3 Krithika Murali gene: TRPC3 was added
gene: TRPC3 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: TRPC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPC3 were set to 32135163; 25477146
Phenotypes for gene: TRPC3 were set to ?Spinocerebellar ataxia 41 - 616410
Review for gene: TRPC3 was set to RED
Added comment: Postulated association with adult-onset cerebellar ataxia based on one case with potentially pathogenic variant (Fogel et al Mov Disorder 2015)

Liang et al 2020 Neurosci Letter observed elevated TRPC3 protein expression in focal cortical dysplasia tissue specimens compared with controls.

No formal gene-disease association with epilepsy has been reported.
Sources: Expert list, Literature
Genetic Epilepsy v0.1276 MAPK8IP3 Zornitza Stark Marked gene: MAPK8IP3 as ready
Genetic Epilepsy v0.1276 MAPK8IP3 Zornitza Stark Gene: mapk8ip3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1276 MAPK8IP3 Zornitza Stark Classified gene: MAPK8IP3 as Amber List (moderate evidence)
Genetic Epilepsy v0.1276 MAPK8IP3 Zornitza Stark Gene: mapk8ip3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1275 MAPK8IP3 Elena Savva gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK8IP3 were set to PMID: 30612693
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities MIM#618443
Review for gene: MAPK8IP3 was set to AMBER
Added comment: 5/13 patients had generalized seizures, but for 3/13 it was a single event, 1/13 it was recurrent. All individuals had missense variants.
Sources: Literature
Genetic Epilepsy v0.1275 TSPYL1 Zornitza Stark Marked gene: TSPYL1 as ready
Genetic Epilepsy v0.1275 TSPYL1 Zornitza Stark Gene: tspyl1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1275 TSPYL1 Zornitza Stark Classified gene: TSPYL1 as Green List (high evidence)
Genetic Epilepsy v0.1275 TSPYL1 Zornitza Stark Gene: tspyl1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1274 TSPYL1 Krithika Murali gene: TSPYL1 was added
gene: TSPYL1 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: TSPYL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPYL1 were set to 32885560; 15273283; 33075815
Phenotypes for gene: TSPYL1 were set to Sudden infant death with dysgenesis of the testes syndrome - 608800; sudden infant death-dysgenesis of the testes syndrome MONDO:0012124
Review for gene: TSPYL1 was set to GREEN
Added comment: First identified in a large Amish family - lethal disease characterized by sudden infant death from cardiorespiratory arrest with dysgenesis of the testes (Puffenberger et al 2004). Cases in non-Amish families reported with additional phenotypic features noted including epilepsy (Slater et al 2020 and Buyse et al 2020)
Sources: Expert list, Literature
Genetic Epilepsy v0.1274 CELF2 Zornitza Stark Phenotypes for gene: CELF2 were changed from Developmental and epileptic encephalopathy 97, MIM#619561 to Developmental and epileptic encephalopathy 97, MIM#619561
Genetic Epilepsy v0.1274 CELF2 Zornitza Stark Phenotypes for gene: CELF2 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 97, MIM#619561
Genetic Epilepsy v0.1273 CELF2 Zornitza Stark edited their review of gene: CELF2: Changed phenotypes: Developmental and epileptic encephalopathy 97, MIM#619561
Genetic Epilepsy v0.1273 CLN5 Zornitza Stark Marked gene: CLN5 as ready
Genetic Epilepsy v0.1273 CLN5 Zornitza Stark Gene: cln5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1273 CLN5 Zornitza Stark Classified gene: CLN5 as Green List (high evidence)
Genetic Epilepsy v0.1273 CLN5 Zornitza Stark Gene: cln5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1272 CLN5 Zornitza Stark gene: CLN5 was added
gene: CLN5 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CLN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLN5 were set to 32983231; 15728307; 20157158
Phenotypes for gene: CLN5 were set to Ceroid lipofuscinosis, neuronal, 5, MIM# 256731
Review for gene: CLN5 was set to GREEN
Added comment: Well established gene-disease association, initial presentation with seizures reported.
Sources: Expert Review
Genetic Epilepsy v0.1271 AP1G1 Zornitza Stark Phenotypes for gene: AP1G1 were changed from Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy to Usmani-Riazuddin syndrome, autosomal dominant, MIM# 619467; Usmani-Riazuddin syndrome, autosomal recessive, MIM# 619548; Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Genetic Epilepsy v0.1270 AP1G1 Zornitza Stark reviewed gene: AP1G1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Usmani-Riazuddin syndrome, autosomal dominant, MIM# 619467, Usmani-Riazuddin syndrome, autosomal recessive, MIM# 619548; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1270 CACNA1C Zornitza Stark Marked gene: CACNA1C as ready
Genetic Epilepsy v0.1270 CACNA1C Zornitza Stark Gene: cacna1c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1270 CACNA1C Zornitza Stark Classified gene: CACNA1C as Green List (high evidence)
Genetic Epilepsy v0.1270 CACNA1C Zornitza Stark Gene: cacna1c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1269 CACNA1C Zornitza Stark gene: CACNA1C was added
gene: CACNA1C was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CACNA1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1C were set to 34163037
Phenotypes for gene: CACNA1C were set to Neurodevelopmental abnormalities and epilepsy, no OMIM#
Review for gene: CACNA1C was set to GREEN
Added comment: Rodan et al. (2021) reported 25 individuals from 22 families with heterozygous truncating and missense variants in CACNA1C. The individuals presented with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy BUT absence of classic features of Timothy syndrome or long QT syndrome. Functional studies of a subgroup of missense variants demonstrated loss of function, neutral effect, and gain of function on channel function in vitro.
Sources: Literature
Genetic Epilepsy v0.1268 PLXNA1 Zornitza Stark Marked gene: PLXNA1 as ready
Genetic Epilepsy v0.1268 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1268 PLXNA1 Zornitza Stark Classified gene: PLXNA1 as Green List (high evidence)
Genetic Epilepsy v0.1268 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1267 PLXNA1 Zornitza Stark gene: PLXNA1 was added
gene: PLXNA1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature
Genetic Epilepsy v0.1266 TUBGCP6 Zornitza Stark Marked gene: TUBGCP6 as ready
Genetic Epilepsy v0.1266 TUBGCP6 Zornitza Stark Gene: tubgcp6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1266 TUBGCP6 Zornitza Stark Classified gene: TUBGCP6 as Green List (high evidence)
Genetic Epilepsy v0.1266 TUBGCP6 Zornitza Stark Gene: tubgcp6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1265 TUBGCP6 Krithika Murali gene: TUBGCP6 was added
gene: TUBGCP6 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: TUBGCP6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP6 were set to 22279524; 33453472
Phenotypes for gene: TUBGCP6 were set to Microcephaly and chorioretinopathy, autosomal recessive, 1 - 251270; Epilepsy
Review for gene: TUBGCP6 was set to GREEN
Added comment: Known association with congenital microcephaly, developmental delay and retinal disorders with epilepsy also reported in some individuals.
Sources: Expert list, Literature
Genetic Epilepsy v0.1265 CLCN2 Zornitza Stark Marked gene: CLCN2 as ready
Genetic Epilepsy v0.1265 CLCN2 Zornitza Stark Gene: clcn2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1265 CLCN2 Zornitza Stark Tag disputed tag was added to gene: CLCN2.
Genetic Epilepsy v0.1265 CLCN2 Zornitza Stark gene: CLCN2 was added
gene: CLCN2 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CLCN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLCN2 were set to 23707145; 19191339; 20037607; 19710712
Phenotypes for gene: CLCN2 were set to {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628
Review for gene: CLCN2 was set to RED
Added comment: Conflicting evidence regarding association with epilepsy syndromes, including one retracted paper.

In 3 of 46 unrelated families with IGE localized to 3q26, Haug et al. (2003) identified 3 mutations in the CLCN2 gene. In a re-evaluation of 2 of the families reported by Haug et al. (2003), Kleefuss-Lie et al. (2009) found discrepancies in the family structure, phenotype, and genetic analysis. On this basis, all but one of the original authors retracted the paper.

Stogmann et al. (2006) did not identify pathogenic mutations in the CLCN2 gene in 61 patients with IGE or 35 patients with temporal lobe epilepsy, suggesting that CLCN2 gene mutations are not a common cause of these disorders.

By sequencing of a large collection of human DNA followed by electrophysiologic analysis, Blanz et al. (2007) concluded that several CLCN2 sequence abnormalities previously found in patients with epilepsy most likely represented benign polymorphisms.

Saint-Martin et al. (2009) identified 2 different heterozygous variants in the CLCN2 gene in affected members of 2 unrelated families with juvenile myoclonic epilepsy (EJM8) and idiopathic generalized epilepsy (EIG11), respectively. In both families, the unaffected father also had the variant, suggesting either reduced penetrance or additional unidentified factors necessary for full phenotypic expression.

Niemeyer et al. (2010) disagreed with the conclusion by Kleefuss-Lie et al. (2009) that some of the work by Haug et al. (2003) had merit. Based on lack of functional consequences of the variants reported by Haug et al. (2003), Niemeyer et al. (2010) asserted that there is no evidence for a role of CLCN2 variants in idiopathic generalized epilepsy.
Sources: Expert Review
Genetic Epilepsy v0.1264 CHRM1 Zornitza Stark Marked gene: CHRM1 as ready
Genetic Epilepsy v0.1264 CHRM1 Zornitza Stark Gene: chrm1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1264 CHRM1 Zornitza Stark gene: CHRM1 was added
gene: CHRM1 was added to Genetic Epilepsy. Sources: Expert Review
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 disorder; intellectual disability; autism; epilepsy
Review for gene: CHRM1 was set to RED
Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways.
PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu)
PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction.
Sources: Expert Review
Genetic Epilepsy v0.1263 U2AF2 Krithika Murali gene: U2AF2 was added
gene: U2AF2 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 34112922
Phenotypes for gene: U2AF2 were set to Epilepsy; Developmental Delay; Intellectual Disability
Review for gene: U2AF2 was set to RED
Added comment: Novel gene. De novo variant identified in a child with epilepsy, global developmental delay and dysmorphism (Hiraide et al, J Hum Genetics 2021)
Sources: Expert list, Literature
Genetic Epilepsy v0.1263 UMPS Zornitza Stark Marked gene: UMPS as ready
Genetic Epilepsy v0.1263 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1263 UMPS Zornitza Stark Classified gene: UMPS as Green List (high evidence)
Genetic Epilepsy v0.1263 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1262 UMPS Krithika Murali gene: UMPS was added
gene: UMPS was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: UMPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UMPS were set to 25757096; 33489760
Phenotypes for gene: UMPS were set to Orotic aciduria - 258900; Epilepsy
Review for gene: UMPS was set to GREEN
Added comment: Gene associated with orotic aciduria. Seizures have been reported in some individuals.
Sources: Expert list, Literature
Genetic Epilepsy v0.1262 UNC13B Zornitza Stark edited their review of gene: UNC13B: Changed rating: RED
Genetic Epilepsy v0.1262 UNC13B Zornitza Stark Mode of inheritance for gene: UNC13B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1261 UNC13B Zornitza Stark Marked gene: UNC13B as ready
Genetic Epilepsy v0.1261 UNC13B Zornitza Stark Added comment: Comment when marking as ready: Agree data is conflicting esp regarding MOI, and evidence for pathogenicity of several of the variants is limited.
Genetic Epilepsy v0.1261 UNC13B Zornitza Stark Gene: unc13b has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1261 UNC13B Zornitza Stark Classified gene: UNC13B as Red List (low evidence)
Genetic Epilepsy v0.1261 UNC13B Zornitza Stark Gene: unc13b has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1260 UNC13B Krithika Murali changed review comment from: 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 de novo splice site 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: Expert list, Literature; to: 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: Expert list, Literature
Genetic Epilepsy v0.1260 UNC13B Krithika Murali gene: UNC13B was added
gene: UNC13B was added to Genetic Epilepsy. Sources: Expert list,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
Penetrance for gene: UNC13B were set to unknown
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 de novo splice site 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: Expert list, Literature
Genetic Epilepsy v0.1260 VARS2 Zornitza Stark Marked gene: VARS2 as ready
Genetic Epilepsy v0.1260 VARS2 Zornitza Stark Gene: vars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1260 VARS2 Zornitza Stark Classified gene: VARS2 as Green List (high evidence)
Genetic Epilepsy v0.1260 VARS2 Zornitza Stark Gene: vars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1259 VARS2 Krithika Murali gene: VARS2 was added
gene: VARS2 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: VARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VARS2 were set to 27502409; 29137650; 31064326; 31623496
Phenotypes for gene: VARS2 were set to Combined oxidative phosphorylation deficiency 20, 615917; Epilepsy
Review for gene: VARS2 was set to GREEN
Added comment: Established gene associated with mitochondrial disorder. Heterogeneous clinical features reported including seizures, epilepsy, encephalopathy, microcephaly, global developmental delay, hypotonia, ataxia, dystonic movements, limb spasticity, hypertrophic cardiomyopathy, hyperlactaemia and MRI-B abnormalities.
Sources: Expert list, Literature
Genetic Epilepsy v0.1259 ZDHHC15 Zornitza Stark Marked gene: ZDHHC15 as ready
Genetic Epilepsy v0.1259 ZDHHC15 Zornitza Stark Gene: zdhhc15 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1259 ZDHHC15 Zornitza Stark Classified gene: ZDHHC15 as Red List (low evidence)
Genetic Epilepsy v0.1259 ZDHHC15 Zornitza Stark Gene: zdhhc15 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1258 CHD4 Zornitza Stark Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome, MIM# 617159 to Sifrim-Hitz-Weiss syndrome, MIM# 617159; Childhood idiopathic epilepsy and sinus arrhythmia
Genetic Epilepsy v0.1257 CHD4 Zornitza Stark Publications for gene: CHD4 were set to 27479907; 27616479
Genetic Epilepsy v0.1256 CHD4 Zornitza Stark Classified gene: CHD4 as Green List (high evidence)
Genetic Epilepsy v0.1256 CHD4 Zornitza Stark Gene: chd4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1255 CHD4 Zornitza Stark edited their review of gene: CHD4: Added comment: New publication, 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).; Changed rating: GREEN; Changed publications: 27479907, 27616479, 34109749; Changed phenotypes: Sifrim-Hitz-Weiss syndrome, MIM# 617159, Childhood idiopathic epilepsy and sinus arrhythmia
Genetic Epilepsy v0.1255 CCM2 Zornitza Stark Marked gene: CCM2 as ready
Genetic Epilepsy v0.1255 CCM2 Zornitza Stark Gene: ccm2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1255 CCM2 Zornitza Stark gene: CCM2 was added
gene: CCM2 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CCM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCM2 were set to 32702807
Phenotypes for gene: CCM2 were set to Cerebral cavernous malformations-2, MIM#603284
Review for gene: CCM2 was set to RED
Added comment: Rare reports of presentation with seizures following bleeding.
Sources: Expert Review
Genetic Epilepsy v0.1254 CARS2 Zornitza Stark Marked gene: CARS2 as ready
Genetic Epilepsy v0.1254 CARS2 Zornitza Stark Gene: cars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1254 CARS2 Zornitza Stark Classified gene: CARS2 as Green List (high evidence)
Genetic Epilepsy v0.1254 CARS2 Zornitza Stark Gene: cars2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1253 CARS2 Zornitza Stark gene: CARS2 was added
gene: CARS2 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CARS2 were set to 25361775; 25787132; 30139652
Phenotypes for gene: CARS2 were set to Combined oxidative phosphorylation deficiency 27, MIM# 616672
Review for gene: CARS2 was set to GREEN
Added comment: Three families reported with supportive functional data, epilepsy is a feature.
Sources: Expert Review
Genetic Epilepsy v0.1252 BPTF Zornitza Stark Marked gene: BPTF as ready
Genetic Epilepsy v0.1252 BPTF Zornitza Stark Gene: bptf has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1252 BPTF Zornitza Stark Classified gene: BPTF as Green List (high evidence)
Genetic Epilepsy v0.1252 BPTF Zornitza Stark Gene: bptf has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1251 BPTF Zornitza Stark gene: BPTF was added
gene: BPTF was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BPTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BPTF were set to 33522091; 28942966
Phenotypes for gene: BPTF were set to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies AD, MIM#617755
Review for gene: BPTF was set to GREEN
Added comment: Over 30 individuals reported, mostly de novo, some inherited variants. Reported features include seizures.
Sources: Literature
Genetic Epilepsy v0.1250 ZDHHC15 Krithika Murali gene: ZDHHC15 was added
gene: ZDHHC15 was added to Genetic Epilepsy. Sources: Expert list,Literature
Mode of inheritance for gene: ZDHHC15 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: ZDHHC15 were set to 34345675; 15915161; 26290131; 32989326
Phenotypes for gene: ZDHHC15 were set to Mental retardation X-linked 91, 300577; cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy
Review for gene: ZDHHC15 was set to RED
Added comment: 1 reported case of an 18 yo M with hypotonic cerebral palsy, focal-onset epilepsy, cortical visual impairment, intellectual disability, autism spectrum disorder, anxiety, and aggressive behaviors with hemizygous p.H158R variant shown to affect protein function in yeast complementation assay (Lewis et al Neurology Genetics 2021 PMID 34345675).

----
Other background info:

Protein function of x4 ZDHHC15 variants assessed by Lewis et al. x2 variants identified through Jin et al Nat Genet 2020 (PMID 32989326) - maternally inherited p.H158R and p.L13P. x1 identified through Gene Matcher p.S330P and x1 through GeneDx maternally inherited p.K115R. Only p.H158R variant shown to affect protein function. In Drosophilia model LoF variants caused flight and co-ordinated movement defects supporting role in motor dysfunction.

Conflicting evidence for ID phenotype

1 case with intellectual disability and balanced translocation with breakpoints near the ZDHHC15 gene - functional studies showing absence of ZDHHC15 transcript variants. This patient showed skewed lyonization, with 100% inactivation of the normal X chromosome. PMID: 15915161

1 case with NO intellectual disability and balanced translocation with breakpoints in the ZDHHC15 gene - functional studies showing no gene expression in the patient's peripheral blood (PMID 26290131)
Sources: Expert list, Literature
Genetic Epilepsy v0.1250 BCL11A Zornitza Stark Marked gene: BCL11A as ready
Genetic Epilepsy v0.1250 BCL11A Zornitza Stark Gene: bcl11a has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1250 BCL11A Zornitza Stark gene: BCL11A was added
gene: BCL11A was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: BCL11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCL11A were set to 27453576; 32903878
Phenotypes for gene: BCL11A were set to Dias-Logan syndrome, MIM# 617101
Review for gene: BCL11A was set to RED
Added comment: Epilepsy appears to be a rare feature of this syndrome.
Sources: Expert Review
Genetic Epilepsy v0.1249 TMTC3 Zornitza Stark Marked gene: TMTC3 as ready
Genetic Epilepsy v0.1249 TMTC3 Zornitza Stark Gene: tmtc3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1249 TMTC3 Zornitza Stark Phenotypes for gene: TMTC3 were changed from Lissencephaly 8 MIM#617255 to Lissencephaly 8, MIM#617255
Genetic Epilepsy v0.1248 TMTC3 Zornitza Stark Classified gene: TMTC3 as Green List (high evidence)
Genetic Epilepsy v0.1248 TMTC3 Zornitza Stark Gene: tmtc3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1247 WDR26 Zornitza Stark Marked gene: WDR26 as ready
Genetic Epilepsy v0.1247 WDR26 Zornitza Stark Gene: wdr26 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1247 WDR26 Zornitza Stark Classified gene: WDR26 as Green List (high evidence)
Genetic Epilepsy v0.1247 WDR26 Zornitza Stark Gene: wdr26 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1246 ZMYND11 Zornitza Stark Marked gene: ZMYND11 as ready
Genetic Epilepsy v0.1246 ZMYND11 Zornitza Stark Gene: zmynd11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1246 ZMYND11 Zornitza Stark Classified gene: ZMYND11 as Green List (high evidence)
Genetic Epilepsy v0.1246 ZMYND11 Zornitza Stark Gene: zmynd11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1245 TMTC3 Danielle Ariti gene: TMTC3 was added
gene: TMTC3 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: TMTC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMTC3 were set to 27773428; 28973161; 32973946
Phenotypes for gene: TMTC3 were set to Lissencephaly 8 MIM#617255
Review for gene: TMTC3 was set to GREEN
Added comment: 14 individuals from 8 unrelated families reported with bi-allelic LoF (frameshift, deletion, insertion) and missense variants.

Lissencephaly-8 is a neurologic disorder characterised by delayed psychomotor development, ID with poor/absent speech, early-onset refractory seizures, hypotonia and appendicular spasticity.

Seizures are considered a prominent phenotype: 6/9 patients developed refractory generalised or myoclonic seizures in infancy (PMID: 27773428) and in a reported family all four affected siblings presented with nocturnal seizures and ID (PMID: 28973161).
Sources: Expert list
Genetic Epilepsy v0.1245 WDR26 Danielle Ariti gene: WDR26 was added
gene: WDR26 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: WDR26 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR26 were set to 28686853; 33675273
Phenotypes for gene: WDR26 were set to Skraban-Deardorff syndrome MIM# 617616
Review for gene: WDR26 was set to GREEN
Added comment: 20 individuals have been reported (only 17 with a clinical description available).

All mono-allelic variants reported were de novo; most variants were LoF (frameshift, nonsense, splice site, deletion) but some were missense.

Skraban-Deardorff syndrome is a neurodevelopmental disorder characterised by a broad range of clinical signs, including ID/DD, febrile and/or non-febrile seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies (Spastic gait).

PMID: 28686853- Reported 15 individuals with pathogenic de novo WDR26 variants. 15/15 patients presented with both ID and seizures.
Sources: Expert list
Genetic Epilepsy v0.1245 ZMYND11 Danielle Ariti gene: ZMYND11 was added
gene: ZMYND11 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: ZMYND11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND11 were set to 32097528; 34216016
Phenotypes for gene: ZMYND11 were set to Mental retardation, autosomal dominant 30 MIM# 616083
Review for gene: ZMYND11 was set to GREEN
Added comment: ZMYND11 variants are associated with a neurodevelopmental disorder, MRD30 that is characterised by developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioural abnormalities, seizures, and hypotonia.
* Most identified variants are likely to result in premature truncation and/or nonsense‐mediated decay.

PMID: 34216016- Study of individuals with pathogenic ZMYND11 variants, 20/47 individuals presented with epilepsy (idiopathic focal epilepsy, Rolandic epilepsy, generalised epilepsies, Atypical Benign Partial Epilepsy etc).

PMID: 32097528- Study of 16 patients with ZMYND11-related syndromic intellectual disability, 31% presented with epilepsy.
Sources: Expert list
Genetic Epilepsy v0.1245 HCFC1 Zornitza Stark Marked gene: HCFC1 as ready
Genetic Epilepsy v0.1245 HCFC1 Zornitza Stark Gene: hcfc1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1245 HCFC1 Zornitza Stark Phenotypes for gene: HCFC1 were changed from to Mental retardation, X-linked 3 (methylmalonic acidaemia and homocysteinaemia, cblX type) MIM# 309541
Genetic Epilepsy v0.1244 HCFC1 Zornitza Stark Publications for gene: HCFC1 were set to
Genetic Epilepsy v0.1243 HCFC1 Zornitza Stark Mode of inheritance for gene: HCFC1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1243 HCFC1 Zornitza Stark Mode of inheritance for gene: HCFC1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1242 EIF2S3 Zornitza Stark Marked gene: EIF2S3 as ready
Genetic Epilepsy v0.1242 EIF2S3 Zornitza Stark Gene: eif2s3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1242 EIF2S3 Zornitza Stark Phenotypes for gene: EIF2S3 were changed from to MEHMO syndrome MIM# 300148
Genetic Epilepsy v0.1241 EIF2S3 Zornitza Stark Publications for gene: EIF2S3 were set to
Genetic Epilepsy v0.1240 EIF2S3 Zornitza Stark Mode of inheritance for gene: EIF2S3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1239 HCFC1 Danielle Ariti changed review comment from: Well-established gene-disease association with >20 individuals reported

Variants in the HCFC1 gene are associated with cases of syndromic and non-syndromic intellectual disability. Individuals present with severely delayed psychomotor development apparent in infancy, and severe neurological defects including intractable epilepsy, facial dysmorphia, and intellectual disability.; to: Well-established gene-disease association with >20 individuals reported

Variants in the HCFC1 gene are associated with cases of syndromic and non-syndromic intellectual disability. Individuals present with severely delayed psychomotor development apparent in infancy, and severe neurological defects including intractable epilepsy, facial dysmorphia, and intellectual disability.
Seizures being a prominent feature in this phenotype.
Genetic Epilepsy v0.1239 HCFC1 Danielle Ariti reviewed gene: HCFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34164576, 24011988; Phenotypes: Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type) MIM# 309541; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1239 EIF2S3 Danielle Ariti changed review comment from: 7 families reported males with hemizygous EIF2S3 variants; one mouse model.

EIF2S3 variants cause intellectual disability syndrome, MEHMO which is derived from the clinical hallmarks: mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity.
Seizures are prominent within this phenotype (more than 60% of patients).; to: 7 families reported males with hemizygous EIF2S3 variants; one mouse model.

EIF2S3 variants cause intellectual disability syndrome, MEHMO which is derived from the clinical hallmarks: mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity.
Seizures are prominent within this phenotype.
Genetic Epilepsy v0.1239 EIF2S3 Danielle Ariti reviewed gene: EIF2S3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33714664, 32799315, 28055140; Phenotypes: MEHMO syndrome MIM# 300148; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1239 CSTB Zornitza Stark Marked gene: CSTB as ready
Genetic Epilepsy v0.1239 CSTB Zornitza Stark Added comment: Comment when marking as ready: Note the most common causative allele is a dodecamer repeat in the promoter region. Missense variants have been reported, most commonly compound het with the repeat, except for p.Gly4Arg which has been reported in the homozygous state also.
Genetic Epilepsy v0.1239 CSTB Zornitza Stark Gene: cstb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1239 CSTB Zornitza Stark Tag 5'UTR tag was added to gene: CSTB.
Tag STR tag was added to gene: CSTB.
Genetic Epilepsy v0.1239 CSTB Zornitza Stark Phenotypes for gene: CSTB were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM# 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM# 254800
Genetic Epilepsy v0.1238 CSTB Zornitza Stark Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM# 254800
Genetic Epilepsy v0.1237 CSTB Zornitza Stark Publications for gene: CSTB were set to
Genetic Epilepsy v0.1236 CSTB Zornitza Stark Mode of inheritance for gene: CSTB was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1235 CSTB Danielle Ariti reviewed gene: CSTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 32920378, 18028412; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) MIM# 254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1235 KDM5C Zornitza Stark Marked gene: KDM5C as ready
Genetic Epilepsy v0.1235 KDM5C Zornitza Stark Gene: kdm5c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1235 KDM5C Zornitza Stark Phenotypes for gene: KDM5C were changed from Epilepsy; Intellectual Disability; microcephaly; Spasticity; hypothyroidism to Epilepsy; Intellectual Disability; microcephaly; Spasticity; hypothyroidism; Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534; MONDO:0010355
Genetic Epilepsy v0.1234 KDM5C Zornitza Stark Publications for gene: KDM5C were set to 23246292; 32279304; 26919706
Genetic Epilepsy v0.1233 KDM5C Zornitza Stark Classified gene: KDM5C as Green List (high evidence)
Genetic Epilepsy v0.1233 KDM5C Zornitza Stark Gene: kdm5c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1232 KDM5C Zornitza Stark reviewed gene: KDM5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 15586325, 32279304; Phenotypes: Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534, MONDO:0010355; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1232 ATP6V1B2 Zornitza Stark Marked gene: ATP6V1B2 as ready
Genetic Epilepsy v0.1232 ATP6V1B2 Zornitza Stark Gene: atp6v1b2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1232 ATP6V1B2 Zornitza Stark Classified gene: ATP6V1B2 as Green List (high evidence)
Genetic Epilepsy v0.1232 ATP6V1B2 Zornitza Stark Gene: atp6v1b2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1231 ATP6V1B2 Zornitza Stark reviewed gene: ATP6V1B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32873933; Phenotypes: Epileptic encephalopathy, Intellectual Disability, Deafness, congenital, with onychodystrophy, autosomal dominant, MIM# 124480; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1231 ATP6V0C Zornitza Stark Marked gene: ATP6V0C as ready
Genetic Epilepsy v0.1231 ATP6V0C Zornitza Stark Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1231 ATP6V0C Zornitza Stark Classified gene: ATP6V0C as Amber List (moderate evidence)
Genetic Epilepsy v0.1231 ATP6V0C Zornitza Stark Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1230 ATP6V0C Zornitza Stark Tag SV/CNV tag was added to gene: ATP6V0C.
Genetic Epilepsy v0.1230 ATP6V0C Zornitza Stark reviewed gene: ATP6V0C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1230 KDM5C Kavitha Kothur gene: KDM5C was added
gene: KDM5C was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KDM5C 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: KDM5C were set to 23246292; 32279304; 26919706
Phenotypes for gene: KDM5C were set to Epilepsy; Intellectual Disability; microcephaly; Spasticity; hypothyroidism
Genetic Epilepsy v0.1230 ATP6V1B2 Kavitha Kothur gene: ATP6V1B2 was added
gene: ATP6V1B2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ATP6V1B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V1B2 were set to 31655144; 32934366; 32597767
Phenotypes for gene: ATP6V1B2 were set to Epileptic encephalopathy; Intellectual Disability; microcephaly, DOORS syndrome
Review for gene: ATP6V1B2 was set to GREEN
Added comment: Sources: Literature
Genetic Epilepsy v0.1230 ATP6V0C Kavitha Kothur gene: ATP6V0C was added
gene: ATP6V0C was added to Genetic Epilepsy. Sources: Literature
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
Penetrance for gene: ATP6V0C were set to unknown
Review for gene: ATP6V0C was set to AMBER
Added comment: Sources: Literature
Genetic Epilepsy v0.1230 ARFGEF1 Zornitza Stark Marked gene: ARFGEF1 as ready
Genetic Epilepsy v0.1230 ARFGEF1 Zornitza Stark Gene: arfgef1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1230 ARFGEF1 Zornitza Stark Classified gene: ARFGEF1 as Green List (high evidence)
Genetic Epilepsy v0.1230 ARFGEF1 Zornitza Stark Gene: arfgef1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1229 ARFGEF1 Zornitza Stark gene: ARFGEF1 was added
gene: ARFGEF1 was added to Genetic Epilepsy. Sources: Expert Review
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; Epilepsy
Review for gene: ARFGEF1 was set to GREEN
Added comment: 13 individuals reported with variants in this gene and a neurodevelopmental disorder characterised by variable ID, seizures present in around half. Variants were inherited from mildly affected parents in 40% of families.
Sources: Expert Review
Genetic Epilepsy v0.1228 AP4B1 Zornitza Stark Marked gene: AP4B1 as ready
Genetic Epilepsy v0.1228 AP4B1 Zornitza Stark Gene: ap4b1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1228 AP4B1 Zornitza Stark Classified gene: AP4B1 as Green List (high evidence)
Genetic Epilepsy v0.1228 AP4B1 Zornitza Stark Gene: ap4b1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1227 AP4B1 Zornitza Stark gene: AP4B1 was added
gene: AP4B1 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to 21620353; 22290197; 24700674; 24781758; 32166732
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Review for gene: AP4B1 was set to GREEN
Added comment: Autosomal recessive neurodegenerative disorder characterised by neonatal hypotonia that progresses to hypertonia and spasticity and severe ID with poor or absent speech development. Microcephaly is an early, presenting feature. Seizures reported in at least 3 families.

>5 unrelated families reported.
Sources: Expert Review
Genetic Epilepsy v0.1226 ACOX1 Zornitza Stark Marked gene: ACOX1 as ready
Genetic Epilepsy v0.1226 ACOX1 Zornitza Stark Gene: acox1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1226 ACOX1 Zornitza Stark Phenotypes for gene: ACOX1 were changed from to Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470; Mitchell syndrome, MIM# 618960
Genetic Epilepsy v0.1225 ACOX1 Zornitza Stark Publications for gene: ACOX1 were set to
Genetic Epilepsy v0.1224 ACOX1 Zornitza Stark Mode of inheritance for gene: ACOX1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1223 ACOX1 Zornitza Stark reviewed gene: ACOX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32169171, 17458872; Phenotypes: Peroxisomal acyl-CoA oxidase deficiency, MIM# 264470, Mitchell syndrome, MIM# 618960; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1223 ALX4 Zornitza Stark Marked gene: ALX4 as ready
Genetic Epilepsy v0.1223 ALX4 Zornitza Stark Gene: alx4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1223 ALX4 Zornitza Stark gene: ALX4 was added
gene: ALX4 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: ALX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALX4 were set to 33269135
Phenotypes for gene: ALX4 were set to Parietal foramina 2, MIM# 609597
Review for gene: ALX4 was set to RED
Added comment: Single case report of seizures in an individual with ALX4 variant and parietal foramina, unclear if related.
Sources: Expert Review
Genetic Epilepsy v0.1222 ADGRV1 Zornitza Stark Phenotypes for gene: ADGRV1 were changed from Myoclonic epilepsy; febrile seizures; epilepsy to Myoclonic epilepsy; febrile seizures; epilepsy; Rolandic epilepsy
Genetic Epilepsy v0.1221 ADGRV1 Zornitza Stark Publications for gene: ADGRV1 were set to 29266188; 29261713; 32962041
Genetic Epilepsy v0.1220 ADGRV1 Zornitza Stark Mode of inheritance for gene: ADGRV1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1219 ADGRV1 Zornitza Stark Classified gene: ADGRV1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1219 ADGRV1 Zornitza Stark Gene: adgrv1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1218 ADGRV1 Zornitza Stark edited their review of gene: ADGRV1: Added comment: Two families reported with bi-allelic variants and Rolandic epilepsy.; Changed rating: AMBER; Changed publications: 29266188, 29261713, 32962041, 34160719; Changed phenotypes: Myoclonic epilepsy, febrile seizures, epilepsy, Rolandic epilepsy; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Classified gene: ACTG1 as Green List (high evidence)
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Gene: actg1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Classified gene: ACTG1 as Green List (high evidence)
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Gene: actg1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Marked gene: ACTG1 as ready
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Gene: actg1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Classified gene: ACTG1 as Green List (high evidence)
Genetic Epilepsy v0.1218 ACTG1 Zornitza Stark Gene: actg1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1217 ACTG1 Zornitza Stark gene: ACTG1 was added
gene: ACTG1 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: ACTG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTG1 were set to 22366783; 25052316
Phenotypes for gene: ACTG1 were set to Baraitser-Winter syndrome 2, MIM# 614583
Review for gene: ACTG1 was set to GREEN
Added comment: Well established gene-disease association. ID and seizures correlate with extent of brain anomalies.
Sources: Expert Review
Genetic Epilepsy v0.1216 AARS2 Zornitza Stark Publications for gene: AARS2 were set to 21549344; 25817015
Genetic Epilepsy v0.1215 AARS2 Zornitza Stark Classified gene: AARS2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1215 AARS2 Zornitza Stark Gene: aars2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1214 AARS2 Zornitza Stark changed review comment from: Seizures not a prominent feature of these conditions.; to: Seizures reported in some.
Genetic Epilepsy v0.1214 AARS2 Zornitza Stark edited their review of gene: AARS2: Changed rating: AMBER; Changed publications: 21549344, 25817015, 32571458, 24808023
Genetic Epilepsy v0.1214 TUBB3 Zornitza Stark Marked gene: TUBB3 as ready
Genetic Epilepsy v0.1214 TUBB3 Zornitza Stark Gene: tubb3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1214 TUBB3 Zornitza Stark Phenotypes for gene: TUBB3 were changed from to Cortical dysplasia, complex, with other brain malformations 1, MIM# 614039
Genetic Epilepsy v0.1213 TUBB3 Zornitza Stark Publications for gene: TUBB3 were set to
Genetic Epilepsy v0.1212 TUBB3 Zornitza Stark Mode of inheritance for gene: TUBB3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1211 TUBB3 Zornitza Stark reviewed gene: TUBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20829227, 25059107, 33318778; Phenotypes: Cortical dysplasia, complex, with other brain malformations 1, MIM# 614039; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1211 SLC4A4 Zornitza Stark Marked gene: SLC4A4 as ready
Genetic Epilepsy v0.1211 SLC4A4 Zornitza Stark Gene: slc4a4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1211 SLC4A4 Zornitza Stark gene: SLC4A4 was added
gene: SLC4A4 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: SLC4A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A4 were set to 33439394
Phenotypes for gene: SLC4A4 were set to Renal tubular acidosis, proximal, with ocular abnormalities, MIM# 604278
Review for gene: SLC4A4 was set to RED
Added comment: Bi-allelic variants in SLC4A4 cause a syndrome characterised by proximal renal tubular acidosis (pRTA), ID, dental and ocular abnormalities, and hemiplegic migraine.

Single family reported with 4 affected individuals, where seizures were a prominent feature, with adult onset. Two developed life-threatening status epilepticus.
Sources: Expert Review
Genetic Epilepsy v0.1210 SLC1A3 Zornitza Stark Marked gene: SLC1A3 as ready
Genetic Epilepsy v0.1210 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1210 SLC1A3 Zornitza Stark Classified gene: SLC1A3 as Green List (high evidence)
Genetic Epilepsy v0.1210 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1209 SLC1A3 Zornitza Stark gene: SLC1A3 was added
gene: SLC1A3 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: SLC1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC1A3 were set to 19139306; 16116111; 29208948; 27829685; 32741053
Phenotypes for gene: SLC1A3 were set to Episodic ataxia, type 6, MIM# 612656
Review for gene: SLC1A3 was set to GREEN
Added comment: Seven families reported. Episodic ataxia type 6 (EA6) differs from other EA forms in long attack duration, epilepsy and absent myokymia, nystagmus, and tinnitus.
Sources: Expert Review
Genetic Epilepsy v0.1208 MAST1 Zornitza Stark Marked gene: MAST1 as ready
Genetic Epilepsy v0.1208 MAST1 Zornitza Stark Gene: mast1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1208 MAST1 Zornitza Stark Classified gene: MAST1 as Green List (high evidence)
Genetic Epilepsy v0.1208 MAST1 Zornitza Stark Gene: mast1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1207 MAST1 Zornitza Stark gene: MAST1 was added
gene: MAST1 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: MAST1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST1 were set to 31721002; 30449657; 32198973
Phenotypes for gene: MAST1 were set to Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations; OMIM #618273
Review for gene: MAST1 was set to GREEN
Added comment: 7 unrelated patients with mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM) with de novo heterozygous mutations in MAST1 gene. Intellectual disability and seizures are clinical features, together with characteristic brain imaging abnormalities.

In vitro functional studies showed that 1 of the variants (lys276del) increased MAST1 binding to microtubules compared to controls. Mutant mice heterozygous for a Mast1 leu278del allele showed a thicker corpus callosum compared to wildtype, and an overall reduction in cortical volume and thickness and decreased cerebellar volume and number of granule and Purkinje cells due to increased apoptosis compared to controls.

1 Emirati patient with ID, microcephaly, and dysmorphic features, with missense variant in MAST1.
Sources: Expert Review
Genetic Epilepsy v0.1206 LAMA2 Zornitza Stark Classified gene: LAMA2 as Green List (high evidence)
Genetic Epilepsy v0.1206 LAMA2 Zornitza Stark Gene: lama2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1205 LAMA2 Zornitza Stark Classified gene: LAMA2 as Green List (high evidence)
Genetic Epilepsy v0.1205 LAMA2 Zornitza Stark Gene: lama2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1204 LAMA2 Zornitza Stark Marked gene: LAMA2 as ready
Genetic Epilepsy v0.1204 LAMA2 Zornitza Stark Gene: lama2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1204 LAMA2 Zornitza Stark gene: LAMA2 was added
gene: LAMA2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: LAMA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA2 were set to 33333793; 34325301
Phenotypes for gene: LAMA2 were set to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855; Muscular dystrophy, limb-girdle, autosomal recessive 23 , MIM#618138
Review for gene: LAMA2 was set to GREEN
Added comment: Epilepsy is a common, often severe, feature of LAMA2-related muscular dystrophy (LAMA2-RD) and could represent its onset and main manifestation, even in the absence of overt muscle involvement, reviewed in PMID 34325301.
Sources: Literature
Genetic Epilepsy v0.1203 CIC Zornitza Stark Marked gene: CIC as ready
Genetic Epilepsy v0.1203 CIC Zornitza Stark Gene: cic has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1203 CIC Zornitza Stark Phenotypes for gene: CIC were changed from to Mental retardation, autosomal dominant 45, MIM# 617600
Genetic Epilepsy v0.1202 CIC Zornitza Stark Publications for gene: CIC were set to
Genetic Epilepsy v0.1201 CIC Zornitza Stark Mode of inheritance for gene: CIC was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1200 CIC Zornitza Stark reviewed gene: CIC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28288114; Phenotypes: Mental retardation, autosomal dominant 45, MIM# 617600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1200 BRAF Zornitza Stark Marked gene: BRAF as ready
Genetic Epilepsy v0.1200 BRAF Zornitza Stark Gene: braf has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1200 BRAF Zornitza Stark Phenotypes for gene: BRAF were changed from to Cardiofaciocutaneous syndrome, MIM# 115150
Genetic Epilepsy v0.1199 BRAF Zornitza Stark Publications for gene: BRAF were set to
Genetic Epilepsy v0.1198 BRAF Zornitza Stark Mode of inheritance for gene: BRAF was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1197 BRAF Zornitza Stark reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: None; Publications: 34309696; Phenotypes: Cardiofaciocutaneous syndrome, MIM# 115150; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1197 ALG10 Zornitza Stark Marked gene: ALG10 as ready
Genetic Epilepsy v0.1197 ALG10 Zornitza Stark Gene: alg10 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1197 ALG10 Zornitza Stark gene: ALG10 was added
gene: ALG10 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ALG10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG10 were set to 33798445
Phenotypes for gene: ALG10 were set to Progressive myoclonus epilepsy; CDG
Review for gene: ALG10 was set to RED
Added comment: Single individual with homozygous variant identified in a progressive myoclonus epilepsy cohort.
Sources: Literature
Genetic Epilepsy v0.1196 KIF4A Zornitza Stark gene: KIF4A was added
gene: KIF4A was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: KIF4A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: KIF4A were set to 24812067; 34346154
Phenotypes for gene: KIF4A were set to Mental retardation, X-linked 100, MIM# 300923
Review for gene: KIF4A was set to AMBER
Added comment: 12 families reported. Major structural brain abnormalities present in at least 3 (hydrocephalus), variable ID in several. At least 3 reported as having seizures, though variable severity (including febrile Sz in one).
Sources: Expert Review
Genetic Epilepsy v0.1195 SPEN Zornitza Stark Marked gene: SPEN as ready
Genetic Epilepsy v0.1195 SPEN Zornitza Stark Gene: spen has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1195 SPEN Zornitza Stark Classified gene: SPEN as Amber List (moderate evidence)
Genetic Epilepsy v0.1195 SPEN Zornitza Stark Gene: spen has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1194 SPEN Elena Savva gene: SPEN was added
gene: SPEN was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPEN were set to PMID: 33596411
Phenotypes for gene: SPEN were set to Radio-Tartaglia syndrome MIM#619312
Review for gene: SPEN was set to AMBER
gene: SPEN was marked as current diagnostic
Added comment: PMID: 33596411
- 34 individuals with truncating variants in SPEN reported, most are de novo variants.
- Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females.
- Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females.

Seizures were observed in only 3/32 (~9%) of patients
Sources: Literature
Genetic Epilepsy v0.1194 HCN2 Zornitza Stark Phenotypes for gene: HCN2 were changed from Genetic epilepsy with febrile seizures plus; Other seizure disorders to Febrile seizures, familial, 2, MIM# 602477; Genetic epilepsy with febrile seizures plus; Other seizure disorders
Genetic Epilepsy v0.1193 HCN2 Zornitza Stark edited their review of gene: HCN2: Changed phenotypes: Febrile seizures, familial, 2, MIM# 602477, Genetic epilepsy with febrile seizures plus, Other seizure disorders
Genetic Epilepsy v0.1193 HCN4 Zornitza Stark Marked gene: HCN4 as ready
Genetic Epilepsy v0.1193 HCN4 Zornitza Stark Gene: hcn4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1193 HCN4 Zornitza Stark gene: HCN4 was added
gene: HCN4 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: HCN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HCN4 were set to 30127718; 29588962
Phenotypes for gene: HCN4 were set to {Epilepsy, idiopathic generalized, susceptibility to, 18}, MIM# 619521
Review for gene: HCN4 was set to RED
Added comment: Two families reported. Variant did not segregate with disease in one (PMID 29588962), and was present in two affected sibs from another family reported in PMID 30127718, some functional data to support impact of variant on protein function.
Sources: Expert list
Genetic Epilepsy v0.1192 PRICKLE2 Zornitza Stark Marked gene: PRICKLE2 as ready
Genetic Epilepsy v0.1192 PRICKLE2 Zornitza Stark Gene: prickle2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1192 PRICKLE2 Zornitza Stark Classified gene: PRICKLE2 as Green List (high evidence)
Genetic Epilepsy v0.1192 PRICKLE2 Zornitza Stark Gene: prickle2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1191 PRICKLE2 Zornitza Stark gene: PRICKLE2 was added
gene: PRICKLE2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PRICKLE2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRICKLE2 were set to 34092786
Phenotypes for gene: PRICKLE2 were set to Neurodevelopmental disorder; global developmental delay; behavioural difficulties ± epilepsy; autistic features; attention deficit hyperactive disorder; psychiatric symptoms
Review for gene: PRICKLE2 was set to GREEN
Added comment: Six subjects from four unrelated families with neurodevelopmental delay, behavioural difficulties and epilepsy had heterozygous variants, either de novo or segregating with disease. Two missense were de novo, c.122 C>T; p.(Pro41Leu) and c.680C>G; p.(Thr227Arg); one nonsense variant was de novo (c.214 C>T; p.(Arg72*); and one frameshift variant segregated with the disorder in three affected females (c.1286_1287delGT; p.(Ser429Thrfs*56)). Loss-of-function (homozygous) variants have been shown to cause seizures in flies; and both heterozygous and homozygous mice have shown behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility (PMID: 21276947).
Sources: Literature
Genetic Epilepsy v0.1190 CACNA1I Seb Lunke Marked gene: CACNA1I as ready
Genetic Epilepsy v0.1190 CACNA1I Seb Lunke Gene: cacna1i has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1190 CACNA1I Seb Lunke Classified gene: CACNA1I as Green List (high evidence)
Genetic Epilepsy v0.1190 CACNA1I Seb Lunke Gene: cacna1i has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1189 GRIK2 Zornitza Stark Marked gene: GRIK2 as ready
Genetic Epilepsy v0.1189 GRIK2 Zornitza Stark Gene: grik2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1189 GRIK2 Zornitza Stark Classified gene: GRIK2 as Green List (high evidence)
Genetic Epilepsy v0.1189 GRIK2 Zornitza Stark Gene: grik2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1188 GRIK2 Zornitza Stark Classified gene: GRIK2 as Green List (high evidence)
Genetic Epilepsy v0.1188 GRIK2 Zornitza Stark Gene: grik2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1187 CACNA1I Kristin Rigbye gene: CACNA1I was added
gene: CACNA1I was added to Genetic Epilepsy. Sources: Literature
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
Review for gene: CACNA1I was set to GREEN
Added comment: 4 different missense variants identified and shown to result in a gain of function.

2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy.

1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases.
Sources: Literature
Genetic Epilepsy v0.1187 GRIK2 Danielle Ariti gene: GRIK2 was added
gene: GRIK2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GRIK2 was set to BOTH monoallelic and 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 MIM# 611092; nonsyndromic neurodevelopmental disorder (NDD)
Review for gene: GRIK2 was set to GREEN
Added comment: Over 10 individuals with variants in GRIK2; Bi-allelic and mono-allelic; loss of function

2 (sibs) with bi-allelic truncating variants and 1 family with bi-allelic deletion (removing exons 7 and 8).
11 individuals with de novo mono-allelic missense variants
(5x with the same missense variant c.1969G>A (p.Ala657Thr) all the others were near this location).

Associated with nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features with 30-50% individuals experiencing seizures.
Sources: Literature
Genetic Epilepsy v0.1187 SLC32A1 Zornitza Stark Marked gene: SLC32A1 as ready
Genetic Epilepsy v0.1187 SLC32A1 Zornitza Stark Gene: slc32a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1187 SLC32A1 Zornitza Stark Classified gene: SLC32A1 as Green List (high evidence)
Genetic Epilepsy v0.1187 SLC32A1 Zornitza Stark Gene: slc32a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1186 SLC32A1 Zornitza Stark gene: SLC32A1 was added
gene: SLC32A1 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.1185 ARF1 Zornitza Stark Marked gene: ARF1 as ready
Genetic Epilepsy v0.1185 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1185 ARF1 Zornitza Stark Classified gene: ARF1 as Green List (high evidence)
Genetic Epilepsy v0.1185 ARF1 Zornitza Stark Gene: arf1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1184 ARF1 Zornitza Stark gene: ARF1 was added
gene: ARF1 was added to Genetic Epilepsy. Sources: Literature
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, MIM# 618185
Review for gene: ARF1 was set to GREEN
Added comment: 5 individuals from 4 untreated families reported. 3/5 individuals presented with seizures and all had developmental delays, especially in speech (one patient had a diagnosis of moderate ID).
Sources: Literature
Genetic Epilepsy v0.1183 CLCN3 Zornitza Stark Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512 to Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512; Neurodevelopmental disorder with seizures and brain abnormalities, MIM# 619517
Genetic Epilepsy v0.1182 CLCN3 Zornitza Stark edited their review of gene: CLCN3: Changed phenotypes: Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512, Neurodevelopmental disorder with seizures and brain abnormalities, MIM# 619517
Genetic Epilepsy v0.1182 CLCN3 Zornitza Stark Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512
Genetic Epilepsy v0.1181 CLCN3 Zornitza Stark edited their review of gene: CLCN3: Changed phenotypes: Neurodevelopmental disorder with hypotonia and brain abnormalities, MIM# 619512
Genetic Epilepsy v0.1181 ANKRD17 Zornitza Stark Phenotypes for gene: ANKRD17 were changed from Intellectual disability; dysmorphic features to Chopra-Amiel-Gordan syndrome, MIM# 619504; Intellectual disability; dysmorphic features
Genetic Epilepsy v0.1180 ANKRD17 Zornitza Stark edited their review of gene: ANKRD17: Changed phenotypes: Chopra-Amiel-Gordan syndrome, MIM# 619504, Intellectual disability, dysmorphic features
Genetic Epilepsy v0.1180 FAME2 Bryony Thompson Marked STR: FAME2 as ready
Genetic Epilepsy v0.1180 FAME2 Bryony Thompson Str: fame2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1180 FAME2 Bryony Thompson Classified STR: FAME2 as Green List (high evidence)
Genetic Epilepsy v0.1180 FAME2 Bryony Thompson Str: fame2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1179 FAME2 Bryony Thompson STR: FAME2 was added
STR: FAME2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for STR: FAME2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FAME2 were set to 11701600; 24114805; 31664034
Phenotypes for STR: FAME2 were set to Epilepsy, familial adult myoclonic, 2 MIM#607876
Review for STR: FAME2 was set to GREEN
STR: FAME2 was marked as clinically relevant
Added comment: NM_020151.3(STARD7):c.291-1572ATTTT[X]ATTTC[X]
158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy with a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat, similar molecular finding in other forms of FAME. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and no effect on STARD7 gene expression, suggesting ATTTC expansions may cause FAME irrespective of the genomic locus involved.
Sources: Literature
Genetic Epilepsy v0.1178 STARD7 Bryony Thompson Classified gene: STARD7 as No list
Genetic Epilepsy v0.1178 STARD7 Bryony Thompson Added comment: Comment on list classification: Added to panel as an STR under FAME2
Genetic Epilepsy v0.1178 STARD7 Bryony Thompson Gene: stard7 has been removed from the panel.
Genetic Epilepsy v0.1171 SAMD12 Bryony Thompson Classified gene: SAMD12 as No list
Genetic Epilepsy v0.1171 SAMD12 Bryony Thompson Added comment: Comment on list classification: Added as an STR to this panel.
Genetic Epilepsy v0.1171 SAMD12 Bryony Thompson Gene: samd12 has been removed from the panel.
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Marked gene: ARF3 as ready
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Classified gene: ARF3 as Amber List (moderate evidence)
Genetic Epilepsy v0.1170 ARF3 Zornitza Stark Gene: arf3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1169 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Genetic Epilepsy. 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
Review for gene: ARF3 was set to AMBER
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
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Marked gene: VPS50 as ready
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Classified gene: VPS50 as Amber List (moderate evidence)
Genetic Epilepsy v0.1169 VPS50 Zornitza Stark Gene: vps50 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1168 VPS50 Konstantinos Varvagiannis gene: VPS50 was added
gene: VPS50 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Marked gene: ROGDI as ready
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Gene: rogdi has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Phenotypes for gene: ROGDI were changed from to Kohlschutter-Tonz syndrome, MIM# 226750
Genetic Epilepsy v0.1168 ROGDI Zornitza Stark Publications for gene: ROGDI were set to
Genetic Epilepsy v0.1167 ROGDI Zornitza Stark Mode of inheritance for gene: ROGDI was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1166 ROGDI Zornitza Stark reviewed gene: ROGDI: Rating: GREEN; Mode of pathogenicity: None; Publications: 22424600, 23086778, 33866847; Phenotypes: Kohlschutter-Tonz syndrome, MIM# 226750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1166 SPTBN1 Zornitza Stark Phenotypes for gene: SPTBN1 were changed from Neurodevelopmental Syndrome to Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475
Genetic Epilepsy v0.1165 SPTBN1 Zornitza Stark reviewed gene: SPTBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay, impaired speech, and behavioural abnormalities, MIM# 619475; Mode of inheritance: None
Genetic Epilepsy v0.1165 SLC46A1 Danielle Ariti gene: SLC46A1 was added
gene: SLC46A1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SLC46A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC46A1 were set to 20301716
Phenotypes for gene: SLC46A1 were set to Folate malabsorption, hereditary MIM# 229050; Decreased Ig levels; megaloblastic anaemia; failure to thrive; Immunodeficiency; if untreated for prolonged periods results in intellectual disability; oral mucositis; hypoimmunoglobulinaemia; recurrent infections; seizures; motor impairment; leukopaenia; thrombocytopaenia
Review for gene: SLC46A1 was set to GREEN
Added comment: ver 30 unrelated individuals reported with variants in SLC46A1 presenting with hereditary folate malabsorption; two mouse model.

In-frame deletion variant has been commonly reported among individuals of Puerto Rican heritage: c.1082-1G>A;
Other variants include homozygous and compound heterozygous deletions, insertion, missense and nonsense report in individuals of other origins (Chinese, Moroccan, Turkish, African American).

Clinically presents in infancy with failure to thrive, recurrent diarrhoea, anaemia, recurrent infections and, frequently, seizures.
Sources: Literature
Genetic Epilepsy v0.1165 TMEM222 Zornitza Stark Phenotypes for gene: TMEM222 were changed from Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality to Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Genetic Epilepsy v0.1164 TMEM222 Zornitza Stark reviewed gene: TMEM222: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with motor and speech delay and behavioural abnormalities, MIM# 619470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Marked gene: PIDD1 as ready
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Classified gene: PIDD1 as Green List (high evidence)
Genetic Epilepsy v0.1164 PIDD1 Zornitza Stark Gene: pidd1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Marked gene: JAKMIP1 as ready
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Classified gene: JAKMIP1 as Amber List (moderate evidence)
Genetic Epilepsy v0.1163 JAKMIP1 Seb Lunke Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1162 JAKMIP1 Seb Lunke gene: JAKMIP1 was added
gene: JAKMIP1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; Seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalisations, and other autistic-like behaviours.
Sources: Literature
Genetic Epilepsy v0.1161 PIDD1 Konstantinos Varvagiannis gene: PIDD1 was added
gene: PIDD1 was added to Genetic Epilepsy. Sources: Literature
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-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
Genetic Epilepsy v0.1161 MAST3 Zornitza Stark Marked gene: MAST3 as ready
Genetic Epilepsy v0.1161 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1161 MAST3 Zornitza Stark Phenotypes for gene: MAST3 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy
Genetic Epilepsy v0.1160 MAST3 Zornitza Stark Phenotypes for gene: MAST3 were changed from Epilepsy to Developmental and epileptic encephalopathy
Genetic Epilepsy v0.1159 MAST3 Zornitza Stark Classified gene: MAST3 as Green List (high evidence)
Genetic Epilepsy v0.1159 MAST3 Zornitza Stark Gene: mast3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1158 MAST3 Zornitza Stark gene: MAST3 was added
gene: MAST3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: MAST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST3 were set to 34185323
Phenotypes for gene: MAST3 were set to Epilepsy
Review for gene: MAST3 was set to GREEN
Added comment: Eleven individuals reported with de novo missense variants in the STK domain, including two recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. Limited functional data.
Sources: Literature
Genetic Epilepsy v0.1157 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from Intellectual disability; Seizures to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428; Intellectual disability; Seizures
Genetic Epilepsy v0.1156 TRIM8 Zornitza Stark edited their review of gene: TRIM8: Changed phenotypes: Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428, Intellectual disability, Seizures
Genetic Epilepsy v0.1156 RNF2 Zornitza Stark Phenotypes for gene: RNF2 were changed from epilepsy; intellectual disability; intrauterine growth retardation to Lou-Schoch-Yamamoto syndrome , MIM#619460; epilepsy; intellectual disability; intrauterine growth retardation
Genetic Epilepsy v0.1155 RNF2 Zornitza Stark edited their review of gene: RNF2: Changed phenotypes: Lou-Schoch-Yamamoto syndrome , MIM#619460, epilepsy, intellectual disability, intrauterine growth retardation
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Marked gene: AP1G1 as ready
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Classified gene: AP1G1 as Green List (high evidence)
Genetic Epilepsy v0.1155 AP1G1 Zornitza Stark Gene: ap1g1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1154 AP1G1 Danielle Ariti gene: AP1G1 was added
gene: AP1G1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Review for gene: AP1G1 was set to GREEN
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site.

Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality.

All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe.
Sources: Literature
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Marked gene: SPTBN1 as ready
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Classified gene: SPTBN1 as Green List (high evidence)
Genetic Epilepsy v0.1154 SPTBN1 Zornitza Stark Gene: sptbn1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Marked gene: CLCN3 as ready
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Classified gene: CLCN3 as Green List (high evidence)
Genetic Epilepsy v0.1153 CLCN3 Zornitza Stark Gene: clcn3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1152 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Genetic Epilepsy. Sources: Literature
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
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

The 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:
- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.
- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.
- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.
- Six have mood or behavioural disorders, particularly anxiety (3/6).
- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.

The severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.

Patch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.

Both loss and gain of function in this gene resulted in the same phenotype.
Sources: Literature
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Marked gene: TNPO2 as ready
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Classified gene: TNPO2 as Green List (high evidence)
Genetic Epilepsy v0.1151 TNPO2 Zornitza Stark Gene: tnpo2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1150 TNPO2 Zornitza Stark gene: TNPO2 was added
gene: TNPO2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability, neurologic deficits and dysmorphic features
Mode of pathogenicity for gene: TNPO2 was set to Other
Review for gene: TNPO2 was set to GREEN
Added comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia). Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF. gnomAD: minimal PTCs present.
Sources: Literature
Genetic Epilepsy v0.1149 SPTBN1 Belinda Chong gene: SPTBN1 was added
gene: SPTBN1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to PMID: 34211179 PMID: 33847457
Phenotypes for gene: SPTBN1 were set to Neurodevelopmental Syndrome
Added comment: PMID: 34211179
- Heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures (9/29) ; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features.
- Show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics.

PMID: 33847457
- Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset.
- identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities).
- Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis.
Sources: Literature
Sources: Literature
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Marked gene: SYNCRIP as ready
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Classified gene: SYNCRIP as Amber List (moderate evidence)
Genetic Epilepsy v0.1149 SYNCRIP Zornitza Stark Gene: syncrip has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1148 SYNCRIP Konstantinos Varvagiannis gene: SYNCRIP was added
gene: SYNCRIP was added to Genetic Epilepsy. 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. 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
Genetic Epilepsy v0.1148 CHRNA4 Zornitza Stark Marked gene: CHRNA4 as ready
Genetic Epilepsy v0.1148 CHRNA4 Zornitza Stark Gene: chrna4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1148 CHRNA4 Zornitza Stark Phenotypes for gene: CHRNA4 were changed from to Epilepsy, nocturnal frontal lobe, 1, MIM# 600513
Genetic Epilepsy v0.1147 CHRNA4 Zornitza Stark Publications for gene: CHRNA4 were set to
Genetic Epilepsy v0.1146 CHRNA4 Zornitza Stark Mode of pathogenicity for gene: CHRNA4 was changed from to Other
Genetic Epilepsy v0.1145 CHRNA4 Zornitza Stark Mode of inheritance for gene: CHRNA4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1144 CHRNA4 Melanie Marty reviewed gene: CHRNA4: Rating: GREEN; Mode of pathogenicity: Other; Publications: 14623738, 23114665; Phenotypes: Epilepsy, nocturnal frontal lobe, 1, MIM# 600513; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1144 PCDHGC4 Zornitza Stark Classified gene: PCDHGC4 as Green List (high evidence)
Genetic Epilepsy v0.1144 PCDHGC4 Zornitza Stark Gene: pcdhgc4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1143 PCDHGC4 Zornitza Stark Classified gene: PCDHGC4 as Green List (high evidence)
Genetic Epilepsy v0.1143 PCDHGC4 Zornitza Stark Gene: pcdhgc4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1142 PCDHGC4 Zornitza Stark Marked gene: PCDHGC4 as ready
Genetic Epilepsy v0.1142 PCDHGC4 Zornitza Stark Gene: pcdhgc4 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1142 PCDHGC4 Zornitza Stark gene: PCDHGC4 was added
gene: PCDHGC4 was added to Genetic Epilepsy. Sources: Literature
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 Intellectual disability; Seizures
Review for gene: PCDHGC4 was set to GREEN
Added comment: Eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty in eight families and seizures in four families. Four of the variants were LoF, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Genetic Epilepsy v0.1141 C2orf69 Zornitza Stark Classified gene: C2orf69 as Green List (high evidence)
Genetic Epilepsy v0.1141 C2orf69 Zornitza Stark Gene: c2orf69 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1140 C2orf69 Zornitza Stark gene: C2orf69 was added
gene: C2orf69 was added to Genetic Epilepsy. Sources: Literature
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 (COXPD53), MIM#619423
Review for gene: C2orf69 was set to GREEN
Added comment: PMID 34038740: 20 affected children from 8 unrelated families reported, presenting with fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. Endogenous C2ORF69 was found to be (1) loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. Zebrafish model.

PMID 33945503: 8 individuals from 5 families reported with muscle hypotonia, developmental delay, progressive microcephaly, and brain MRI abnormalities. Age at onset ranged from birth to 6 months of age. Six patients had vision impairment, liver abnormalities, inflammation/inflammatory arthritis, and 5 patients had seizures.
Sources: Literature
Genetic Epilepsy v0.1139 RNF2 Zornitza Stark Marked gene: RNF2 as ready
Genetic Epilepsy v0.1139 RNF2 Zornitza Stark Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1139 RNF2 Zornitza Stark Classified gene: RNF2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1139 RNF2 Zornitza Stark Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1138 RNF2 Zornitza Stark gene: RNF2 was added
gene: RNF2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF2 were set to 33864376
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
Genetic Epilepsy v0.1137 HID1 Zornitza Stark Marked gene: HID1 as ready
Genetic Epilepsy v0.1137 HID1 Zornitza Stark Gene: hid1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1137 HID1 Zornitza Stark Classified gene: HID1 as Green List (high evidence)
Genetic Epilepsy v0.1137 HID1 Zornitza Stark Gene: hid1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1136 HID1 Zornitza Stark gene: HID1 was added
gene: HID1 was added to Genetic Epilepsy. Sources: Literature
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
Review for gene: HID1 was set to GREEN
Added comment: 7 individuals from 6 unrelated families reported. Clinical features included: hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy
Sources: Literature
Genetic Epilepsy v0.1135 HEATR5B Seb Lunke Marked gene: HEATR5B as ready
Genetic Epilepsy v0.1135 HEATR5B Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1135 HEATR5B Seb Lunke Classified gene: HEATR5B as Amber List (moderate evidence)
Genetic Epilepsy v0.1135 HEATR5B Seb Lunke Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1134 HEATR5B Seb Lunke gene: HEATR5B was added
gene: HEATR5B was added to Genetic Epilepsy. Sources: Literature
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; intellectual disability; seizures
Review for gene: HEATR5B was set to AMBER
Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay. Two homozygous splice variants were reported (c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. Homozygous knockout mice were not viable. *NOTE: gene (and alias) not found in OMIM
Sources: Literature
Genetic Epilepsy v0.1133 ATP1A2 Zornitza Stark Marked gene: ATP1A2 as ready
Genetic Epilepsy v0.1133 ATP1A2 Zornitza Stark Gene: atp1a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1133 ATP1A2 Zornitza Stark Phenotypes for gene: ATP1A2 were changed from to developmental and epileptic encephalopathy; early or neonatal onset seizures, polymicrogyria
Genetic Epilepsy v0.1132 ATP1A2 Zornitza Stark Publications for gene: ATP1A2 were set to
Genetic Epilepsy v0.1131 ATP1A2 Zornitza Stark Mode of inheritance for gene: ATP1A2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1130 ATP1A3 Zornitza Stark Marked gene: ATP1A3 as ready
Genetic Epilepsy v0.1130 ATP1A3 Zornitza Stark Gene: atp1a3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1130 ATP1A3 Zornitza Stark Phenotypes for gene: ATP1A3 were changed from to developmental and epileptic encephalopathy; early or neonatal onset seizures, polymicrogyria
Genetic Epilepsy v0.1129 ATP1A3 Zornitza Stark Publications for gene: ATP1A3 were set to
Genetic Epilepsy v0.1128 ATP1A3 Zornitza Stark Mode of inheritance for gene: ATP1A3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1127 ATP1A3 Zornitza Stark reviewed gene: ATP1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1127 DNM1 Zornitza Stark Phenotypes for gene: DNM1 were changed from to Developmental and epileptic encephalopathy 31, OMIM:616346
Genetic Epilepsy v0.1126 DNM1 Zornitza Stark Publications for gene: DNM1 were set to
Genetic Epilepsy v0.1125 DNM1 Zornitza Stark Mode of inheritance for gene: DNM1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1124 DNM1 Arina Puzriakova reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25262651, 27066543, 33372033, 34172529; Phenotypes: Developmental and epileptic encephalopathy 31, OMIM:616346; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1124 ATP1A2 Ee Ming Wong reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33880529; Phenotypes: developmental and epileptic encephalopathy, early or neonatal onset seizures, polymicrogyria; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Genetic Epilepsy v0.1124 ATP1A2 Ee Ming Wong Deleted their review
Genetic Epilepsy v0.1124 ATP1A2 Ee Ming Wong reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33880529; Phenotypes: developmental and epileptic encephalopathy, early or neonatal onset seizures, polymicrogyria; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1124 ATP1A3 Ee Ming Wong changed review comment from: - sixteen individuals with de novo or inherited variants (1 variant was mosaic)
- Mutant constructs transfected into COS-1 cells demonstrated impaired NKA-pump activity; to: - sixteen individuals with de novo or inherited variants (1 variant was mosaic)
- Mutant constructs transfected into COS-1 cells demonstrated impaired NKA-pump activity
Genetic Epilepsy v0.1124 ATP1A3 Ee Ming Wong changed review comment from: - six individuals with de novo missense variants
- Mutant constructs transfected into COS-1 cells demonstrated impaired NKA-pump activity; to: - sixteen individuals with de novo or inherited variants (1 variant was mosaic)
- Mutant constructs transfected into COS-1 cells demonstrated impaired NKA-pump activity
Genetic Epilepsy v0.1124 ATP1A3 Ee Ming Wong reviewed gene: ATP1A3: Rating: ; Mode of pathogenicity: None; Publications: PMID: 33880529; Phenotypes: developmental and epileptic encephalopathy, early or neonatal onset seizures, polymicrogyria; Mode of inheritance: None
Genetic Epilepsy v0.1124 ARHGEF9 Zornitza Stark Mode of inheritance for gene: ARHGEF9 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)
Genetic Epilepsy v0.1123 PPP2R1A Zornitza Stark Phenotypes for gene: PPP2R1A were changed from Mental retardation, autosomal dominant 36 MIM#616362 to Mental retardation, autosomal dominant 36, MIM#616362; Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome, MONDO:0014605
Genetic Epilepsy v0.1122 PPP2R1A Zornitza Stark Marked gene: PPP2R1A as ready
Genetic Epilepsy v0.1122 PPP2R1A Zornitza Stark Gene: ppp2r1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1122 PPP2R1A Zornitza Stark Classified gene: PPP2R1A as Green List (high evidence)
Genetic Epilepsy v0.1122 PPP2R1A Zornitza Stark Gene: ppp2r1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1121 PPP2R1A Elena Savva gene: PPP2R1A was added
gene: PPP2R1A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PPP2R1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP2R1A were set to PMID: 33106617; 26168268
Phenotypes for gene: PPP2R1A were set to Mental retardation, autosomal dominant 36 MIM#616362
Mode of pathogenicity for gene: PPP2R1A was set to Other
Review for gene: PPP2R1A was set to GREEN
Added comment: Likely dominant negative. For some variants, binding assays using HEK293T cells transfected with either WT or mutant constructs demonstrated decreased binding to B subunit families or C subunit with corresponding decrease in PP2A activity by affecting the trimeric holoenzyme (hypothesized by authors) ((PMIDs: 26168268, 33106617).

10/26 patients were reported with epilepsy, interestingly none also presented with macrocephaly (otherwise observed in 38% of the cohort)
Sources: Literature
Genetic Epilepsy v0.1121 NCDN Zornitza Stark Phenotypes for gene: NCDN were changed from neurodevelopmental delay, intellectual disability, and epilepsy to Neurodevelopmental disorder with infantile epileptic spasms (NEDIES), MIM#619373
Genetic Epilepsy v0.1120 NCDN Zornitza Stark reviewed gene: NCDN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with infantile epileptic spasms (NEDIES), MIM#619373; Mode of inheritance: None
Genetic Epilepsy v0.1120 SLC13A5 Zornitza Stark Marked gene: SLC13A5 as ready
Genetic Epilepsy v0.1120 SLC13A5 Zornitza Stark Gene: slc13a5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1120 SLC13A5 Zornitza Stark Publications for gene: SLC13A5 were set to
Genetic Epilepsy v0.1119 SLC13A5 Zornitza Stark Phenotypes for gene: SLC13A5 were changed from to Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905; MONDO:0014392
Genetic Epilepsy v0.1118 SLC13A5 Zornitza Stark Mode of inheritance for gene: SLC13A5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1117 SLC13A5 Teresa Zhao reviewed gene: SLC13A5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24995870, 26384929; Phenotypes: Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1117 GNAI1 Zornitza Stark Marked gene: GNAI1 as ready
Genetic Epilepsy v0.1117 GNAI1 Zornitza Stark Gene: gnai1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1117 GNAI1 Zornitza Stark Classified gene: GNAI1 as Green List (high evidence)
Genetic Epilepsy v0.1117 GNAI1 Zornitza Stark Gene: gnai1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1116 GNAI1 Zornitza Stark gene: GNAI1 was added
gene: GNAI1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GNAI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNAI1 were set to 28135719; 33473207
Phenotypes for gene: GNAI1 were set to Intellectual disability; seizures; hypotonia
Review for gene: GNAI1 was set to GREEN
Added comment: Over 30 individuals reported, most had a severe neurodevelopmental disorder with global developmental delay, intellectual disability, hypotonia, and epilepsy.
Sources: Literature
Genetic Epilepsy v0.1115 PARP6 Zornitza Stark Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Genetic Epilepsy v0.1114 PARP6 Zornitza Stark edited their review of gene: PARP6: Changed publications: 34067418
Genetic Epilepsy v0.1114 BCAS3 Sue White Marked gene: BCAS3 as ready
Genetic Epilepsy v0.1114 BCAS3 Sue White Gene: bcas3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1114 BCAS3 Sue White Classified gene: BCAS3 as Green List (high evidence)
Genetic Epilepsy v0.1114 BCAS3 Sue White Gene: bcas3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1113 BCAS3 Paul De Fazio gene: BCAS3 was added
gene: BCAS3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Review for gene: BCAS3 was set to GREEN
gene: BCAS3 was marked as current diagnostic
Added comment: 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. Patient fibroblasts confirmed absence of BCAS3 protein.

8 patients had epilepsy.
Sources: Literature
Genetic Epilepsy v0.1113 ZEB2 Zornitza Stark Tag SV/CNV tag was added to gene: ZEB2.
Genetic Epilepsy v0.1113 ZEB2 Zornitza Stark Publications for gene: ZEB2 were set to
Genetic Epilepsy v0.1112 ZEB2 Zornitza Stark edited their review of gene: ZEB2: Changed publications: 29300384, 27831545, 24715670, 19215041, 17958891
Genetic Epilepsy v0.1112 ZEB2 Zornitza Stark Marked gene: ZEB2 as ready
Genetic Epilepsy v0.1112 ZEB2 Zornitza Stark Gene: zeb2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1112 ZEB2 Zornitza Stark Phenotypes for gene: ZEB2 were changed from to Mowat-Wilson syndrome, MIM# 235730; MONDO:0009341
Genetic Epilepsy v0.1111 ZEB2 Zornitza Stark Mode of inheritance for gene: ZEB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1110 ZEB2 Zornitza Stark reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mowat-Wilson syndrome, MIM# 235730, MONDO:0009341; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1110 SLC9A6 Zornitza Stark Marked gene: SLC9A6 as ready
Genetic Epilepsy v0.1110 SLC9A6 Zornitza Stark Gene: slc9a6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1110 SLC9A6 Zornitza Stark Phenotypes for gene: SLC9A6 were changed from to Mental retardation, X-linked syndromic, Christianson type, MIM# 300243; MONDO:0010278
Genetic Epilepsy v0.1109 SLC9A6 Zornitza Stark Publications for gene: SLC9A6 were set to
Genetic Epilepsy v0.1108 SLC9A6 Zornitza Stark Mode of inheritance for gene: SLC9A6 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1107 SLC9A6 Zornitza Stark reviewed gene: SLC9A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18342287, 19377476, 25044251, 33278113, 32569089, 31879735; Phenotypes: Mental retardation, X-linked syndromic, Christianson type, MIM# 300243, MONDO:0010278; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1107 SATB2 Zornitza Stark Phenotypes for gene: SATB2 were changed from Glass syndrome, MIM# 612313 to Glass syndrome, MIM# 612313; MONDO:0100147
Genetic Epilepsy v0.1106 MEF2C Zornitza Stark Tag SV/CNV tag was added to gene: MEF2C.
Tag 5'UTR tag was added to gene: MEF2C.
Genetic Epilepsy v0.1106 MEF2C Zornitza Stark Marked gene: MEF2C as ready
Genetic Epilepsy v0.1106 MEF2C Zornitza Stark Gene: mef2c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1106 MEF2C Zornitza Stark Phenotypes for gene: MEF2C were changed from to Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MIM# 613443; MONDO:0013266
Genetic Epilepsy v0.1105 MEF2C Zornitza Stark Publications for gene: MEF2C were set to
Genetic Epilepsy v0.1104 MEF2C Zornitza Stark Mode of inheritance for gene: MEF2C was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1103 MEF2C Zornitza Stark reviewed gene: MEF2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 19876902, 19471318, 19592390, 19592390, 20513142, 34055696, 34022131; Phenotypes: Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MIM# 613443, MONDO:0013266 Edit; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1103 MBD5 Zornitza Stark Marked gene: MBD5 as ready
Genetic Epilepsy v0.1103 MBD5 Zornitza Stark Gene: mbd5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1103 MBD5 Zornitza Stark Phenotypes for gene: MBD5 were changed from to Mental retardation, autosomal dominant 1, MIM# 156200; MONDO:0007974
Genetic Epilepsy v0.1102 MBD5 Zornitza Stark Publications for gene: MBD5 were set to
Genetic Epilepsy v0.1101 MBD5 Zornitza Stark Mode of inheritance for gene: MBD5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1100 MBD5 Zornitza Stark Tag SV/CNV tag was added to gene: MBD5.
Genetic Epilepsy v0.1100 MBD5 Zornitza Stark reviewed gene: MBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 18812405, 21981781, 23708187, 22726846, 33912662; Phenotypes: Mental retardation, autosomal dominant 1, MIM# 156200, MONDO:0007974; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1100 IQSEC2 Zornitza Stark Marked gene: IQSEC2 as ready
Genetic Epilepsy v0.1100 IQSEC2 Zornitza Stark Gene: iqsec2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1100 IQSEC2 Zornitza Stark Phenotypes for gene: IQSEC2 were changed from to Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347
Genetic Epilepsy v0.1099 IQSEC2 Zornitza Stark Publications for gene: IQSEC2 were set to
Genetic Epilepsy v0.1098 IQSEC2 Zornitza Stark Mode of inheritance for gene: IQSEC2 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1097 IQSEC2 Zornitza Stark reviewed gene: IQSEC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31415821, 20473311, 30842726, 33368194, 23674175; Phenotypes: Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656, Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1097 EHMT1 Zornitza Stark Marked gene: EHMT1 as ready
Genetic Epilepsy v0.1097 EHMT1 Zornitza Stark Gene: ehmt1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1097 EHMT1 Zornitza Stark Phenotypes for gene: EHMT1 were changed from to Kleefstra syndrome 1, MIM# 610253; MONDO:0027407
Genetic Epilepsy v0.1096 EHMT1 Zornitza Stark Publications for gene: EHMT1 were set to
Genetic Epilepsy v0.1095 EHMT1 Zornitza Stark Mode of inheritance for gene: EHMT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1094 EHMT1 Zornitza Stark Tag SV/CNV tag was added to gene: EHMT1.
Genetic Epilepsy v0.1094 EHMT1 Zornitza Stark reviewed gene: EHMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826528, 19264732, 19293338, 22670143, 30448833; Phenotypes: Kleefstra syndrome 1, MIM# 610253, MONDO:0027407; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1094 EEF1A2 Zornitza Stark edited their review of gene: EEF1A2: Changed publications: 24697219, 32196822, 32160274, 32062104, 31893083
Genetic Epilepsy v0.1094 EEF1A2 Zornitza Stark Publications for gene: EEF1A2 were set to 32160274
Genetic Epilepsy v0.1093 EEF1A2 Zornitza Stark Phenotypes for gene: EEF1A2 were changed from Epileptic encephalopathy, early infantile, 33, MIM# 616409; Mental retardation, autosomal dominant 38, MIM# 616393 to Mental retardation, autosomal dominant 38, MIM# 616393; MONDO:0014617; Developmental and epileptic encephalopathy 33, MIM# 616409; MONDO:0014625
Genetic Epilepsy v0.1092 EEF1A2 Zornitza Stark edited their review of gene: EEF1A2: Changed phenotypes: Mental retardation, autosomal dominant 38, MIM# 616393, MONDO:0014617, Developmental and epileptic encephalopathy 33, MIM# 616409, MONDO:0014625
Genetic Epilepsy v0.1092 SCN9A Elena Savva reviewed gene: SCN9A: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33216760; Phenotypes: monogenic human epilepsy disorders; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic Epilepsy v0.1092 NSF Zornitza Stark Phenotypes for gene: NSF were changed from Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 96, MIM# 619340; Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Genetic Epilepsy v0.1091 NSF Zornitza Stark edited their review of gene: NSF: Changed phenotypes: Developmental and epileptic encephalopathy 96, MIM# 619340, Seizures, EEG with burst suppression, Global developmental delay, Intellectual disability
Genetic Epilepsy v0.1091 RAB11B Zornitza Stark Marked gene: RAB11B as ready
Genetic Epilepsy v0.1091 RAB11B Zornitza Stark Gene: rab11b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1091 RAB11B Zornitza Stark Phenotypes for gene: RAB11B were changed from to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter 617807
Genetic Epilepsy v0.1090 RAB11B Zornitza Stark Publications for gene: RAB11B were set to
Genetic Epilepsy v0.1089 RAB11B Zornitza Stark Mode of inheritance for gene: RAB11B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1088 RAB11B Zornitza Stark reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter 617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1088 UFSP2 Zornitza Stark reviewed gene: UFSP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Abnormal muscle tone, Seizures, Global developmental delay, Delayed speech and language development, Intellectual disability, Strabismus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1088 UFSP2 Zornitza Stark Classified gene: UFSP2 as Green List (high evidence)
Genetic Epilepsy v0.1088 UFSP2 Zornitza Stark Gene: ufsp2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1087 PARP6 Zornitza Stark Marked gene: PARP6 as ready
Genetic Epilepsy v0.1087 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1087 PARP6 Zornitza Stark Classified gene: PARP6 as Green List (high evidence)
Genetic Epilepsy v0.1087 PARP6 Zornitza Stark Gene: parp6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1086 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to Cells 2021, 10(6), 1289; https://doi.org/10.3390/cells10061289
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Genetic Epilepsy v0.1085 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.
Sources: Literature; 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.
Sources: Literature
Genetic Epilepsy v0.1085 UFSP2 Zornitza Stark Marked gene: UFSP2 as ready
Genetic Epilepsy v0.1085 UFSP2 Zornitza Stark Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1085 UFSP2 Zornitza Stark Classified gene: UFSP2 as Amber List (moderate evidence)
Genetic Epilepsy v0.1085 UFSP2 Zornitza Stark Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1084 UFSP2 Zornitza Stark Tag founder tag was added to gene: UFSP2.
Genetic Epilepsy v0.1084 UFSP2 Konstantinos Varvagiannis gene: UFSP2 was added
gene: UFSP2 was added to Genetic Epilepsy. Sources: Literature
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 Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Penetrance for gene: UFSP2 were set to Complete
Review for gene: UFSP2 was set to AMBER
Added comment: 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.
Sources: Literature
Genetic Epilepsy v0.1084 TBC1D2B Zornitza Stark 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 (NEDSGO), MIM#619323; Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Genetic Epilepsy v0.1083 TBC1D2B Zornitza Stark reviewed gene: TBC1D2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO), MIM#619323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1083 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Epilepsy, generalized, with febrile seizures plus, type 2 604403; Epileptic encephalopathy, early infantile, 6 (Dravet syndrome) 607208; Febrile seizures, familial, 3A 604403 to Epilepsy, generalized, with febrile seizures plus, type 2 604403; Epileptic encephalopathy, early infantile, 6 (Dravet syndrome) 607208; Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317; Febrile seizures, familial, 3A 604403
Genetic Epilepsy v0.1082 SCN1A Zornitza Stark edited their review of gene: SCN1A: Changed phenotypes: Epilepsy, generalized, with febrile seizures plus, type 2 604403, Epileptic encephalopathy, early infantile, 6 (Dravet syndrome) 607208, Developmental and epileptic encephalopathy 6B, non-Dravet, MIM# 619317, Febrile seizures, familial, 3A 604403
Genetic Epilepsy v0.1082 KDM4B Zornitza Stark Phenotypes for gene: KDM4B were changed from Global developmental delay, intellectual disability and neuroanatomical defects to Intellectual developmental disorder, autosomal dominant 65, MIM# 619320; Global developmental delay, intellectual disability and neuroanatomical defects
Genetic Epilepsy v0.1081 KDM4B Zornitza Stark reviewed gene: KDM4B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 65, MIM# 619320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1081 SPTAN1 Zornitza Stark changed review comment from: At least 4 unrelated families reported.; to: At least 4 unrelated families reported, dominant negative mechanism postulated.
Genetic Epilepsy v0.1081 AFF3 Zornitza Stark Phenotypes for gene: AFF3 were changed from Intellectual disability; seizures; hypertrichosis to KINSSHIP syndrome, MIM# 619297; Intellectual disability; seizures; hypertrichosis
Genetic Epilepsy v0.1080 AFF3 Zornitza Stark Publications for gene: AFF3 were set to
Genetic Epilepsy v0.1079 AFF3 Zornitza Stark edited their review of gene: AFF3: Added comment: 16 affected individuals reported with de novo missense variants. All variants occurred within the degron motif of the ALF domain. The highly conserved 9-amino acid motif mediates the interaction with SIAH E3 ubiquitin ligases and regulates their degradation. Thirteen of the probands carried variants affecting the same codon in exon 6, ala258.

All probands presented with severe developmental epileptic encephalopathy along with mesomelic dysplasia (12/18) and failure to thrive (14/18). The skeletal features included short forearms, radial head dislocation/subluxation, triangular and/or short tibia, fibular hypoplasia, hip dislocation, and tarsal and/or metatarsal synostosis resembling Nievergelt/Savarirayan mesomelic skeletal dysplasia. Other features included microcephaly (9/18), global brain atrophy and/or ventriculomegaly (13/15), fibular hypoplasia (12/16), horseshoe or hypoplastic kidney (13/17), abnormalities of muscle tone (12/16), gastroesophageal reflux disease (6/16), and other gastrointestinal symptoms (14/17). The patients also shared common dysmorphic facial features such as a bulbous nasal tip (10/15), a wide mouth (10/16) often with a square upper lip, abnormalities of the teeth and gums (12/15), and hypertrichosis (12/15). The constellation of features recalled some features of CHOPS syndrome, which is caused by mutations in a related gene, AFF4.; Changed publications: 31388108, 33961779; Changed phenotypes: KINSSHIP syndrome, MIM# 619297, Intellectual disability, seizures, hypertrichosis
Genetic Epilepsy v0.1079 RALA Zornitza Stark Phenotypes for gene: RALA were changed from Intellectual disability; Seizures to Hiatt-Neu-Cooper neurodevelopmental syndrome, MIM# 619311; Intellectual disability; Seizures
Genetic Epilepsy v0.1078 RALA Zornitza Stark edited their review of gene: RALA: Changed phenotypes: Hiatt-Neu-Cooper neurodevelopmental syndrome, MIM# 619311, Intellectual disability, Seizures
Genetic Epilepsy v0.1078 TMEM222 Zornitza Stark Marked gene: TMEM222 as ready
Genetic Epilepsy v0.1078 TMEM222 Zornitza Stark Gene: tmem222 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1078 TMEM222 Zornitza Stark Classified gene: TMEM222 as Green List (high evidence)
Genetic Epilepsy v0.1078 TMEM222 Zornitza Stark Gene: tmem222 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1077 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.1077 CHD5 Zornitza Stark Marked gene: CHD5 as ready
Genetic Epilepsy v0.1077 CHD5 Zornitza Stark Gene: chd5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1077 CHD5 Zornitza Stark Classified gene: CHD5 as Green List (high evidence)
Genetic Epilepsy v0.1077 CHD5 Zornitza Stark Gene: chd5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1076 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Genetic Epilepsy. Sources: 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; Epilepsy
Review for gene: CHD5 was set to GREEN
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Genetic Epilepsy v0.1075 ANKRD17 Zornitza Stark Publications for gene: ANKRD17 were set to
Genetic Epilepsy v0.1074 ANKRD17 Zornitza Stark Classified gene: ANKRD17 as Green List (high evidence)
Genetic Epilepsy v0.1074 ANKRD17 Zornitza Stark Gene: ankrd17 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1073 YWHAG Zornitza Stark Marked gene: YWHAG as ready
Genetic Epilepsy v0.1073 YWHAG Zornitza Stark Gene: ywhag has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1073 YWHAG Zornitza Stark Phenotypes for gene: YWHAG were changed from to Developmental and epileptic encephalopathy 56, (MIMI#617665)
Genetic Epilepsy v0.1072 YWHAG Zornitza Stark Publications for gene: YWHAG were set to 33393734; 33590706; 31926053; 33767733
Genetic Epilepsy v0.1072 YWHAG Zornitza Stark Publications for gene: YWHAG were set to 33393734; 33590706; 31926053; 33767733
Genetic Epilepsy v0.1072 YWHAG Zornitza Stark Publications for gene: YWHAG were set to
Genetic Epilepsy v0.1071 YWHAG Zornitza Stark Mode of inheritance for gene: YWHAG was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1070 YWHAG Zornitza Stark reviewed gene: YWHAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 33393734, 33590706, 31926053, 33767733; Phenotypes: Developmental and epileptic encephalopathy 56, (MIMI#617665); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1070 ANKRD17 Paul De Fazio changed review comment from: 34 predominantly LoF variants reported - 29 de novo, 1 inherited from an affected parent, 1 inherited from a suspected mosaic parent. Main phenotypes were dev delay/ID, motor delay, and speech delay.; to: 34 predominantly LoF variants reported - 29 de novo, 1 inherited from an affected parent, 1 inherited from a suspected mosaic parent. Main phenotypes were dev delay/ID, motor delay, and speech delay. Epilepsy reported in 9/33.
Genetic Epilepsy v0.1070 ANKRD17 Paul De Fazio reviewed gene: ANKRD17: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909992; Phenotypes: Intellectual disability, speech delay, and dysmorphism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Genetic Epilepsy v0.1070 PPIL1 Zornitza Stark Phenotypes for gene: PPIL1 were changed from Pontocerebellar hypoplasia; microcephaly; seizures to Pontocerebellar hypoplasia, type 14, MIM# 619301; microcephaly; seizures
Genetic Epilepsy v0.1069 PPIL1 Zornitza Stark edited their review of gene: PPIL1: Changed phenotypes: Pontocerebellar hypoplasia, type 14, MIM# 619301, microcephaly, seizures
Genetic Epilepsy v0.1069 KCNQ5 Zornitza Stark Marked gene: KCNQ5 as ready
Genetic Epilepsy v0.1069 KCNQ5 Zornitza Stark Gene: kcnq5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1069 KCNQ5 Zornitza Stark Phenotypes for gene: KCNQ5 were changed from to Mental retardation, autosomal dominant 46, MIM# 617601
Genetic Epilepsy v0.1068 KCNQ5 Zornitza Stark Publications for gene: KCNQ5 were set to
Genetic Epilepsy v0.1067 KCNQ5 Zornitza Stark Mode of inheritance for gene: KCNQ5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1066 KCNQ5 Zornitza Stark reviewed gene: KCNQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: 28669405, 30359776; Phenotypes: Mental retardation, autosomal dominant 46, MIM# 617601; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1066 TBC1D2B Zornitza Stark Marked gene: TBC1D2B as ready
Genetic Epilepsy v0.1066 TBC1D2B Zornitza Stark Gene: tbc1d2b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1066 CACNA1D Zornitza Stark Marked gene: CACNA1D as ready
Genetic Epilepsy v0.1066 CACNA1D Zornitza Stark Gene: cacna1d has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1066 CACNA1D Zornitza Stark Phenotypes for gene: CACNA1D were changed from to Primary aldosteronism, seizures, and neurologic abnormalities MIM#615474
Genetic Epilepsy v0.1065 CACNA1D Zornitza Stark Publications for gene: CACNA1D were set to
Genetic Epilepsy v0.1064 CACNA1D Zornitza Stark Mode of inheritance for gene: CACNA1D was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1063 VPS4A Zornitza Stark Phenotypes for gene: VPS4A were changed from Neurodevelopmental disorder to CIMDAG syndrome MIM# 619273
Genetic Epilepsy v0.1062 VPS4A Zornitza Stark reviewed gene: VPS4A: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: CIMDAG syndrome MIM# 619273; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1062 CACNA1D Teresa Zhao reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: Other; Publications: 25620733, 28472301, 31139143; Phenotypes: Primary aldosteronism, seizures, and neurologic abnormalities MIM#615474; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic Epilepsy v0.1062 CAMK2A Zornitza Stark Marked gene: CAMK2A as ready
Genetic Epilepsy v0.1062 CAMK2A Zornitza Stark Gene: camk2a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1062 CAMK2A Zornitza Stark Mode of pathogenicity for gene: CAMK2A was changed from None to Other
Genetic Epilepsy v0.1061 CAMK2A Zornitza Stark Classified gene: CAMK2A as Green List (high evidence)
Genetic Epilepsy v0.1061 CAMK2A Zornitza Stark Gene: camk2a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1060 CAMK2A Elena Savva edited their review of gene: CAMK2A: Added comment: Chia (2018): 2 hom sibs with a missense, carrier parents/sibs normal. Patients had ID and additional features of hypotonia, myoclonic seizures. Supported by functional work showing loss of function
Isolated example of AR inheritance, all other reports are AD

Rudolf (2020): 1 de novo missense patient with focal epilepsy of childhood, autism and ID

Akita (2018): seizures reported in 3/5 patients with de novo variants. GOF through loss of autoinhibition-> constitutive activation

Sources: Literature; Changed mode of pathogenicity: Other
Genetic Epilepsy v0.1060 CAMK2A Elena Savva gene: CAMK2A was added
gene: CAMK2A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CAMK2A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CAMK2A were set to PMID: 32600977; 29784083; 29560374
Phenotypes for gene: CAMK2A were set to ?Mental retardation, autosomal recessive 63 MIM#618095; Mental retardation, autosomal dominant 53 MIM#617798
Review for gene: CAMK2A was set to GREEN
Added comment: Chia (2018): 2 hom sibs with a missense, supported by functional work, carrier parents/sibs normal. Patients had ID and additional features of hypotonia, myoclonic seizures.
Isolated example of AR inheritance, all other reports are AD

Rudolf (2020): 1 de novo missense patient with focal epilepsy of childhood, autism and ID

Akita (2018): seizures reported in 3/5 patients with de novo variants
Sources: Literature
Genetic Epilepsy v0.1060 CHD3 Zornitza Stark Marked gene: CHD3 as ready
Genetic Epilepsy v0.1060 CHD3 Zornitza Stark Added comment: Comment when marking as ready: Patient identified through our service where seizures were the presenting feature.
Genetic Epilepsy v0.1060 CHD3 Zornitza Stark Gene: chd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1060 CHD3 Zornitza Stark Classified gene: CHD3 as Green List (high evidence)
Genetic Epilepsy v0.1060 CHD3 Zornitza Stark Gene: chd3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1059 YIPF5 Zornitza Stark Phenotypes for gene: YIPF5 were changed from Neonatal diabetes; microcephaly; seizures to Microcephaly, epilepsy, and diabetes syndrome 2 , MIM#619278
Genetic Epilepsy v0.1058 YIPF5 Zornitza Stark edited their review of gene: YIPF5: Changed phenotypes: Microcephaly, epilepsy, and diabetes syndrome 2 , MIM#619278
Genetic Epilepsy v0.1058 CHD3 Naomi Baker gene: CHD3 was added
gene: CHD3 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CHD3 were set to PMID: 32483341
Phenotypes for gene: CHD3 were set to Snijders Blok-Campeau syndrome MIM#618205
Review for gene: CHD3 was set to GREEN
Added comment: A review of the phenotypic findings in two cohorts of Snijders Blok-Campeau syndrome patients, indicated that 16% (9/55) of patients had seizures.
Sources: Literature
Genetic Epilepsy v0.1058 EMC10 Zornitza Stark Marked gene: EMC10 as ready
Genetic Epilepsy v0.1058 EMC10 Zornitza Stark Gene: emc10 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1058 EMC10 Zornitza Stark Classified gene: EMC10 as Green List (high evidence)
Genetic Epilepsy v0.1058 EMC10 Zornitza Stark Gene: emc10 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1057 EMC10 Zornitza Stark gene: EMC10 was added
gene: EMC10 was added to Genetic Epilepsy. Sources: Literature
founder 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, MIM# 619264
Review for gene: EMC10 was set to GREEN
Added comment: Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders.

PMID 32869858 : One Saudi family with 2 affected individuals with mild ID, speech delay, and GDD. WES and Sanger sequencing revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 . Variant segregated within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients.

PMID 33531666: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).
Sources: Literature
Genetic Epilepsy v0.1056 GRIA3 Zornitza Stark Marked gene: GRIA3 as ready
Genetic Epilepsy v0.1056 GRIA3 Zornitza Stark Gene: gria3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1056 GRIA3 Zornitza Stark Classified gene: GRIA3 as Green List (high evidence)
Genetic Epilepsy v0.1056 GRIA3 Zornitza Stark Gene: gria3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1055 GRIA3 Zornitza Stark gene: GRIA3 was added
gene: GRIA3 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: GRIA3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GRIA3 were set to 32977175; 17989220
Phenotypes for gene: GRIA3 were set to Intellectual developmental disorder, X-linked, syndromic, Wu type (MIM#300699)
Review for gene: GRIA3 was set to GREEN
Added comment: PMID: 32977175;17989220: Around 20 individuals with ID reported, mostly males inherited from unaffected mother. Missense have been shown to result in either protein expression reduction or minimal or no channel current, only a couple PTC reported. ID ranges from mild to severe, epilepsy has not been reported in all patients (6/19 by PMID: 32977175), and different types of epilepsy were found.
Sources: Expert Review
Genetic Epilepsy v0.1054 NCDN Alison Yeung Marked gene: NCDN as ready
Genetic Epilepsy v0.1054 NCDN Alison Yeung Gene: ncdn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1054 NCDN Alison Yeung Classified gene: NCDN as Green List (high evidence)
Genetic Epilepsy v0.1054 NCDN Alison Yeung Gene: ncdn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1053 NCDN Ain Roesley gene: NCDN was added
gene: NCDN was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to neurodevelopmental delay, intellectual disability, and epilepsy
Penetrance for gene: NCDN were set to unknown
Review for gene: NCDN was set to GREEN
Added comment: 4x families all missense and de novo except for 1 consag family where 3 affecteds were homozygous and carrier parents unaffected

ID ranged from mild to severe
3/4 probands had seizures
only 3 affecteds had MRI done, with 1 delayed myelination

in vitro studies were done
Sources: Literature
Genetic Epilepsy v0.1053 SLC45A1 Zornitza Stark reviewed gene: SLC45A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28434495; Phenotypes: Intellectual developmental disorder with neuropsychiatric features, MIM# 617532; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1053 WDR62 Zornitza Stark Phenotypes for gene: WDR62 were changed from Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435 to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435
Genetic Epilepsy v0.1053 WDR62 Zornitza Stark Phenotypes for gene: WDR62 were changed from Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM#604317 to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317; MONDO:0011435
Genetic Epilepsy v0.1052 WDR62 Zornitza Stark edited their review of gene: WDR62: Changed phenotypes: Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, MIM# 604317, MONDO:0011435
Genetic Epilepsy v0.1052 STAMBP Zornitza Stark Marked gene: STAMBP as ready
Genetic Epilepsy v0.1052 STAMBP Zornitza Stark Gene: stambp has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1052 STAMBP Zornitza Stark Phenotypes for gene: STAMBP were changed from to Microcephaly-capillary malformation syndrome, MIM# 614261; MONDO:0013659
Genetic Epilepsy v0.1051 STAMBP Zornitza Stark Publications for gene: STAMBP were set to
Genetic Epilepsy v0.1050 STAMBP Zornitza Stark Mode of inheritance for gene: STAMBP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1049 STAMBP Zornitza Stark reviewed gene: STAMBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23542699, 31638258, 29907875, 27531570, 25692795, 25266620; Phenotypes: Microcephaly-capillary malformation syndrome, MIM# 614261, MONDO:0013659; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1049 IER3IP1 Zornitza Stark Marked gene: IER3IP1 as ready
Genetic Epilepsy v0.1049 IER3IP1 Zornitza Stark Gene: ier3ip1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1049 IER3IP1 Zornitza Stark Phenotypes for gene: IER3IP1 were changed from to Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231; Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647
Genetic Epilepsy v0.1048 IER3IP1 Zornitza Stark Publications for gene: IER3IP1 were set to
Genetic Epilepsy v0.1047 IER3IP1 Zornitza Stark Mode of inheritance for gene: IER3IP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1046 IER3IP1 Zornitza Stark reviewed gene: IER3IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21835305, 22991235, 24138066, 28711742; Phenotypes: Microcephaly, epilepsy, and diabetes syndrome, MIM# 614231, Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome, MONDO:0013647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1046 CUL3 Zornitza Stark Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate to Neurodevelopmental disorder with or without autism or seizures, MIM# 619239; Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate
Genetic Epilepsy v0.1045 CUL3 Zornitza Stark reviewed gene: CUL3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with or without autism or seizures 619239; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1045 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Kohlschutter-Tonz syndrome-like, MIM# 619229; Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression to Kohlschutter-Tonz syndrome-like, MIM# 619229; Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression
Genetic Epilepsy v0.1044 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Kohlschutter-Tonz syndrome-like, MIM# 619229; Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression to Kohlschutter-Tonz syndrome-like, MIM# 619229; Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression
Genetic Epilepsy v0.1044 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression to Kohlschutter-Tonz syndrome-like, MIM# 619229; Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression
Genetic Epilepsy v0.1043 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.

Note Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228 is a milder, allelic disorder.; Changed phenotypes: Kohlschutter-Tonz syndrome-like, MIM# 619229
Genetic Epilepsy v0.1043 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression to Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression
Genetic Epilepsy v0.1042 SATB1 Zornitza Stark reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1042 DOCK7 Zornitza Stark Marked gene: DOCK7 as ready
Genetic Epilepsy v0.1042 DOCK7 Zornitza Stark Gene: dock7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1042 DOCK7 Zornitza Stark Publications for gene: DOCK7 were set to
Genetic Epilepsy v0.1041 DOCK7 Zornitza Stark Phenotypes for gene: DOCK7 were changed from to Developmental and epileptic encephalopathy 23 MIM#615859; MONDO:0014371
Genetic Epilepsy v0.1040 DOCK7 Zornitza Stark Mode of inheritance for gene: DOCK7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1039 DOCK7 Paul De Fazio reviewed gene: DOCK7: Rating: GREEN; Mode of pathogenicity: None; Publications: 24814191, 30771731, 30807358; Phenotypes: Developmental and epileptic encephalopathy 23 MIM#615859; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v0.1039 SLC1A4 Zornitza Stark Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657; MONDO:0014725
Genetic Epilepsy v0.1038 SLC1A4 Zornitza Stark Tag founder tag was added to gene: SLC1A4.
Genetic Epilepsy v0.1038 SLC1A4 Zornitza Stark changed review comment from: Multiple affected individuals reported in the literature, seizures/EE are part of the phenotype. While initial reports identified a recurrent missense variant in individuals of Ashkenazi Jewish ancestry, there have been more recent reports of individuals from other ethnic backgrounds with different variants
Sources: Expert list; to: Multiple affected individuals reported in the literature, seizures/EE are part of the phenotype. While initial reports identified a recurrent missense variant in individuals of Ashkenazi Jewish ancestry (p.Glu256Lys), there have been more recent reports of individuals from other ethnic backgrounds with different variants
Sources: Expert list
Genetic Epilepsy v0.1038 HACE1 Zornitza Stark Marked gene: HACE1 as ready
Genetic Epilepsy v0.1038 HACE1 Zornitza Stark Gene: hace1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1038 HACE1 Zornitza Stark Phenotypes for gene: HACE1 were changed from to Spastic paraplegia and psychomotor retardation with or without seizures, 616756; MONDO:0014764
Genetic Epilepsy v0.1037 HACE1 Zornitza Stark Publications for gene: HACE1 were set to
Genetic Epilepsy v0.1036 HACE1 Zornitza Stark Mode of inheritance for gene: HACE1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1035 HACE1 Zornitza Stark reviewed gene: HACE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26424145, 26437029, 31321300; Phenotypes: Spastic paraplegia and psychomotor retardation with or without seizures, 616756, MONDO:0014764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1035 AIMP1 Zornitza Stark Marked gene: AIMP1 as ready
Genetic Epilepsy v0.1035 AIMP1 Zornitza Stark Gene: aimp1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1035 AIMP1 Zornitza Stark Phenotypes for gene: AIMP1 were changed from to Leukodystrophy, hypomyelinating, 3, MIM# 260600
Genetic Epilepsy v0.1034 AIMP1 Zornitza Stark Publications for gene: AIMP1 were set to
Genetic Epilepsy v0.1033 AIMP1 Zornitza Stark Mode of inheritance for gene: AIMP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1032 AIMP1 Zornitza Stark reviewed gene: AIMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21092922, 24958424, 33402283, 32531460, 30486714, 30477741; Phenotypes: Leukodystrophy, hypomyelinating, 3, MIM# 260600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1032 DYRK1A Zornitza Stark Marked gene: DYRK1A as ready
Genetic Epilepsy v0.1032 DYRK1A Zornitza Stark Gene: dyrk1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1032 DYRK1A Zornitza Stark Tag SV/CNV tag was added to gene: DYRK1A.
Genetic Epilepsy v0.1032 DYRK1A Zornitza Stark Phenotypes for gene: DYRK1A were changed from to Mental retardation, autosomal dominant 7, MIM# 614104; MONDO:0013578
Genetic Epilepsy v0.1031 DYRK1A Zornitza Stark Publications for gene: DYRK1A were set to
Genetic Epilepsy v0.1030 DYRK1A Zornitza Stark Mode of inheritance for gene: DYRK1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1029 DYRK1A Zornitza Stark reviewed gene: DYRK1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 25707398, 21294719, 23160955, 23099646, 33159716; Phenotypes: Mental retardation, autosomal dominant 7, MIM# 614104, MONDO:0013578; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1029 NHLRC1 Zornitza Stark Marked gene: NHLRC1 as ready
Genetic Epilepsy v0.1029 NHLRC1 Zornitza Stark Gene: nhlrc1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1029 NHLRC1 Zornitza Stark Phenotypes for gene: NHLRC1 were changed from to Epilepsy, progressive myoclonic 2B (Lafora) 254780
Genetic Epilepsy v0.1028 NHLRC1 Zornitza Stark Publications for gene: NHLRC1 were set to
Genetic Epilepsy v0.1027 NHLRC1 Zornitza Stark Mode of inheritance for gene: NHLRC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1026 NHLRC1 Zornitza Stark reviewed gene: NHLRC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21505799, 12958597; Phenotypes: Epilepsy, progressive myoclonic 2B (Lafora) 254780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1026 SPTAN1 Zornitza Stark Marked gene: SPTAN1 as ready
Genetic Epilepsy v0.1026 SPTAN1 Zornitza Stark Gene: sptan1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1026 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from to Developmental and epileptic encephalopathy 5, MIM# 613477
Genetic Epilepsy v0.1025 SPTAN1 Zornitza Stark Publications for gene: SPTAN1 were set to
Genetic Epilepsy v0.1024 SPTAN1 Zornitza Stark Mode of inheritance for gene: SPTAN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1023 SPTAN1 Zornitza Stark reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20493457, 22258530, 32811770; Phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1023 SLC7A6OS Zornitza Stark Phenotypes for gene: SLC7A6OS were changed from Progressive myoclonus epilepsy to Epilepsy, progressive myoclonic, 12, MIM# 619191; Progressive myoclonus epilepsy
Genetic Epilepsy v0.1022 SLC7A6OS Zornitza Stark edited their review of gene: SLC7A6OS: Changed phenotypes: Epilepsy, progressive myoclonic, 12, MIM# 619191, Progressive myoclonus epilepsy
Genetic Epilepsy v0.1022 UBR7 Zornitza Stark Phenotypes for gene: UBR7 were changed from Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features to Li-Campeau syndrome, MIM# 619189; Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Genetic Epilepsy v0.1021 UBR7 Zornitza Stark edited their review of gene: UBR7: Changed phenotypes: Li-Campeau syndrome, MIM# 619189, Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features
Genetic Epilepsy v0.1021 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy
Genetic Epilepsy v0.1020 FGF13 Zornitza Stark edited their review of gene: FGF13: Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual disability, epilepsy
Genetic Epilepsy v0.1020 PCDH19 Zornitza Stark Marked gene: PCDH19 as ready
Genetic Epilepsy v0.1020 PCDH19 Zornitza Stark Gene: pcdh19 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1020 PCDH19 Zornitza Stark Phenotypes for gene: PCDH19 were changed from to Epileptic encephalopathy, early infantile, 9 300088; PCDH19-related epilepsy (early seizure onset, generalised or focused seizures); cognitive impairment
Genetic Epilepsy v0.1019 PCDH19 Zornitza Stark Publications for gene: PCDH19 were set to 18469813; 30287595
Genetic Epilepsy v0.1019 PCDH19 Zornitza Stark Publications for gene: PCDH19 were set to
Genetic Epilepsy v0.1018 PCDH19 Zornitza Stark Mode of inheritance for gene: PCDH19 was changed from Unknown to Other
Genetic Epilepsy v0.1017 PCDH19 Zornitza Stark reviewed gene: PCDH19: Rating: GREEN; Mode of pathogenicity: None; Publications: 18469813, 30287595; Phenotypes: Epileptic encephalopathy, early infantile, 9 300088, PCDH19-related epilepsy (early seizure onset, generalised or focused seizures), cognitive impairment; Mode of inheritance: Other
Genetic Epilepsy v0.1017 SLC7A6OS Zornitza Stark Marked gene: SLC7A6OS as ready
Genetic Epilepsy v0.1017 SLC7A6OS Zornitza Stark Gene: slc7a6os has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1017 SLC7A6OS Zornitza Stark gene: SLC7A6OS was added
gene: SLC7A6OS was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.1016 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression to Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression
Genetic Epilepsy v0.1016 SATB1 Zornitza Stark Marked gene: SATB1 as ready
Genetic Epilepsy v0.1016 SATB1 Zornitza Stark Gene: satb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1016 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Neurodevelopmental disorders to Neurodevelopmental disorder; Intellectual disability; Epilepsy; Microcephaly; Regression
Genetic Epilepsy v0.1015 SATB1 Zornitza Stark Classified gene: SATB1 as Green List (high evidence)
Genetic Epilepsy v0.1015 SATB1 Zornitza Stark Gene: satb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1014 CCDC186 Zornitza Stark Marked gene: CCDC186 as ready
Genetic Epilepsy v0.1014 CCDC186 Zornitza Stark Gene: ccdc186 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1014 SATB1 Elena Savva gene: SATB1 was added
gene: SATB1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SATB1 were set to PMID: 33513338; 33057194
Phenotypes for gene: SATB1 were set to Neurodevelopmental disorders
Mode of pathogenicity for gene: SATB1 was set to Other
Review for gene: SATB1 was set to GREEN
Added comment: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease

Functional studies show missense variants have a STRONGER binding to downstream targets
Sources: Literature
Genetic Epilepsy v0.1014 KCNN2 Sebastian Lunke Marked gene: KCNN2 as ready
Genetic Epilepsy v0.1014 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1014 KCNN2 Sebastian Lunke Phenotypes for gene: KCNN2 were changed from 33242881 to Neurological Disorder; Developmental Delay; Seizures
Genetic Epilepsy v0.1013 KCNN2 Sebastian Lunke Classified gene: KCNN2 as Green List (high evidence)
Genetic Epilepsy v0.1013 KCNN2 Sebastian Lunke Gene: kcnn2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1012 KCNN2 Ain Roesley gene: KCNN2 was added
gene: KCNN2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KCNN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNN2 were set to 33242881
Phenotypes for gene: KCNN2 were set to 33242881
Penetrance for gene: KCNN2 were set to unknown
Review for gene: KCNN2 was set to GREEN
Added comment: - 11 probands all de novo except for 1 mother-daughter pair.
- a mix of null and missense variants
- 2/11 with microcephaly, 10/11 motor delay, 7/11 language delay (excluding 2 with regression), all with varying degrees of ID, 3/11 seizures, 7/11 movement disorder, 4/11 cerebellar ataxia, 6/11 MRI anomalies

additional variants were noted in 2 patients: 1x cHet for variants in MED12L and 1x de novo TNK2 variant

patch clamp functional studies were also done
Sources: Literature
Genetic Epilepsy v0.1012 CCDC186 Zornitza Stark gene: CCDC186 was added
gene: CCDC186 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.1011 ALG14 Zornitza Stark Marked gene: ALG14 as ready
Genetic Epilepsy v0.1011 ALG14 Zornitza Stark Gene: alg14 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1011 ALG14 Zornitza Stark Classified gene: ALG14 as Green List (high evidence)
Genetic Epilepsy v0.1011 ALG14 Zornitza Stark Gene: alg14 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1010 ALG14 Zornitza Stark gene: ALG14 was added
gene: ALG14 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 30221345; 23404334; 28733338
Phenotypes for gene: ALG14 were set to intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (IDDEBF), MIM#619031; Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036
Review for gene: ALG14 was set to GREEN
Added comment: 5 individuals from unrelated families described in the literature: one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype; and three more with a neurodegenerative phenotype.
Sources: Expert Review
Genetic Epilepsy v0.1009 ANKRD11 Zornitza Stark Marked gene: ANKRD11 as ready
Genetic Epilepsy v0.1009 ANKRD11 Zornitza Stark Gene: ankrd11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1009 ANKRD11 Zornitza Stark Classified gene: ANKRD11 as Green List (high evidence)
Genetic Epilepsy v0.1009 ANKRD11 Zornitza Stark Gene: ankrd11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1008 ANKRD11 Zornitza Stark gene: ANKRD11 was added
gene: ANKRD11 was added to Genetic Epilepsy. 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; 30182498
Phenotypes for gene: ANKRD11 were set to KBG syndrome, MIM#148050
Review for gene: ANKRD11 was set to GREEN
Added comment: Seizures are a prominent feature in a subset of individuals with KBG syndrome.
Sources: Expert Review
Genetic Epilepsy v0.1007 NBEA Zornitza Stark Phenotypes for gene: NBEA were changed from Intellectual disability; Seizures to Neurodevelopmental disorder with or without early-onset generalized epilepsy, MIM# 619157; Intellectual disability; Seizures
Genetic Epilepsy v0.1006 NBEA Zornitza Stark edited their review of gene: NBEA: Changed phenotypes: Neurodevelopmental disorder with or without early-onset generalized epilepsy, MIM# 619157, Intellectual disability, Seizures
Genetic Epilepsy v0.1006 HNRNPU Zornitza Stark Phenotypes for gene: HNRNPU were changed from Epileptic encephalopathy, early infantile, 54, MIM#617391 to Developmental and epileptic encephalopathy 54 MIM# 617391
Genetic Epilepsy v0.1005 SCAMP5 Zornitza Stark Mode of pathogenicity for gene: SCAMP5 was changed from None to Other
Genetic Epilepsy v0.1004 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Changed mode of pathogenicity: Other
Genetic Epilepsy v0.1004 SCAMP5 Zornitza Stark Publications for gene: SCAMP5 were set to 31439720
Genetic Epilepsy v0.1003 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Added comment: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp.

The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed rating: GREEN; Changed publications: 31439720, 33390987
Genetic Epilepsy v0.1003 ZNF526 Zornitza Stark Marked gene: ZNF526 as ready
Genetic Epilepsy v0.1003 ZNF526 Zornitza Stark Gene: znf526 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1003 ZNF526 Zornitza Stark Classified gene: ZNF526 as Green List (high evidence)
Genetic Epilepsy v0.1003 ZNF526 Zornitza Stark Gene: znf526 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1002 ZNF526 Zornitza Stark gene: ZNF526 was added
gene: ZNF526 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ZNF526 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF526 were set to 21937992; 25558065; 33397746
Phenotypes for gene: ZNF526 were set to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Review for gene: ZNF526 was set to GREEN
Added comment: - PMID: 21937992 (2011) - Two unrelated families (with 4 affected individuals in each) with non-syndromic ID (mild or moderate, respectively) identified harbouring different biallelic missense variants in the ZNF526 gene.

- PMID: 25558065 (2015) - One family with ID, Noonan-like facies, pulmonary stenosis and a homozygous missense variant in this gene. No further details provided.

- PMID: 33397746 (2021) - Five individuals from four unrelated families with homozygous ZNF526 variants. Four harboured truncating variants, and were all affected by profound DD and severe ID, microcephaly (ranging from -4 SD to -8 SD), bilateral progressive cataracts, hypertonic-dystonic movements, epilepsy and brain MRI anomalies. The fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe ID, and normal brain MRI. Zebrafish model demonstrated brain and eye malformations resembling findings seen in the human holoprosencephaly spectrum
Sources: Literature
Genetic Epilepsy v0.1001 SCAMP5 Emma Goss Deleted their review
Genetic Epilepsy v0.1001 SCAMP5 Emma Goss changed review comment from: An additional four unrelated patients with the previously reported missense variant de
novo SCAMP5 variant (p. Gly180Trp) from three countries,
including detailed descriptions of initial clinical presentations
and long-term follow-up (ranged from 1 to 33 years).

: Epilepsy, severe developmental delay, abnormal neurological exam findings,
with or without ASD or variably dysmorphic features and were common in patients with
SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI
findings were not consistent, but diverse and nonspecific. The motor ability of patients with
Edited by:
Tieliu Shi,
East China Normal University, China
Reviewed by:
Juliet Taylor,
The University of Melbourne, Australia
Chin Moi Chow,
The University of Sydney, Australia
*Correspondence:
Xiaodong Wang
xdwang@ciphergene.com
Zhixian Yang
zhixian.yang@163.com
Specialty section:
This article was submitted to
Translational Pharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 26 August 2020
Accepted: 11 November 2020
Published: 18 December 2020
Citation:
Jiao X, Morleo M, Nigro V, Torella A,
D’Arrigo S, Ciaccio C, Pantaleoni C,
Gong P, Grand K, Sanchez-Lara PA,
Krier J, Fieg E, Stergachis A, Wang X
and Yang Z (2020) Identification of an
Identical de Novo SCAMP5 Missense
Variant in Four Unrelated Patients With
Seizures and Severe
Neurodevelopmental Delay.
Front. Pharmacol. 11:599191.
doi: 10.3389/fphar.2020.599191
Frontiers in Pharmacology | www.frontiersin.org 1 December 2020 | Volume 11 | Article 599191
ORIGINAL RESEARCH
published: 18 December 2020
doi: 10.3389/fphar.2020.599191
heterozygous SCAMP5 variant might have a regressive course; language development
was more severely affected.; to: An additional four unrelated patients with the previously reported missense variant de
novo SCAMP5 variant (p. Gly180Trp) from three countries,
including detailed descriptions of initial clinical presentations
and long-term follow-up (ranged from 1 to 33 years).

Epilepsy, severe developmental delay, abnormal neurological exam findings,
with or without ASD or variably dysmorphic features and were common in patients with
SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI
findings were not consistent, but diverse and nonspecific.
heterozygous SCAMP5 variant might have a regressive course.
Genetic Epilepsy v0.1001 SCAMP5 Emma Goss reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1001 CELF2 Zornitza Stark Marked gene: CELF2 as ready
Genetic Epilepsy v0.1001 CELF2 Zornitza Stark Gene: celf2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1001 CELF2 Zornitza Stark Classified gene: CELF2 as Green List (high evidence)
Genetic Epilepsy v0.1001 CELF2 Zornitza Stark Gene: celf2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1000 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.999 FGF13 Zornitza Stark Marked gene: FGF13 as ready
Genetic Epilepsy v0.999 FGF13 Zornitza Stark Gene: fgf13 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.999 FGF13 Zornitza Stark Classified gene: FGF13 as Green List (high evidence)
Genetic Epilepsy v0.999 FGF13 Zornitza Stark Gene: fgf13 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.998 FGF13 Zornitza Stark gene: FGF13 was added
gene: FGF13 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: FGF13 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Intellectual disability; epilepsy
Review for gene: FGF13 was set to GREEN
Added comment: Two sibling pairs and three unrelated males reported who presented in infancy with intractable focal seizures and severe developmental delay. The variants were located in the N-terminal domain of the A isoform of FGF13/FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Nav channels. Functional characterization of mutant FHF2A co-expressed with wild-type Nav1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants.
Sources: Literature
Genetic Epilepsy v0.997 UBR7 Zornitza Stark Marked gene: UBR7 as ready
Genetic Epilepsy v0.997 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.997 UBR7 Zornitza Stark Classified gene: UBR7 as Green List (high evidence)
Genetic Epilepsy v0.997 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.996 UBR7 Zornitza Stark gene: UBR7 was added
gene: UBR7 was added to Genetic Epilepsy. Sources: Literature
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: Seven individuals from 6 unrelated families. 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). Physical examination revealed various dysmorphic features, including prominent forehead (3/7), hypertelorism (4/7), telecanthus (1/7), epicanthus(1/7), downslanting palpebral fissures (3/7), thick eyebrow (1/7), low-set ears (3/7), long philtrum (2/7), unilateral single transverse palmar crease (1/7), and hypertrichosis (1/7).
Sources: Literature
Genetic Epilepsy v0.995 CAMK2B Zornitza Stark Marked gene: CAMK2B as ready
Genetic Epilepsy v0.995 CAMK2B Zornitza Stark Gene: camk2b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.995 CAMK2B Zornitza Stark Classified gene: CAMK2B as Green List (high evidence)
Genetic Epilepsy v0.995 CAMK2B Zornitza Stark Gene: camk2b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.994 CAMK2B Zornitza Stark gene: CAMK2B was added
gene: CAMK2B was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CAMK2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK2B were set to 29100089; 29560374; 32875707
Phenotypes for gene: CAMK2B were set to Mental retardation, autosomal dominant 54, MIM# 617799
Review for gene: CAMK2B was set to GREEN
Added comment: More than 10 unrelated individuals reported, at least 5 had seizures.
Sources: Expert Review
Genetic Epilepsy v0.993 RALGAPB Seb Lunke Marked gene: RALGAPB as ready
Genetic Epilepsy v0.993 RALGAPB Seb Lunke Gene: ralgapb has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.993 RALGAPB Seb Lunke Classified gene: RALGAPB as Amber List (moderate evidence)
Genetic Epilepsy v0.993 RALGAPB Seb Lunke Gene: ralgapb has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.992 RALGAPB Elena Savva gene: RALGAPB was added
gene: RALGAPB was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RALGAPB were set to PMID: 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.
Sources: Literature
Genetic Epilepsy v0.992 CPA6 Zornitza Stark Mode of inheritance for gene: CPA6 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.991 CPA6 Zornitza Stark Classified gene: CPA6 as Amber List (moderate evidence)
Genetic Epilepsy v0.991 CPA6 Zornitza Stark Gene: cpa6 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.990 CPA6 Zornitza Stark changed review comment from: Homozygous p.A270V variant reported in four siblings with Febrile seizures, familial, 11 (MIM 614418)(PMID:21922598), some functional data. Also note one of the heterozygous individuals initially reported was subsequently found to have a second missense variant, PMID 23105115.

Disputed association between mono allelic variants and disease.; to: Homozygous p.A270V variant reported in four siblings with Febrile seizures, familial, 11 (MIM 614418)(PMID:21922598), some functional data. Present in gnomad as hets but no homs. Also note one of the heterozygous individuals initially reported was subsequently found to have a second missense variant, PMID 23105115.

Disputed association between mono allelic variants and disease.
Genetic Epilepsy v0.990 CPA6 Zornitza Stark edited their review of gene: CPA6: Added comment: Homozygous p.A270V variant reported in four siblings with Febrile seizures, familial, 11 (MIM 614418)(PMID:21922598), some functional data. Also note one of the heterozygous individuals initially reported was subsequently found to have a second missense variant, PMID 23105115.

Disputed association between mono allelic variants and disease.; Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.990 CPA6 Elena Savva reviewed gene: CPA6: Rating: RED; Mode of pathogenicity: None; Publications: PMID:25875328, 21922598, 23105115, 32207733; Phenotypes: Epilepsy, familial temporal lobe, 5 MIM#614417, Febrile seizures, familial, 11 MIM#614418; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.990 KCNQ3 Zornitza Stark Marked gene: KCNQ3 as ready
Genetic Epilepsy v0.990 KCNQ3 Zornitza Stark Gene: kcnq3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.990 KCNQ3 Zornitza Stark Phenotypes for gene: KCNQ3 were changed from to Seizures, benign neonatal, 2, MIM# 121201
Genetic Epilepsy v0.989 KCNQ3 Zornitza Stark Publications for gene: KCNQ3 were set to
Genetic Epilepsy v0.988 KCNQ3 Zornitza Stark Mode of inheritance for gene: KCNQ3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.987 KCNQ3 Zornitza Stark reviewed gene: KCNQ3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33337327, 25524373, 24851285; Phenotypes: Seizures, benign neonatal, 2, MIM# 121201; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.987 YIF1B Zornitza Stark Phenotypes for gene: YIF1B were changed from Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement to Kaya-Barakat-Masson syndrome, MIM# 619125; Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Genetic Epilepsy v0.986 YIF1B Zornitza Stark reviewed gene: YIF1B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Kaya-Barakat-Masson syndrome, MIM# 619125, Central hypotonia, Failure to thrive, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Spasticity, Abnormality of movement; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.986 WDR37 Zornitza Stark Marked gene: WDR37 as ready
Genetic Epilepsy v0.986 WDR37 Zornitza Stark Gene: wdr37 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.986 WDR37 Zornitza Stark Phenotypes for gene: WDR37 were changed from to Neurooculocardiogenitourinary syndrome, MIM# 618652
Genetic Epilepsy v0.985 WDR37 Zornitza Stark Publications for gene: WDR37 were set to
Genetic Epilepsy v0.984 WDR37 Zornitza Stark Mode of inheritance for gene: WDR37 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.983 WDR37 Zornitza Stark reviewed gene: WDR37: Rating: GREEN; Mode of pathogenicity: None; Publications: 31327508, 31327508; Phenotypes: Neurooculocardiogenitourinary syndrome, MIM# 618652; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.983 GAD1 Zornitza Stark Phenotypes for gene: GAD1 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 89, MIM# 619124
Genetic Epilepsy v0.982 GAD1 Zornitza Stark edited their review of gene: GAD1: Changed phenotypes: Developmental and epileptic encephalopathy 89, MIM# 619124
Genetic Epilepsy v0.982 ST3GAL5 Zornitza Stark Tag founder tag was added to gene: ST3GAL5.
Genetic Epilepsy v0.982 ST3GAL5 Zornitza Stark Marked gene: ST3GAL5 as ready
Genetic Epilepsy v0.982 ST3GAL5 Zornitza Stark Gene: st3gal5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.982 ST3GAL5 Zornitza Stark Phenotypes for gene: ST3GAL5 were changed from to Salt and pepper developmental regression syndrome 609056; GM3 synthase deficiency, MONDO:0018274; Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation)
Genetic Epilepsy v0.981 ST3GAL5 Zornitza Stark Publications for gene: ST3GAL5 were set to
Genetic Epilepsy v0.980 ST3GAL5 Zornitza Stark Mode of inheritance for gene: ST3GAL5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.979 ST3GAL5 Zornitza Stark reviewed gene: ST3GAL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23436467, 22990144, 15502825, 27232954, 30691927, 30688114, 30576498; Phenotypes: Salt and pepper developmental regression syndrome 609056, GM3 synthase deficiency, MONDO:0018274, Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.979 RFT1 Zornitza Stark Marked gene: RFT1 as ready
Genetic Epilepsy v0.979 RFT1 Zornitza Stark Gene: rft1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.979 RFT1 Zornitza Stark Phenotypes for gene: RFT1 were changed from to Congenital disorder of glycosylation, type In, MIM# 612015; RFT1-CDG, MONDO:0012783
Genetic Epilepsy v0.978 RFT1 Zornitza Stark Publications for gene: RFT1 were set to
Genetic Epilepsy v0.977 RFT1 Zornitza Stark Mode of inheritance for gene: RFT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.976 RFT1 Zornitza Stark reviewed gene: RFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18313027, 19701946, 19856127, 23111317, 30071302, 29923091, 27927990, 26892341; Phenotypes: Congenital disorder of glycosylation, type In, MIM# 612015, RFT1-CDG, MONDO:0012783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.976 PGAP3 Zornitza Stark Marked gene: PGAP3 as ready
Genetic Epilepsy v0.976 PGAP3 Zornitza Stark Gene: pgap3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.976 PGAP3 Zornitza Stark Classified gene: PGAP3 as Green List (high evidence)
Genetic Epilepsy v0.976 PGAP3 Zornitza Stark Gene: pgap3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.975 PGAP3 Zornitza Stark gene: PGAP3 was added
gene: PGAP3 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: PGAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGAP3 were set to 24439110; 29620724; 30345601; 30217754
Phenotypes for gene: PGAP3 were set to Hyperphosphatasia with mental retardation syndrome 4, MIM# 615716, MONDO:0014318
Review for gene: PGAP3 was set to GREEN
Added comment: Bi-allelic variants in this gene are associated with severe DD/ID, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies show increased serum alkaline phosphatase. More than 15 unrelated families reported.
Sources: Expert Review
Genetic Epilepsy v0.974 PGAP2 Zornitza Stark Marked gene: PGAP2 as ready
Genetic Epilepsy v0.974 PGAP2 Zornitza Stark Gene: pgap2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.974 PGAP2 Zornitza Stark Classified gene: PGAP2 as Amber List (moderate evidence)
Genetic Epilepsy v0.974 PGAP2 Zornitza Stark Gene: pgap2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.973 PGAP2 Zornitza Stark gene: PGAP2 was added
gene: PGAP2 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: PGAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGAP2 were set to 23561846; 23561847; 31805394; 29119105; 27871432
Phenotypes for gene: PGAP2 were set to Hyperphosphatasia with mental retardation syndrome 3, MIM# 614207, MONDO:0013628
Review for gene: PGAP2 was set to AMBER
Added comment: Bi-allelic variants in this gene are typically associated with severe DD/ID, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase, although presentations with milder ID have also been reported. More than 10 unrelated families reported.

Although HPMRS disorders are frequently associated with seizures, this seems a less frequently reported feature associated with variants in this gene.
Sources: Expert Review
Genetic Epilepsy v0.972 PIGV Zornitza Stark Marked gene: PIGV as ready
Genetic Epilepsy v0.972 PIGV Zornitza Stark Gene: pigv has been classified as Green List (High Evidence).
Genetic Epilepsy v0.972 PIGV Zornitza Stark Classified gene: PIGV as Green List (high evidence)
Genetic Epilepsy v0.972 PIGV Zornitza Stark Gene: pigv has been classified as Green List (High Evidence).
Genetic Epilepsy v0.971 PIGV Zornitza Stark gene: PIGV was added
gene: PIGV was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: PIGV was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGV were set to 20802478; 22315194; 28817240; 24129430
Phenotypes for gene: PIGV were set to Hyperphosphatasia with mental retardation syndrome 1, MIM# 239300, MONDO:0009398
Review for gene: PIGV was set to GREEN
Added comment: Bi-allelic variants in this gene are associated with intellectual disability, seizures, hypotonia, and hyperphosphatasia. Other features include facial dysmorphism, variable degrees of brachytelephalangy and congenital anomalies.
Sources: Expert Review
Genetic Epilepsy v0.970 PIGT Zornitza Stark Phenotypes for gene: PIGT were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398 to Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398, MONDO:0014165
Genetic Epilepsy v0.969 PIGT Zornitza Stark edited their review of gene: PIGT: Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398, MONDO:0014165
Genetic Epilepsy v0.969 PIGO Zornitza Stark Marked gene: PIGO as ready
Genetic Epilepsy v0.969 PIGO Zornitza Stark Gene: pigo has been classified as Green List (High Evidence).
Genetic Epilepsy v0.969 PIGO Zornitza Stark Phenotypes for gene: PIGO were changed from to Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882
Genetic Epilepsy v0.968 PIGO Zornitza Stark Publications for gene: PIGO were set to
Genetic Epilepsy v0.967 PIGO Zornitza Stark Mode of inheritance for gene: PIGO was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.966 PIGO Zornitza Stark reviewed gene: PIGO: Rating: GREEN; Mode of pathogenicity: None; Publications: 22683086, 31698102, 28900819, 28545593, 28337824; Phenotypes: Hyperphosphatasia with mental retardation syndrome 2, MIM# 614749, MONDO:0013882; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.966 PIGN Zornitza Stark Marked gene: PIGN as ready
Genetic Epilepsy v0.966 PIGN Zornitza Stark Gene: pign has been classified as Green List (High Evidence).
Genetic Epilepsy v0.966 PIGN Zornitza Stark Phenotypes for gene: PIGN were changed from to Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563
Genetic Epilepsy v0.965 PIGN Zornitza Stark Publications for gene: PIGN were set to
Genetic Epilepsy v0.964 PIGN Zornitza Stark Mode of inheritance for gene: PIGN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.963 PIGN Zornitza Stark reviewed gene: PIGN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21493957, 24253414, 26364997, 26394714, 33193741, 32585529, 29330547; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 1, MIM# 614080, MONDO:0013563; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.963 MPDU1 Zornitza Stark Marked gene: MPDU1 as ready
Genetic Epilepsy v0.963 MPDU1 Zornitza Stark Gene: mpdu1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.963 MPDU1 Zornitza Stark Phenotypes for gene: MPDU1 were changed from to Congenital disorder of glycosylation, type If, MIM# 609180; MPDU1-CDG, MONDO:0012211
Genetic Epilepsy v0.962 MPDU1 Zornitza Stark Publications for gene: MPDU1 were set to
Genetic Epilepsy v0.961 MPDU1 Zornitza Stark Mode of inheritance for gene: MPDU1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.960 MPDU1 Zornitza Stark reviewed gene: MPDU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11733564, 11733556, 31741824, 29721919; Phenotypes: Congenital disorder of glycosylation, type If, MIM# 609180, MPDU1-CDG, MONDO:0012211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.960 DPAGT1 Zornitza Stark Marked gene: DPAGT1 as ready
Genetic Epilepsy v0.960 DPAGT1 Zornitza Stark Gene: dpagt1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.960 DPAGT1 Zornitza Stark Phenotypes for gene: DPAGT1 were changed from to Congenital disorder of glycosylation, type Ij, MIM# 608093; DPAGT1-CDG MONDO:0011964
Genetic Epilepsy v0.959 DPAGT1 Zornitza Stark Publications for gene: DPAGT1 were set to
Genetic Epilepsy v0.958 DPAGT1 Zornitza Stark Mode of inheritance for gene: DPAGT1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.957 DPAGT1 Zornitza Stark reviewed gene: DPAGT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872255, 22492991, 22304930, 31153949, 30653653, 30117111; Phenotypes: Congenital disorder of glycosylation, type Ij, MIM# 608093, DPAGT1-CDG MONDO:0011964; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.957 PPIL1 Zornitza Stark Marked gene: PPIL1 as ready
Genetic Epilepsy v0.957 PPIL1 Zornitza Stark Gene: ppil1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.957 PPIL1 Zornitza Stark Classified gene: PPIL1 as Green List (high evidence)
Genetic Epilepsy v0.957 PPIL1 Zornitza Stark Gene: ppil1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.956 PPIL1 Zornitza Stark gene: PPIL1 was added
gene: PPIL1 was added to Genetic Epilepsy. Sources: Literature
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 Pontocerebellar hypoplasia; microcephaly; seizures
Review for gene: PPIL1 was set to GREEN
Added comment: 17 individuals from 9 unrelated families reported with bi-allelic variants in the gene and PCH, microcephaly, hypotonia, seizures, severe DD/ID. Mouse models support gene-disease association.
Sources: Literature
Genetic Epilepsy v0.955 CEP85L Zornitza Stark Marked gene: CEP85L as ready
Genetic Epilepsy v0.955 CEP85L Zornitza Stark Gene: cep85l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.955 CEP85L Zornitza Stark Classified gene: CEP85L as Green List (high evidence)
Genetic Epilepsy v0.955 CEP85L Zornitza Stark Gene: cep85l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.954 CEP85L Zornitza Stark Classified gene: CEP85L as Green List (high evidence)
Genetic Epilepsy v0.954 CEP85L Zornitza Stark Gene: cep85l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.953 CEP85L Zornitza Stark gene: CEP85L was added
gene: CEP85L was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CEP85L were set to 32097630
Phenotypes for gene: CEP85L were set to Lissencephaly, posterior predominant
Review for gene: CEP85L was set to GREEN
Added comment: PMID: 32097630 (2020) - 13 individuals 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.
Sources: Expert Review
Genetic Epilepsy v0.952 FBXO28 Zornitza Stark Marked gene: FBXO28 as ready
Genetic Epilepsy v0.952 FBXO28 Zornitza Stark Gene: fbxo28 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.952 FBXO28 Zornitza Stark Classified gene: FBXO28 as Green List (high evidence)
Genetic Epilepsy v0.952 FBXO28 Zornitza Stark Gene: fbxo28 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.951 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.950 KDM4B Zornitza Stark Marked gene: KDM4B as ready
Genetic Epilepsy v0.950 KDM4B Zornitza Stark Gene: kdm4b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.950 KDM4B Zornitza Stark Classified gene: KDM4B as Green List (high evidence)
Genetic Epilepsy v0.950 KDM4B Zornitza Stark Gene: kdm4b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.949 VPS4A Elena Savva Added comment: Comment on mode of pathogenicity: Dominant negative
Genetic Epilepsy v0.949 VPS4A Elena Savva Mode of pathogenicity for gene: VPS4A was changed from None to Other
Genetic Epilepsy v0.948 VPS4A Elena Savva Marked gene: VPS4A as ready
Genetic Epilepsy v0.948 VPS4A Elena Savva Added comment: Comment when marking as ready: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain. 1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance). Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly). Demonstrated that the variants had a dominant-negative effect on VPS4A function. "The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Genetic Epilepsy v0.948 VPS4A Elena Savva Gene: vps4a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.948 VPS4A Elena Savva Classified gene: VPS4A as Green List (high evidence)
Genetic Epilepsy v0.948 VPS4A Elena Savva Gene: vps4a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.947 VPS4A Kristin Rigbye gene: VPS4A was added
gene: VPS4A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS4A were set to 33186543; 33186545
Phenotypes for gene: VPS4A were set to Neurodevelopmental disorder
Review for gene: VPS4A was set to GREEN
Added comment: PMID: 33186543 - 2x de novo hetorozygous missense variants in the AAA (large ATPase) domain.
1x homozygous missense in the MIT domain (milder phenotype and unaffected parents - possibly just a simple LoF mechanism for AR inheritance).
Demonstrated defective CD71 trafficking in all 3 patients.

PMID: 33186545 - 6x probands with de novo missense variants in the AAA domain. 5 of the variants were at amino acid position 284 (changes to Trp and Gly).
Demonstrated that the variants had a dominant-negative effect on VPS4A function.

"The six probands with de novo substitutions affecting Glu206 or Arg284 had a consistent phenotype characterized by severe DD, profound ID, and dystonia. Children were very delayed in establishing head control and none achieved independent walking. Other common findings were cerebellar hypoplasia (five individuals out of six, the other showing uncharacterized severe cerebral atrophy) with a variable degree of corpus callosum hypoplasia. One individual also had bilateral polymicrogyria. Epilepsy was present in three and dystonia in five subjects. Eye involvement was also a common finding, including congenital cataract, retinal dystrophy, and in one case congenital Leber amaurosis. Four individuals were diagnosed with hepatosplenomegaly and/or steatosis. Three subjects had anemia, which was characterized as dyserythropoietic in two. Severe feeding difficulties were present in four individuals, requiring assisted feeding in three. Two had sensorineural deafness. Severe growth retardation, generally for all parameters, was present in most cases. Notably, severe microcephaly (typically with Z scores < −5) was universal. Overall, the disorder seems to have a poor prognosis as two affected individuals died in childhood or early adult life."
Sources: Literature
Genetic Epilepsy v0.947 KDM4B Kristin Rigbye gene: KDM4B was added
gene: KDM4B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KDM4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM4B were set to PMID: 33232677
Phenotypes for gene: KDM4B were set to Global developmental delay, intellectual disability and neuroanatomical defects
Review for gene: KDM4B was set to GREEN
Added comment: Nine individuals with mono-allelic de novo or inherited variants in KDM4B.

All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria.

In a knockout mouse the total brain volume was significantly reduced with decreased
size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly.
Sources: Literature
Genetic Epilepsy v0.947 KAT5 Zornitza Stark Phenotypes for gene: KAT5 were changed from 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 to Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB), MIM#619103; 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
Genetic Epilepsy v0.946 KAT5 Zornitza Stark reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities (NEDFASB), MIM#619103; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.946 H3F3B Zornitza Stark Marked gene: H3F3B as ready
Genetic Epilepsy v0.946 H3F3B Zornitza Stark Gene: h3f3b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.946 H3F3B Zornitza Stark Classified gene: H3F3B as Green List (high evidence)
Genetic Epilepsy v0.946 H3F3B Zornitza Stark Gene: h3f3b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.945 H3F3B Zornitza Stark gene: H3F3B was added
gene: H3F3B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: H3F3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: H3F3B were set to 33268356
Phenotypes for gene: H3F3B were set to Intellectual disability; regression; seizures
Review for gene: H3F3B was set to GREEN
Added comment: 13 unrelated individuals reported with missense variants in H3F3B. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.
Sources: Literature
Genetic Epilepsy v0.944 H3F3A Zornitza Stark Marked gene: H3F3A as ready
Genetic Epilepsy v0.944 H3F3A Zornitza Stark Gene: h3f3a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.944 H3F3A Zornitza Stark Classified gene: H3F3A as Green List (high evidence)
Genetic Epilepsy v0.944 H3F3A Zornitza Stark Gene: h3f3a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.943 H3F3A Zornitza Stark gene: H3F3A was added
gene: H3F3A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: H3F3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: H3F3A were set to 33268356
Phenotypes for gene: H3F3A were set to Intellectual disability; regression; seizures
Review for gene: H3F3A was set to GREEN
Added comment: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.
Sources: Literature
Genetic Epilepsy v0.942 WWOX Zornitza Stark Marked gene: WWOX as ready
Genetic Epilepsy v0.942 WWOX Zornitza Stark Gene: wwox has been classified as Green List (High Evidence).
Genetic Epilepsy v0.942 WWOX Zornitza Stark Phenotypes for gene: WWOX were changed from to Developmental and epileptic encephalopathy 28, MIM# 616211
Genetic Epilepsy v0.941 WWOX Zornitza Stark Publications for gene: WWOX were set to
Genetic Epilepsy v0.940 WWOX Zornitza Stark Mode of inheritance for gene: WWOX was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.939 WWOX Zornitza Stark Tag SV/CNV tag was added to gene: WWOX.
Genetic Epilepsy v0.939 WWOX Zornitza Stark reviewed gene: WWOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 24456803, 25411445, 32051108, 32037574; Phenotypes: Developmental and epileptic encephalopathy 28, MIM# 616211; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.939 WWOX Teresa Zhao reviewed gene: WWOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 30356099, 29808465; Phenotypes: Developmental and epileptic encephalopathy 28 (MIM#616211), Spinocerebellar ataxia 12; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.939 YIPF5 Zornitza Stark Marked gene: YIPF5 as ready
Genetic Epilepsy v0.939 YIPF5 Zornitza Stark Gene: yipf5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.939 YIPF5 Zornitza Stark Classified gene: YIPF5 as Green List (high evidence)
Genetic Epilepsy v0.939 YIPF5 Zornitza Stark Gene: yipf5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.938 YIPF5 Zornitza Stark gene: YIPF5 was added
gene: YIPF5 was added to Genetic Epilepsy. Sources: Literature
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 Neonatal diabetes; microcephaly; seizures
Review for gene: YIPF5 was set to GREEN
Added comment: Six individuals from 5 unrelated consanguineous families reported with bi-allelic variants in this gene and neonatal/early-onset diabetes, severe microcephaly, and epilepsy. Functional data supports gene-disease association.
Sources: Literature
Genetic Epilepsy v0.937 TFE3 Zornitza Stark Publications for gene: TFE3 were set to 30595499; 31833172
Genetic Epilepsy v0.936 TFE3 Zornitza Stark Mode of pathogenicity for gene: TFE3 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
Genetic Epilepsy v0.935 TFE3 Zornitza Stark Mode of inheritance for gene: TFE3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.934 TFE3 Zornitza Stark edited their review of gene: TFE3: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.934 TFE3 Zornitza Stark edited their review of gene: TFE3: Added comment: PMID: 32409512 (2020) - 14 variants reported as de novo events in 17 unrelated cases (including 5 previously published) of severe intellectual disability with pigmentary mosaicism and storage disorder-like features; 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: 30595499, 31833172, 32409512; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.934 PIGP Zornitza Stark Phenotypes for gene: PIGP were changed from Epileptic encephalopathy, early infantile, 55, MIM# 617599 to Developmental and epileptic encephalopathy 55, MIM# 617599
Genetic Epilepsy v0.933 PIGP Zornitza Stark edited their review of gene: PIGP: Changed phenotypes: Developmental and epileptic encephalopathy 55, MIM# 617599
Genetic Epilepsy v0.933 PIGK Zornitza Stark Phenotypes for gene: PIGK were changed from Intellectual disability; seizures; cerebellar atrophy to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, MIM# 618879
Genetic Epilepsy v0.932 PIGK Zornitza Stark edited their review of gene: PIGK: Changed phenotypes: Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, MIM# 618879
Genetic Epilepsy v0.932 PIGH Zornitza Stark Marked gene: PIGH as ready
Genetic Epilepsy v0.932 PIGH Zornitza Stark Gene: pigh has been classified as Green List (High Evidence).
Genetic Epilepsy v0.932 PIGH Zornitza Stark Phenotypes for gene: PIGH were changed from to Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010
Genetic Epilepsy v0.931 PIGH Zornitza Stark Publications for gene: PIGH were set to
Genetic Epilepsy v0.930 PIGH Zornitza Stark Mode of inheritance for gene: PIGH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.929 PIGH Zornitza Stark reviewed gene: PIGH: Rating: GREEN; Mode of pathogenicity: None; Publications: 29573052, 29603516, 33156547; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 17, MIM# 618010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.929 PIGB Zornitza Stark Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80; OMIM #618580 to Developmental and epileptic encephalopathy 80, MIM# 618580
Genetic Epilepsy v0.928 PIGB Zornitza Stark edited their review of gene: PIGB: Changed phenotypes: Developmental and epileptic encephalopathy 80, MIM# 618580
Genetic Epilepsy v0.928 GPAA1 Zornitza Stark Marked gene: GPAA1 as ready
Genetic Epilepsy v0.928 GPAA1 Zornitza Stark Gene: gpaa1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.928 GPAA1 Zornitza Stark Phenotypes for gene: GPAA1 were changed from to Glycosylphosphatidylinositol biosynthesis defect 15, MIM# 617810
Genetic Epilepsy v0.927 GPAA1 Zornitza Stark Publications for gene: GPAA1 were set to
Genetic Epilepsy v0.926 GPAA1 Zornitza Stark Mode of inheritance for gene: GPAA1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.925 GPAA1 Zornitza Stark reviewed gene: GPAA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100095; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 15, MIM# 617810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.925 ALG9 Zornitza Stark Marked gene: ALG9 as ready
Genetic Epilepsy v0.925 ALG9 Zornitza Stark Gene: alg9 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.925 ALG9 Zornitza Stark Phenotypes for gene: ALG9 were changed from to Congenital disorder of glycosylation, type Il, MIM#608776
Genetic Epilepsy v0.924 ALG9 Zornitza Stark Publications for gene: ALG9 were set to
Genetic Epilepsy v0.923 ALG9 Zornitza Stark Mode of inheritance for gene: ALG9 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.922 ALG9 Zornitza Stark reviewed gene: ALG9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28932688; Phenotypes: Congenital disorder of glycosylation, type Il, MIM#608776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.922 ALG8 Zornitza Stark Marked gene: ALG8 as ready
Genetic Epilepsy v0.922 ALG8 Zornitza Stark Gene: alg8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.922 ALG8 Zornitza Stark Phenotypes for gene: ALG8 were changed from Congenital disorder of glycosylation, type Ih, MIM# 608104 to Congenital disorder of glycosylation, type Ih, MIM# 608104
Genetic Epilepsy v0.921 ALG8 Zornitza Stark Phenotypes for gene: ALG8 were changed from to Congenital disorder of glycosylation, type Ih, MIM# 608104
Genetic Epilepsy v0.920 ALG8 Zornitza Stark Publications for gene: ALG8 were set to 26066342
Genetic Epilepsy v0.920 ALG8 Zornitza Stark Publications for gene: ALG8 were set to
Genetic Epilepsy v0.919 ALG8 Zornitza Stark Mode of inheritance for gene: ALG8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.918 ALG8 Zornitza Stark reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 26066342; Phenotypes: Congenital disorder of glycosylation, type Ih, MIM# 608104; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.918 ALG3 Zornitza Stark Marked gene: ALG3 as ready
Genetic Epilepsy v0.918 ALG3 Zornitza Stark Gene: alg3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.918 ALG3 Zornitza Stark Phenotypes for gene: ALG3 were changed from to Congenital disorder of glycosylation, type Id, MIM# 601110
Genetic Epilepsy v0.917 ALG3 Zornitza Stark Publications for gene: ALG3 were set to
Genetic Epilepsy v0.916 ALG3 Zornitza Stark Mode of inheritance for gene: ALG3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.915 ALG3 Zornitza Stark reviewed gene: ALG3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31067009; Phenotypes: Congenital disorder of glycosylation, type Id, MIM# 601110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.915 ALG6 Zornitza Stark Marked gene: ALG6 as ready
Genetic Epilepsy v0.915 ALG6 Zornitza Stark Gene: alg6 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.915 ALG6 Zornitza Stark Phenotypes for gene: ALG6 were changed from to Congenital disorder of glycosylation, type Ic (MIM#603147)
Genetic Epilepsy v0.914 ALG6 Zornitza Stark Publications for gene: ALG6 were set to
Genetic Epilepsy v0.913 ALG6 Zornitza Stark Mode of inheritance for gene: ALG6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.912 ALG6 Zornitza Stark reviewed gene: ALG6: Rating: GREEN; Mode of pathogenicity: None; Publications: 10914684, 27498540; Phenotypes: Congenital disorder of glycosylation, type Ic (MIM#603147); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.912 MOGS Zornitza Stark Marked gene: MOGS as ready
Genetic Epilepsy v0.912 MOGS Zornitza Stark Gene: mogs has been classified as Green List (High Evidence).
Genetic Epilepsy v0.912 MOGS Zornitza Stark Phenotypes for gene: MOGS were changed from to Congenital disorder of glycosylation, type IIb, MIM# 606056
Genetic Epilepsy v0.911 MOGS Zornitza Stark Publications for gene: MOGS were set to
Genetic Epilepsy v0.910 MOGS Zornitza Stark Mode of inheritance for gene: MOGS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.909 MOGS Zornitza Stark reviewed gene: MOGS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31925597, 30587846, 33058492; Phenotypes: Congenital disorder of glycosylation, type IIb, MIM# 606056; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.909 RORB Zornitza Stark Marked gene: RORB as ready
Genetic Epilepsy v0.909 RORB Zornitza Stark Gene: rorb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.909 RORB Zornitza Stark Phenotypes for gene: RORB were changed from to {Epilepsy, idiopathic generalized, susceptibility to, 15} (MIM#618357), AD; Genetic generalized epilepsy (GGE); Photosensitive generalized and occipital epilepsy
Genetic Epilepsy v0.908 RORB Zornitza Stark Publications for gene: RORB were set to
Genetic Epilepsy v0.907 RORB Zornitza Stark Mode of inheritance for gene: RORB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.906 RORB Kristin Rigbye reviewed gene: RORB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27352968, 32162308; Phenotypes: {Epilepsy, idiopathic generalized, susceptibility to, 15} (MIM#618357), AD, Genetic generalized epilepsy (GGE), Photosensitive generalized and occipital epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.906 NARS Zornitza Stark 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 (NEDMILG), MIM#619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092; Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Genetic Epilepsy v0.905 NARS Zornitza Stark reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG), MIM#619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG), MIM#619092, Abnormal muscle tone, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Ataxia, Abnormality of the face, Demyelinating peripheral neuropathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.905 GABBR2 Zornitza Stark Marked gene: GABBR2 as ready
Genetic Epilepsy v0.905 GABBR2 Zornitza Stark Gene: gabbr2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.905 GABBR2 Zornitza Stark Phenotypes for gene: GABBR2 were changed from to Developmental and epileptic encephalopathy 59, MIM# 617904
Genetic Epilepsy v0.904 GABBR2 Zornitza Stark Publications for gene: GABBR2 were set to
Genetic Epilepsy v0.903 GABBR2 Zornitza Stark Mode of inheritance for gene: GABBR2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.902 GABBR2 Zornitza Stark reviewed gene: GABBR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100083, 25262651, 28856709; Phenotypes: Developmental and epileptic encephalopathy 59, MIM# 617904; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.902 KCNQ2 Zornitza Stark Marked gene: KCNQ2 as ready
Genetic Epilepsy v0.902 KCNQ2 Zornitza Stark Gene: kcnq2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.902 KCNQ2 Zornitza Stark Phenotypes for gene: KCNQ2 were changed from to Epileptic encephalopathy, early infantile, 7, 613720; Seizures, benign neonatal, 1, 121200
Genetic Epilepsy v0.901 KCNQ2 Zornitza Stark Publications for gene: KCNQ2 were set to
Genetic Epilepsy v0.900 KCNQ2 Zornitza Stark Mode of pathogenicity for gene: KCNQ2 was changed from to Other
Genetic Epilepsy v0.899 KCNQ2 Zornitza Stark Mode of inheritance for gene: KCNQ2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.898 KCNQ2 Zornitza Stark reviewed gene: KCNQ2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 25959266, 32917465, 24318194; Phenotypes: Epileptic encephalopathy, early infantile, 7, 613720, Seizures, benign neonatal, 1, 121200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.898 UNC80 Zornitza Stark Marked gene: UNC80 as ready
Genetic Epilepsy v0.898 UNC80 Zornitza Stark Gene: unc80 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.898 UNC80 Zornitza Stark Phenotypes for gene: UNC80 were changed from to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801; MONDO:0014777
Genetic Epilepsy v0.897 UNC80 Zornitza Stark Publications for gene: UNC80 were set to
Genetic Epilepsy v0.896 UNC80 Zornitza Stark Mode of inheritance for gene: UNC80 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.895 UNC80 Zornitza Stark commented on gene: UNC80: UNC80 is part of the NALCN complex, and this is considered a NALCN channelopathy.

More than 20 individuals from more than 5 unrelated families reported with bi-allelic variants in this gene and severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Affected individuals show severe global developmental delay with poor or absent speech and absent or limited ability to walk. Some have had seizures; brain structure is typically normal.

UNC80 knockout mice are neonatal lethal.
Genetic Epilepsy v0.895 UNC80 Zornitza Stark reviewed gene: UNC80: Rating: GREEN; Mode of pathogenicity: None; Publications: 26708751, 26708753, 26545877, 32620897, 30167850, 30167850; Phenotypes: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, MIM# 616801, MONDO:0014777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.895 NUS1 Zornitza Stark Phenotypes for gene: NUS1 were changed from Epilepsy; intellectual disability to Mental retardation, autosomal dominant 55, with seizures, MIM# 617831
Genetic Epilepsy v0.894 NUS1 Zornitza Stark edited their review of gene: NUS1: Changed phenotypes: Mental retardation, autosomal dominant 55, with seizures, MIM# 617831
Genetic Epilepsy v0.894 STXBP1 Zornitza Stark Phenotypes for gene: STXBP1 were changed from Epileptic encephalopathy, early infantile, 4, MIM#612164 to Developmental and epileptic encephalopathy 4, MIM# 612164
Genetic Epilepsy v0.893 STXBP1 Zornitza Stark edited their review of gene: STXBP1: Changed phenotypes: Developmental and epileptic encephalopathy 4, MIM# 612164
Genetic Epilepsy v0.893 PET100 Zornitza Stark Marked gene: PET100 as ready
Genetic Epilepsy v0.893 PET100 Zornitza Stark Gene: pet100 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.893 PET100 Zornitza Stark Phenotypes for gene: PET100 were changed from to Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055
Genetic Epilepsy v0.892 PET100 Zornitza Stark Publications for gene: PET100 were set to
Genetic Epilepsy v0.891 PET100 Zornitza Stark Mode of inheritance for gene: PET100 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.890 PET100 Zornitza Stark Tag founder tag was added to gene: PET100.
Genetic Epilepsy v0.890 PET100 Zornitza Stark reviewed gene: PET100: Rating: GREEN; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.890 SCO1 Zornitza Stark Marked gene: SCO1 as ready
Genetic Epilepsy v0.890 SCO1 Zornitza Stark Gene: sco1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.890 SCO1 Zornitza Stark Phenotypes for gene: SCO1 were changed from to Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048
Genetic Epilepsy v0.889 SCO1 Zornitza Stark Publications for gene: SCO1 were set to
Genetic Epilepsy v0.888 SCO1 Zornitza Stark Mode of inheritance for gene: SCO1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.887 SCO1 Zornitza Stark Classified gene: SCO1 as Amber List (moderate evidence)
Genetic Epilepsy v0.887 SCO1 Zornitza Stark Gene: sco1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.886 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.886 SETD1A Zornitza Stark Phenotypes for gene: SETD1A were changed from Epilepsy to Epilepsy, early-onset, with or without developmental delay, MIM# 618832; Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Genetic Epilepsy v0.885 SETD1A Zornitza Stark Publications for gene: SETD1A were set to 31197650
Genetic Epilepsy v0.884 SETD1A Zornitza Stark edited their review of gene: SETD1A: Added comment: OMIM has assigned a second phenotype in relation to the syndromic ID cohort reported in PMID 32346159. All variants were predicted to disrupt or delete the SET catalytic domain, and LOF is the established mechanism.

In addition, there are 4 families reported with a predominantly seizure phenotype without ID, PMID 31197650. All the variants are missense and mechanism of pathogenicity is not clearly established, hence it is difficult to know whether these are two distinct conditions or part of a spectrum of severity for SETD1A-related disorders.; Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM# 618832, Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM# 619056
Genetic Epilepsy v0.884 SETD1A Zornitza Stark changed review comment from: Four unrelated families reported: in three, the variants occurred de novo, and in the fourth, it segregated with disease. Some functional data.
Sources: Literature; to: PMID: 31197650. Four unrelated families reported: in three, the variants occurred de novo, and in the fourth, it segregated with disease. Some functional data.
Sources: Literature
Genetic Epilepsy v0.884 HECW2 Zornitza Stark Marked gene: HECW2 as ready
Genetic Epilepsy v0.884 HECW2 Zornitza Stark Gene: hecw2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.884 HECW2 Zornitza Stark Phenotypes for gene: HECW2 were changed from to Neurodevelopmental disorder with hypotonia, seizures, and absent language, MIM# 617268; intellectual disability; epilepsy; regression; microcephaly
Genetic Epilepsy v0.883 HECW2 Zornitza Stark Mode of pathogenicity for gene: HECW2 was changed from to Other
Genetic Epilepsy v0.882 HECW2 Zornitza Stark Publications for gene: HECW2 were set to
Genetic Epilepsy v0.881 HECW2 Zornitza Stark Mode of inheritance for gene: HECW2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.880 HECW2 Zornitza Stark reviewed gene: HECW2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29807643, 29395664, 27334371, 27389779; Phenotypes: Neurodevelopmental disorder with hypotonia, seizures, and absent language, MIM# 617268, intellectual disability, epilepsy, regression, microcephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.880 ADGRV1 Zornitza Stark Marked gene: ADGRV1 as ready
Genetic Epilepsy v0.880 ADGRV1 Zornitza Stark Gene: adgrv1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.880 ADGRV1 Zornitza Stark changed review comment from: Bi-allelic variants in this gene are associated with Usher syndrome.

Some evidence that variants in this gene are implicated in epilepsy, based on animal model, presence in the recurrent 5q14.3 deletion, and over-representation of rare variants in myoclonic epilepsy cohorts (29266188) and identification in individual cases (29261713; 32962041). However, some of the variants do not meet pathogenicity criteria (present in pop datasets, no segregation information available) and contribution may be under a polygenic model.
Sources: Expert Review; to: Bi-allelic variants in this gene are associated with Usher syndrome.

Some evidence that mono-allelic variants in this gene are implicated in epilepsy, based on animal model, presence in the recurrent 5q14.3 deletion, and over-representation of rare variants in myoclonic epilepsy cohorts (29266188) and identification in individual cases (29261713; 32962041). However, some of the variants do not meet pathogenicity criteria (present in pop datasets, no segregation information available) and contribution may be under a polygenic model.
Sources: Expert Review
Genetic Epilepsy v0.880 ADGRV1 Zornitza Stark gene: ADGRV1 was added
gene: ADGRV1 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: ADGRV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADGRV1 were set to 29266188; 29261713; 32962041
Phenotypes for gene: ADGRV1 were set to Myoclonic epilepsy; febrile seizures; epilepsy
Review for gene: ADGRV1 was set to RED
Added comment: Bi-allelic variants in this gene are associated with Usher syndrome.

Some evidence that variants in this gene are implicated in epilepsy, based on animal model, presence in the recurrent 5q14.3 deletion, and over-representation of rare variants in myoclonic epilepsy cohorts (29266188) and identification in individual cases (29261713; 32962041). However, some of the variants do not meet pathogenicity criteria (present in pop datasets, no segregation information available) and contribution may be under a polygenic model.
Sources: Expert Review
Genetic Epilepsy v0.879 EPG5 Zornitza Stark Marked gene: EPG5 as ready
Genetic Epilepsy v0.879 EPG5 Zornitza Stark Gene: epg5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.879 EPG5 Zornitza Stark Publications for gene: EPG5 were set to 23222957; 26917586
Genetic Epilepsy v0.878 EPG5 Zornitza Stark Phenotypes for gene: EPG5 were changed from to Vici syndrome, MIM# 242840
Genetic Epilepsy v0.878 EPG5 Zornitza Stark Publications for gene: EPG5 were set to
Genetic Epilepsy v0.877 EPG5 Zornitza Stark Mode of inheritance for gene: EPG5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.876 EPG5 Zornitza Stark reviewed gene: EPG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23222957, 26917586; Phenotypes: Vici syndrome, MIM# 242840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.876 SATB2 Zornitza Stark Marked gene: SATB2 as ready
Genetic Epilepsy v0.876 SATB2 Zornitza Stark Gene: satb2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.876 SATB2 Zornitza Stark Classified gene: SATB2 as Green List (high evidence)
Genetic Epilepsy v0.876 SATB2 Zornitza Stark Gene: satb2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.875 SATB2 Zornitza Stark gene: SATB2 was added
gene: SATB2 was added to Genetic Epilepsy. 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
Review for gene: SATB2 was set to GREEN
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
Genetic Epilepsy v0.874 SETD1A Zornitza Stark edited their review of gene: SETD1A: Added comment: PMID 32346159: Described 15 individuals with de novo SETD1A variants presenting with global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. Examined cellular phenotypes in three patient-derived cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp and results suggested that that these variants behave as loss-of-function (LoF) alleles.; Changed publications: 31197650, 32346159; Changed phenotypes: Epilepsy, Intellectual disability
Genetic Epilepsy v0.874 HPDL Zornitza Stark Marked gene: HPDL as ready
Genetic Epilepsy v0.874 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.874 HPDL Zornitza Stark Classified gene: HPDL as Green List (high evidence)
Genetic Epilepsy v0.874 HPDL Zornitza Stark Gene: hpdl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.873 HPDL Zornitza Stark gene: HPDL was added
gene: HPDL was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Review for gene: HPDL was set to GREEN
Added comment: 17 individuals from 13 families, with a spectrum of neurologic impairment ranging from a severe congenital form without any neurological development (n = 2/17, 12%) to infantile-onset presentations (n = 10/17, 59%) with moderate to severe neurodevelopmental issues, partly with a pathology reminiscent of mitochondrial disease (Leigh-like syndrome), to juvenile-onset spastic paraplegia (n = 5/17, 29%).

Seizures/epilepsy were reported in 9/17, 53%.

Frequently observed additional clinical findings included chronic progression of neurological signs (n = 16/17, 94%), motor developmental delay (n = 12/17, 71%), intellectual impairment (n = 11/17, 65%), microcephaly (n = 9/16, 56%) . Other relevant clinical findings were visual disturbances/strabismus (n = 9/17, 53%) and loss of developmental milestones (n = 6/17, 35%).

Acute central respiratory failure leading to life-threatening events requiring partly mechanically assisted ventilation occurred in half of individuals with infantile presentation (n = 5/10, 50%), respectively one third of all individuals (n = 5/17, 29%).

Demyelinating neuropathy was present in three individuals (n = 3/11, 27%), with reduced sensory nerve conduction velocity (NCV) in all and severely reduced motor NCV in one.
Sources: Literature
Genetic Epilepsy v0.872 KPTN Zornitza Stark Publications for gene: KPTN were set to 25847626; 24239382; 32358097; 32808430
Genetic Epilepsy v0.871 KPTN Zornitza Stark Publications for gene: KPTN were set to 25847626; 24239382
Genetic Epilepsy v0.870 KPTN Zornitza Stark Classified gene: KPTN as Green List (high evidence)
Genetic Epilepsy v0.870 KPTN Zornitza Stark Gene: kptn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.869 KPTN Zornitza Stark edited their review of gene: KPTN: Added comment: Two further publications (PMID 32358097; 32808430), more individuals reported with seizures, upgrade to Green.; Changed rating: GREEN; Changed publications: 25847626, 24239382, 32358097, 32808430
Genetic Epilepsy v0.869 PIGT Zornitza Stark Marked gene: PIGT as ready
Genetic Epilepsy v0.869 PIGT Zornitza Stark Gene: pigt has been classified as Green List (High Evidence).
Genetic Epilepsy v0.869 PIGT Zornitza Stark Phenotypes for gene: PIGT were changed from to Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398
Genetic Epilepsy v0.868 PIGT Zornitza Stark Publications for gene: PIGT were set to
Genetic Epilepsy v0.867 PIGT Zornitza Stark Mode of inheritance for gene: PIGT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.866 PIGT Zornitza Stark reviewed gene: PIGT: Rating: GREEN; Mode of pathogenicity: None; Publications: 30976099, 25943031, 24906948, 24906948, 24906948, 28728837, 28728837, 28728837; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 3, MIM# 615398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.866 ALG13 Zornitza Stark Marked gene: ALG13 as ready
Genetic Epilepsy v0.866 ALG13 Zornitza Stark Gene: alg13 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.866 ALG13 Zornitza Stark Phenotypes for gene: ALG13 were changed from to Congenital disorder of glycosylation, type Is (MIM# 300884)
Genetic Epilepsy v0.865 ALG13 Zornitza Stark Publications for gene: ALG13 were set to
Genetic Epilepsy v0.864 ALG13 Zornitza Stark Mode of inheritance for gene: ALG13 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.863 ALG13 Zornitza Stark reviewed gene: ALG13: Rating: GREEN; Mode of pathogenicity: None; Publications: 23033978, 23934111, 24781210, 24896178, 25732998, 26138355, 26482601, 28940310, 32238909; Phenotypes: Congenital disorder of glycosylation, type Is (MIM# 300884); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.863 MADD Zornitza Stark 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 DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities); Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005
Genetic Epilepsy v0.862 MADD Zornitza Stark reviewed gene: MADD: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 29302074, 32761064; Phenotypes: DEEAH syndrome, MIM#619004 (Developmental Delay With Endocrine, Exocrine, Autonomic, and Hematologic Abnormalities), Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (NEDDISH), MIM# 619005; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.862 LMNB1 Zornitza Stark Marked gene: LMNB1 as ready
Genetic Epilepsy v0.862 LMNB1 Zornitza Stark Added comment: Comment when marking as ready: Note different mechanism for LMNB1-related neurodevelopmental phenotype cf Adult-onset leukodystrophy phenotype previously associated with this gene.
Genetic Epilepsy v0.862 LMNB1 Zornitza Stark Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.862 LMNB1 Zornitza Stark Mode of pathogenicity for gene: LMNB1 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Genetic Epilepsy v0.861 LMNB1 Zornitza Stark Classified gene: LMNB1 as Amber List (moderate evidence)
Genetic Epilepsy v0.861 LMNB1 Zornitza Stark Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.860 LMNB1 Konstantinos Varvagiannis edited their review of gene: LMNB1: 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
Genetic Epilepsy v0.860 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Genetic Epilepsy. 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 Other
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
Genetic Epilepsy v0.860 VPS11 Zornitza Stark Tag founder tag was added to gene: VPS11.
Genetic Epilepsy v0.860 RORA Zornitza Stark Marked gene: RORA as ready
Genetic Epilepsy v0.860 RORA Zornitza Stark Gene: rora has been classified as Green List (High Evidence).
Genetic Epilepsy v0.860 RORA Zornitza Stark Phenotypes for gene: RORA were changed from to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060
Genetic Epilepsy v0.859 RORA Zornitza Stark Publications for gene: RORA were set to
Genetic Epilepsy v0.858 RORA Zornitza Stark Mode of inheritance for gene: RORA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.857 RORA Zornitza Stark reviewed gene: RORA: Rating: GREEN; Mode of pathogenicity: None; Publications: 29656859; Phenotypes: Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.857 KCNA2 Zornitza Stark Marked gene: KCNA2 as ready
Genetic Epilepsy v0.857 KCNA2 Zornitza Stark Gene: kcna2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.857 KCNA2 Zornitza Stark Phenotypes for gene: KCNA2 were changed from to Early infantile encephalopathy 32, MIM#616366
Genetic Epilepsy v0.856 KCNA2 Zornitza Stark Publications for gene: KCNA2 were set to
Genetic Epilepsy v0.855 KCNA2 Zornitza Stark Mode of inheritance for gene: KCNA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.854 KCNA2 Zornitza Stark reviewed gene: KCNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29050392; Phenotypes: Early infantile encephalopathy 32, MIM#616366; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.854 ADPRHL2 Zornitza Stark Marked gene: ADPRHL2 as ready
Genetic Epilepsy v0.854 ADPRHL2 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is ADPRS.
Genetic Epilepsy v0.854 ADPRHL2 Zornitza Stark Gene: adprhl2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.854 ADPRHL2 Zornitza Stark Tag new gene name tag was added to gene: ADPRHL2.
Genetic Epilepsy v0.854 ADPRHL2 Zornitza Stark reviewed gene: ADPRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30100084, 30401461; Phenotypes: Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM#618170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.854 ATAD1 Zornitza Stark Marked gene: ATAD1 as ready
Genetic Epilepsy v0.854 ATAD1 Zornitza Stark Gene: atad1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.854 ATAD1 Zornitza Stark Classified gene: ATAD1 as Green List (high evidence)
Genetic Epilepsy v0.854 ATAD1 Zornitza Stark Gene: atad1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.853 ATAD1 Zornitza Stark gene: ATAD1 was added
gene: ATAD1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: ATAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD1 were set to 28180185; 29390050; 29659736
Phenotypes for gene: ATAD1 were set to Hyperekplexia 4, MIM#618011
Review for gene: ATAD1 was set to GREEN
Added comment: Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Three unrelated families reported. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures.
Sources: Expert list
Genetic Epilepsy v0.852 VAMP2 Zornitza Stark Phenotypes for gene: VAMP2 were changed from Cortical visual impairment; Seizures; Stereotypic behaviour; Generalized hypotonia; Intellectual disability to Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements 618760; Cortical visual impairment; Seizures; Stereotypic behaviour; Generalized hypotonia; Intellectual disability
Genetic Epilepsy v0.851 VAMP2 Zornitza Stark edited their review of gene: VAMP2: Changed phenotypes: Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements 618760, Cortical visual impairment, Seizures, Stereotypic behaviour, Generalized hypotonia, Intellectual disability
Genetic Epilepsy v0.851 SLC16A2 Zornitza Stark Marked gene: SLC16A2 as ready
Genetic Epilepsy v0.851 SLC16A2 Zornitza Stark Gene: slc16a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.851 SLC16A2 Zornitza Stark Phenotypes for gene: SLC16A2 were changed from to Allan-Herndon-Dudley syndrome, MIM# 300523
Genetic Epilepsy v0.850 SLC16A2 Zornitza Stark Publications for gene: SLC16A2 were set to
Genetic Epilepsy v0.849 SLC16A2 Zornitza Stark Mode of inheritance for gene: SLC16A2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.848 SLC16A2 Zornitza Stark reviewed gene: SLC16A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15980113, 31410843, 20301789; Phenotypes: Allan-Herndon-Dudley syndrome, MIM# 300523; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.848 TRIP13 Zornitza Stark Tag founder tag was added to gene: TRIP13.
Genetic Epilepsy v0.848 MYT1L Zornitza Stark Marked gene: MYT1L as ready
Genetic Epilepsy v0.848 MYT1L Zornitza Stark Gene: myt1l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.848 MYT1L Zornitza Stark Classified gene: MYT1L as Green List (high evidence)
Genetic Epilepsy v0.848 MYT1L Zornitza Stark Gene: myt1l has been classified as Green List (High Evidence).
Genetic Epilepsy v0.847 MYT1L Zornitza Stark gene: MYT1L was added
gene: MYT1L was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: MYT1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYT1L were set to 32065501
Phenotypes for gene: MYT1L were set to Mental retardation, autosomal dominant 39, MIM# 616521
Review for gene: MYT1L was set to GREEN
Added comment: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems. 66% in a recent cohort had seizures.
Sources: Literature
Genetic Epilepsy v0.846 IRF2BPL Zornitza Stark Marked gene: IRF2BPL as ready
Genetic Epilepsy v0.846 IRF2BPL Zornitza Stark Gene: irf2bpl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.846 IRF2BPL Zornitza Stark Phenotypes for gene: IRF2BPL were changed from to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088
Genetic Epilepsy v0.845 IRF2BPL Zornitza Stark Publications for gene: IRF2BPL were set to
Genetic Epilepsy v0.844 IRF2BPL Zornitza Stark Mode of inheritance for gene: IRF2BPL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.843 IRF2BPL Zornitza Stark reviewed gene: IRF2BPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 30057031, 30166628; Phenotypes: Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.843 GTPBP2 Zornitza Stark changed review comment from: Six unrelated families with this neurodevelopmental syndrome, seizures are a feature.
Sources: Expert list; to: Nine individuals from six unrelated families with bi-allelic variants in this gene causing a neuro-ectodermal syndrome. Key features include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation.
Sources: Expert list
Genetic Epilepsy v0.843 GTPBP2 Zornitza Stark changed review comment from: Four unrelated families with this neurodevelopmental syndrome, seizures are a feature.
Sources: Expert list; to: Six unrelated families with this neurodevelopmental syndrome, seizures are a feature.
Sources: Expert list
Genetic Epilepsy v0.843 GTPBP2 Zornitza Stark edited their review of gene: GTPBP2: Changed publications: 26675814, 29449720, 30790272
Genetic Epilepsy v0.843 SETD1B Zornitza Stark Phenotypes for gene: SETD1B were changed from Epilepsy with myoclonic absences; intellectual disability; SETD1B-related neurodevelopmental disorder to Epilepsy with myoclonic absences; intellectual disability; Intellectual developmental disorder with seizures and language delay (IDDSELD), MIM#619000
Genetic Epilepsy v0.842 TRIP13 Zornitza Stark Marked gene: TRIP13 as ready
Genetic Epilepsy v0.842 TRIP13 Zornitza Stark Gene: trip13 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.842 TRIP13 Zornitza Stark Phenotypes for gene: TRIP13 were changed from to Mosaic variegated aneuploidy syndrome 3, MIM# 617598
Genetic Epilepsy v0.841 TRIP13 Zornitza Stark Publications for gene: TRIP13 were set to
Genetic Epilepsy v0.840 TRIP13 Zornitza Stark Mode of inheritance for gene: TRIP13 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.839 TRIP13 Zornitza Stark Classified gene: TRIP13 as Amber List (moderate evidence)
Genetic Epilepsy v0.839 TRIP13 Zornitza Stark Gene: trip13 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.838 TRIP13 Zornitza Stark reviewed gene: TRIP13: Rating: AMBER; Mode of pathogenicity: None; Publications: 28553959; Phenotypes: Mosaic variegated aneuploidy syndrome 3, MIM# 617598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.838 TRAPPC6B Zornitza Stark Marked gene: TRAPPC6B as ready
Genetic Epilepsy v0.838 TRAPPC6B Zornitza Stark Gene: trappc6b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.838 TRAPPC6B Zornitza Stark Publications for gene: TRAPPC6B were set to 28626029; 28397838; 31687267
Genetic Epilepsy v0.837 TRAPPC6B Zornitza Stark Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Genetic Epilepsy v0.836 TRAPPC6B Zornitza Stark Phenotypes for gene: TRAPPC6B were changed from to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Genetic Epilepsy v0.836 TRAPPC6B Zornitza Stark Publications for gene: TRAPPC6B were set to
Genetic Epilepsy v0.835 TRAPPC6B Zornitza Stark Mode of inheritance for gene: TRAPPC6B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.834 TRAPPC6B Zornitza Stark reviewed gene: TRAPPC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28626029, 28397838, 31687267; Phenotypes: Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.834 CLTC Zornitza Stark Marked gene: CLTC as ready
Genetic Epilepsy v0.834 CLTC Zornitza Stark Gene: cltc has been classified as Green List (High Evidence).
Genetic Epilepsy v0.834 CLTC Zornitza Stark Phenotypes for gene: CLTC were changed from to Mental retardation, autosomal dominant 56, MIM# 617854
Genetic Epilepsy v0.833 CLTC Zornitza Stark Publications for gene: CLTC were set to
Genetic Epilepsy v0.832 CLTC Zornitza Stark Mode of inheritance for gene: CLTC was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.831 CLTC Zornitza Stark reviewed gene: CLTC: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100083, 26822784; Phenotypes: Mental retardation, autosomal dominant 56, MIM# 617854; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.831 TRAPPC2L Zornitza Stark Marked gene: TRAPPC2L as ready
Genetic Epilepsy v0.831 TRAPPC2L Zornitza Stark Gene: trappc2l has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.831 TRAPPC2L Zornitza Stark changed review comment from: Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Amber as additional cases required to delineate the genotype-phenotype relationship. PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect. The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11. PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family. Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature; to: Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Red on this panel as seizures not reported in all families. PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect. The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11. PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family. Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Genetic Epilepsy v0.831 TRAPPC2L Zornitza Stark edited their review of gene: TRAPPC2L: Changed rating: RED
Genetic Epilepsy v0.831 TRAPPC2L Zornitza Stark gene: TRAPPC2L was added
gene: TRAPPC2L was added to Genetic Epilepsy. Sources: Literature
founder tags were added to gene: TRAPPC2L.
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Amber as additional cases required to delineate the genotype-phenotype relationship. PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect. The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11. PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family. Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Genetic Epilepsy v0.830 ADARB1 Zornitza Stark Marked gene: ADARB1 as ready
Genetic Epilepsy v0.830 ADARB1 Zornitza Stark Gene: adarb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.830 ADARB1 Zornitza Stark Phenotypes for gene: ADARB1 were changed from Intellectual disability; microcephaly; seizures to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Intellectual disability; microcephaly; seizures
Genetic Epilepsy v0.829 ADARB1 Zornitza Stark Publications for gene: ADARB1 were set to 32220291
Genetic Epilepsy v0.828 ADARB1 Arina Puzriakova reviewed gene: ADARB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220291, 32719099; Phenotypes: Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.828 MOCS1 Zornitza Stark Marked gene: MOCS1 as ready
Genetic Epilepsy v0.828 MOCS1 Zornitza Stark Gene: mocs1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.828 MOCS1 Zornitza Stark Phenotypes for gene: MOCS1 were changed from to Molybdenum cofactor deficiency A, MIM# 252150
Genetic Epilepsy v0.827 MOCS1 Zornitza Stark Publications for gene: MOCS1 were set to
Genetic Epilepsy v0.826 MOCS1 Zornitza Stark Mode of inheritance for gene: MOCS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.825 MOCS1 Zornitza Stark reviewed gene: MOCS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9921896, 12754701, 21031595; Phenotypes: Molybdenum cofactor deficiency A, MIM# 252150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.825 AARS Zornitza Stark Marked gene: AARS as ready
Genetic Epilepsy v0.825 AARS Zornitza Stark Gene: aars has been classified as Green List (High Evidence).
Genetic Epilepsy v0.825 AARS Zornitza Stark Phenotypes for gene: AARS were changed from to Epileptic encephalopathy, early infantile, 29, MIM# 616339
Genetic Epilepsy v0.824 AARS Zornitza Stark Publications for gene: AARS were set to
Genetic Epilepsy v0.823 AARS Zornitza Stark Mode of inheritance for gene: AARS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.823 AARS Zornitza Stark Mode of inheritance for gene: AARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.822 AARS Zornitza Stark reviewed gene: AARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28493438, 25817015; Phenotypes: Epileptic encephalopathy, early infantile, 29, MIM# 616339; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.822 RELN Zornitza Stark Marked gene: RELN as ready
Genetic Epilepsy v0.822 RELN Zornitza Stark Gene: reln has been classified as Green List (High Evidence).
Genetic Epilepsy v0.822 RELN Zornitza Stark Phenotypes for gene: RELN were changed from to {Epilepsy, familial temporal lobe, 7}, MIM# 616436; MONDO:0014639
Genetic Epilepsy v0.821 RELN Zornitza Stark Publications for gene: RELN were set to
Genetic Epilepsy v0.820 RELN Zornitza Stark Mode of inheritance for gene: RELN was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.819 RELN Zornitza Stark reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 28142128; Phenotypes: {Epilepsy, familial temporal lobe, 7}, MIM# 616436, MONDO:0014639; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.819 PAFAH1B1 Zornitza Stark Marked gene: PAFAH1B1 as ready
Genetic Epilepsy v0.819 PAFAH1B1 Zornitza Stark Gene: pafah1b1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.819 PAFAH1B1 Zornitza Stark Tag SV/CNV tag was added to gene: PAFAH1B1.
Genetic Epilepsy v0.819 PAFAH1B1 Zornitza Stark Phenotypes for gene: PAFAH1B1 were changed from to Lissencephaly 1, MIM# 607432; Subcortical laminar heterotopia, MIM# 607432; MONDO:0011830
Genetic Epilepsy v0.818 PAFAH1B1 Zornitza Stark Publications for gene: PAFAH1B1 were set to
Genetic Epilepsy v0.817 PAFAH1B1 Zornitza Stark Mode of inheritance for gene: PAFAH1B1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.816 PAFAH1B1 Zornitza Stark reviewed gene: PAFAH1B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11754098, 18285425; Phenotypes: Lissencephaly 1, MIM# 607432, Subcortical laminar heterotopia, MIM# 607432, MONDO:0011830; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.816 KIF5C Zornitza Stark Marked gene: KIF5C as ready
Genetic Epilepsy v0.816 KIF5C Zornitza Stark Gene: kif5c has been classified as Green List (High Evidence).
Genetic Epilepsy v0.816 KIF5C Zornitza Stark Phenotypes for gene: KIF5C were changed from to Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282
Genetic Epilepsy v0.815 KIF5C Zornitza Stark Publications for gene: KIF5C were set to
Genetic Epilepsy v0.814 KIF5C Zornitza Stark Mode of inheritance for gene: KIF5C was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.813 KIF5C Zornitza Stark reviewed gene: KIF5C: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 23033978, 32562872; Phenotypes: Cortical dysplasia, complex, with other brain malformations 2, MIM# 615282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.813 KIF2A Zornitza Stark Marked gene: KIF2A as ready
Genetic Epilepsy v0.813 KIF2A Zornitza Stark Gene: kif2a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.813 KIF2A Zornitza Stark Phenotypes for gene: KIF2A were changed from to Cortical dysplasia, complex, with other brain malformations 3, MIM# 615411
Genetic Epilepsy v0.812 KIF2A Zornitza Stark Publications for gene: KIF2A were set to
Genetic Epilepsy v0.811 KIF2A Zornitza Stark Mode of inheritance for gene: KIF2A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.810 KIF2A Zornitza Stark reviewed gene: KIF2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 23603762, 27896282, 27747449, 29077851, 31919497; Phenotypes: Cortical dysplasia, complex, with other brain malformations 3, MIM# 615411; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.810 GRIN2B Zornitza Stark Marked gene: GRIN2B as ready
Genetic Epilepsy v0.810 GRIN2B Zornitza Stark Gene: grin2b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.810 GRIN2B Zornitza Stark Phenotypes for gene: GRIN2B were changed from to Mental retardation, autosomal dominant 6, MIM# 613970; Epileptic encephalopathy, early infantile, 27, MIM# 616139
Genetic Epilepsy v0.809 GRIN2B Zornitza Stark Publications for gene: GRIN2B were set to
Genetic Epilepsy v0.808 GRIN2B Zornitza Stark Mode of inheritance for gene: GRIN2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.807 GRIN2B Zornitza Stark reviewed gene: GRIN2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28377535; Phenotypes: Mental retardation, autosomal dominant 6, MIM# 613970, Epileptic encephalopathy, early infantile, 27, MIM# 616139; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.807 GRIN1 Zornitza Stark Marked gene: GRIN1 as ready
Genetic Epilepsy v0.807 GRIN1 Zornitza Stark Gene: grin1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.807 GRIN1 Zornitza Stark Phenotypes for gene: GRIN1 were changed from to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254
Genetic Epilepsy v0.806 GRIN1 Zornitza Stark Publications for gene: GRIN1 were set to
Genetic Epilepsy v0.805 GRIN1 Zornitza Stark Mode of inheritance for gene: GRIN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.804 GRIN1 Zornitza Stark reviewed gene: GRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29365063, 27164704; Phenotypes: Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.804 ALG11 Zornitza Stark Marked gene: ALG11 as ready
Genetic Epilepsy v0.804 ALG11 Zornitza Stark Gene: alg11 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.804 ALG11 Zornitza Stark Phenotypes for gene: ALG11 were changed from to Congenital disorder of glycosylation, type Ip, MIM# 613661
Genetic Epilepsy v0.803 ALG11 Zornitza Stark Publications for gene: ALG11 were set to
Genetic Epilepsy v0.802 ALG11 Zornitza Stark Mode of inheritance for gene: ALG11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.801 ALG11 Zornitza Stark reviewed gene: ALG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 30676690; Phenotypes: Congenital disorder of glycosylation, type Ip, MIM# 613661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.801 NPRL2 Zornitza Stark Marked gene: NPRL2 as ready
Genetic Epilepsy v0.801 NPRL2 Zornitza Stark Gene: nprl2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.801 NPRL2 Zornitza Stark Phenotypes for gene: NPRL2 were changed from to Epilepsy, familial focal, with variable foci 2 617116; focal seizures; frontal lobe epilepsy; nocturnal frontal lobe epilepsy; temporal lobe epilepsy; focal cortical dysplasia
Genetic Epilepsy v0.800 NPRL2 Zornitza Stark Publications for gene: NPRL2 were set to
Genetic Epilepsy v0.799 NPRL2 Zornitza Stark Mode of inheritance for gene: NPRL2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.798 NPRL2 Dean Phelan reviewed gene: NPRL2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26505888, 27173016, 28199897, 31594065; Phenotypes: focal seizures, frontal lobe epilepsy, nocturnal frontal lobe epilepsy, temporal lobe epilepsy, focal cortical dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.798 GABRA6 Zornitza Stark Classified gene: GABRA6 as Red List (low evidence)
Genetic Epilepsy v0.798 GABRA6 Zornitza Stark Gene: gabra6 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.797 GABRA6 Zornitza Stark Classified gene: GABRA6 as Red List (low evidence)
Genetic Epilepsy v0.797 GABRA6 Zornitza Stark Gene: gabra6 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.796 GABRA6 Anna Le Fevre gene: GABRA6 was added
gene: GABRA6 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GABRA6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRA6 were set to PMID: 21930603; 29215089; 19429026
Phenotypes for gene: GABRA6 were set to BFIE; CAE
Penetrance for gene: GABRA6 were set to unknown
Review for gene: GABRA6 was set to RED
Added comment: One report in a cohort of patients with BFIE
Potential susceptibility allele in CAE
Sources: Literature
Genetic Epilepsy v0.796 GPHN Zornitza Stark Marked gene: GPHN as ready
Genetic Epilepsy v0.796 GPHN Zornitza Stark Gene: gphn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.796 GPHN Zornitza Stark Tag SV/CNV tag was added to gene: GPHN.
Genetic Epilepsy v0.796 GPHN Zornitza Stark Phenotypes for gene: GPHN were changed from to Molybdenum cofactor deficiency C, MIM# 615501; Epilepsy; Autism; Intellectual disability
Genetic Epilepsy v0.795 GPHN Zornitza Stark Publications for gene: GPHN were set to
Genetic Epilepsy v0.794 GPHN Zornitza Stark Mode of inheritance for gene: GPHN was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.793 GPHN Zornitza Stark reviewed gene: GPHN: Rating: GREEN; Mode of pathogenicity: None; Publications: 22040219, 11095995, 26613940, 24561070, 23393157; Phenotypes: Molybdenum cofactor deficiency C, MIM# 615501, Epilepsy, Autism, Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.793 GABRG2 Zornitza Stark Marked gene: GABRG2 as ready
Genetic Epilepsy v0.793 GABRG2 Zornitza Stark Gene: gabrg2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.793 GABRG2 Zornitza Stark Phenotypes for gene: GABRG2 were changed from to Epileptic encephalopathy, early infantile, 74 618396; Epilepsy, generalized, with febrile seizures plus, type 3 607681
Genetic Epilepsy v0.792 GABRG2 Zornitza Stark Publications for gene: GABRG2 were set to
Genetic Epilepsy v0.791 GABRG2 Zornitza Stark Mode of inheritance for gene: GABRG2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.790 GABRG2 Zornitza Stark reviewed gene: GABRG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11326274, 11326275, 27864268; Phenotypes: Epileptic encephalopathy, early infantile, 74 618396, Epilepsy, generalized, with febrile seizures plus, type 3 607681; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.790 GABRB3 Zornitza Stark Marked gene: GABRB3 as ready
Genetic Epilepsy v0.790 GABRB3 Zornitza Stark Gene: gabrb3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.790 GABRB3 Zornitza Stark Phenotypes for gene: GABRB3 were changed from to Epileptic encephalopathy, early infantile, 43, MIM# 617113
Genetic Epilepsy v0.789 GABRB3 Zornitza Stark Publications for gene: GABRB3 were set to
Genetic Epilepsy v0.788 GABRB3 Zornitza Stark Mode of inheritance for gene: GABRB3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.787 GABRB3 Zornitza Stark reviewed gene: GABRB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23934111, 27476654; Phenotypes: Epileptic encephalopathy, early infantile, 43, MIM# 617113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.787 FOLR1 Zornitza Stark Marked gene: FOLR1 as ready
Genetic Epilepsy v0.787 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.787 FOLR1 Zornitza Stark Phenotypes for gene: FOLR1 were changed from to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068
Genetic Epilepsy v0.786 FOLR1 Zornitza Stark Publications for gene: FOLR1 were set to
Genetic Epilepsy v0.785 FOLR1 Zornitza Stark Mode of inheritance for gene: FOLR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.784 FOLR1 Zornitza Stark reviewed gene: FOLR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19732866, 30420205, 27743887; Phenotypes: Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.784 ARHGEF9 Zornitza Stark Marked gene: ARHGEF9 as ready
Genetic Epilepsy v0.784 ARHGEF9 Zornitza Stark Gene: arhgef9 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.784 ARHGEF9 Zornitza Stark Phenotypes for gene: ARHGEF9 were changed from to Epileptic encephalopathy, early infantile, 8, MIM# 300607
Genetic Epilepsy v0.783 ARHGEF9 Zornitza Stark Publications for gene: ARHGEF9 were set to
Genetic Epilepsy v0.782 ARHGEF9 Zornitza Stark Mode of inheritance for gene: ARHGEF9 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.781 ARHGEF9 Zornitza Stark reviewed gene: ARHGEF9: Rating: GREEN; Mode of pathogenicity: None; Publications: 31942680, 30048823, 29130122, 28620718; Phenotypes: Epileptic encephalopathy, early infantile, 8, MIM# 300607; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.781 ALDH5A1 Zornitza Stark Marked gene: ALDH5A1 as ready
Genetic Epilepsy v0.781 ALDH5A1 Zornitza Stark Gene: aldh5a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.781 ALDH5A1 Zornitza Stark Phenotypes for gene: ALDH5A1 were changed from to Succinic semialdehyde dehydrogenase deficiency, MIM# 271980
Genetic Epilepsy v0.780 ALDH5A1 Zornitza Stark Publications for gene: ALDH5A1 were set to
Genetic Epilepsy v0.779 ALDH5A1 Zornitza Stark Mode of inheritance for gene: ALDH5A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.778 ALDH5A1 Zornitza Stark reviewed gene: ALDH5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9683595, 14635103, 32402538; Phenotypes: Succinic semialdehyde dehydrogenase deficiency, MIM# 271980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.778 LMBRD2 Zornitza Stark reviewed gene: LMBRD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Seizures, Abnormality of nervous system morphology, Abnormality of the eye; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.778 LMBRD2 Zornitza Stark Marked gene: LMBRD2 as ready
Genetic Epilepsy v0.778 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.778 LMBRD2 Zornitza Stark Classified gene: LMBRD2 as Green List (high evidence)
Genetic Epilepsy v0.778 LMBRD2 Zornitza Stark Gene: lmbrd2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.777 KAT5 Zornitza Stark Marked gene: KAT5 as ready
Genetic Epilepsy v0.777 KAT5 Zornitza Stark Gene: kat5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.777 KAT5 Zornitza Stark Classified gene: KAT5 as Green List (high evidence)
Genetic Epilepsy v0.777 KAT5 Zornitza Stark Gene: kat5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.776 KAT5 Konstantinos Varvagiannis gene: KAT5 was added
gene: KAT5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KAT5 were set to 32822602
Phenotypes for gene: KAT5 were set 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
Penetrance for gene: KAT5 were set to unknown
Mode of pathogenicity for gene: KAT5 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: KAT5 was set to GREEN
Added comment: Humbert el al (2020 - PMID: 32822602) report 3 individuals with de novo missense KAT5 variants.

Features included severe DD (3/3) and ID (2/2 - the 3rd was 18m on last examination), microcephaly (2/3), behavioral anomalies (3/3) including severe sleep disorder (3/3 - table S1 / night walking, sleep onset delay, excessive daytime sleepiness), seizures (3/3 - variable type and age of onset), brain MRI abnormalities (3/3 - CC, cerebellar atrophy each in 2 subjects, focal polymicrogyria in 1), various genitourinary anomalies (3/3). All had moderately short stature (-1.95 SD to -2.9SD). Cleft LP and submucous cleft P were observed in 2/3. Facial features included round face, flat profile, depressed nasal bridge, downturned corners of mouth and prognathism (each in at least 2 subjects).

KAT5 encodes a lysine acetyltransferase involved in gene expression, DNA repair, chromatine remodeling, apoptosis and cell proliferation. It is part of the NuA4 histone acetyltransferase (HAT) complex also called TIP60/p400 (TIP60 being another name for KAT5). Regulation by histone acetylation is important for proper development.

3 missense KAT5 SNVs were identified, one within the chromobarrel domain (aa 7-65 / NM_006388.3) and 2 in the acetyl-CoA binding domain (aa 365-420).

Following generation of K562 cells expressing either WT or variants, it was demonstrated that wt/mt KAT5 assemble normally into NuA4/TIP60 complexes. Histone acetyltransferase activity was however impaired for all variants, suggesting a partial loss of function mechanism.

As Humbert et al comment, it is possible that KAT5 haploinsufficiency does not lead to a
syndrome. Over 10 high-confidence LoF variants are listed in gnomAD. Heterozygous Kat5 ko mice have normal development, growth and fertility. Homozygous ko mice are embryonic lethal. In haploinsufficient mice, reduction of mRNA to 50% has been shown to be compensated at the protein level in adipose and/or other tissues (several studies cited).

RNA-Seq in fibroblasts from 2 affected individuals revealed dysregulation of highly relevant genes (e.g. for neurodevelopment, circadian clock, etc).

Mutations in KAT6A/B, encoding two other acetyltransferases cause neurodevelopmental disorders with features overlapping those observed in individuals with KAT5 variants (e.g. DD/ID, microcephaly, seizures, sleep disturbance, clefts, CC or genital anomalies).

Consider inclusion in the ID and epilepsy panels with green rating as well as the gene panel for clefting with amber.
Sources: Literature
Genetic Epilepsy v0.776 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.776 KAT8 Zornitza Stark Phenotypes for gene: KAT8 were changed from Intellectual disability; seizures; autism; dysmorphic features to Intellectual disability; seizures; autism; dysmorphic features; Li-Ghorbani-Weisz syndrome, MIM#618974
Genetic Epilepsy v0.775 KAT8 Zornitza Stark edited their review of gene: KAT8: Changed phenotypes: Intellectual disability, seizures, autism, dysmorphic features, Li-Ghorbani-Weisz syndrome, MIM#618974
Genetic Epilepsy v0.775 KAT8 Zornitza Stark edited their review of gene: KAT8: Changed phenotypes: Intellectual disability, seizures, autism, dysmorphic features, Li-Ghorbani_Weisz syndrome, MIM#618974
Genetic Epilepsy v0.775 MADD Zornitza Stark Marked gene: MADD as ready
Genetic Epilepsy v0.775 MADD Zornitza Stark Gene: madd has been classified as Green List (High Evidence).
Genetic Epilepsy v0.775 MADD Zornitza Stark Classified gene: MADD as Green List (high evidence)
Genetic Epilepsy v0.775 MADD Zornitza Stark Gene: madd has been classified as Green List (High Evidence).
Genetic Epilepsy v0.774 MADD Konstantinos Varvagiannis gene: MADD was added
gene: MADD was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.774 SLC5A6 Zornitza Stark Phenotypes for gene: SLC5A6 were changed from Developmental delay; epilepsy; neurodegeneration to Developmental delay; epilepsy; neurodegeneration; Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Genetic Epilepsy v0.773 FAM50A Zornitza Stark Marked gene: FAM50A as ready
Genetic Epilepsy v0.773 FAM50A Zornitza Stark Gene: fam50a has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.773 FAM50A Zornitza Stark Classified gene: FAM50A as Amber List (moderate evidence)
Genetic Epilepsy v0.773 FAM50A Zornitza Stark Gene: fam50a has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.772 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.772 CNTN2 Zornitza Stark gene: CNTN2 was added
gene: CNTN2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CNTN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN2 were set to 23518707
Phenotypes for gene: CNTN2 were set to Epilepsy
Review for gene: CNTN2 was set to RED
Added comment: Single family reported in 2013, supportive mouse model.
Sources: Literature
Genetic Epilepsy v0.771 FBXO11 Zornitza Stark edited their review of gene: FBXO11: Changed publications: 30679813, 30057029, 29796876
Genetic Epilepsy v0.771 PIGQ Zornitza Stark Publications for gene: PIGQ were set to 25558065; 24463883; 31148362
Genetic Epilepsy v0.770 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: ; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.770 SCAF4 Zornitza Stark Marked gene: SCAF4 as ready
Genetic Epilepsy v0.770 SCAF4 Zornitza Stark Gene: scaf4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.770 SCAF4 Zornitza Stark Classified gene: SCAF4 as Green List (high evidence)
Genetic Epilepsy v0.770 SCAF4 Zornitza Stark Gene: scaf4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.769 SCAF4 Crystle Lee gene: SCAF4 was added
gene: SCAF4 was added to Genetic Epilepsy. Sources: Expert Review
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 Mild intellectual disability; seizures; behavioral abnormalities
Review for gene: SCAF4 was set to GREEN
Added comment: > 5 variants reported in individuals with variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies.
Sources: Expert Review
Genetic Epilepsy v0.769 PIGP Seb Lunke Publications for gene: PIGP were set to 28334793; 31139695
Genetic Epilepsy v0.768 PIGP Seb Lunke Classified gene: PIGP as Green List (high evidence)
Genetic Epilepsy v0.768 PIGP Seb Lunke Gene: pigp has been classified as Green List (High Evidence).
Genetic Epilepsy v0.767 PIGP Seb Lunke reviewed gene: PIGP: Rating: GREEN; Mode of pathogenicity: None; Publications: 32042915; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.767 NARS Zornitza Stark Marked gene: NARS as ready
Genetic Epilepsy v0.767 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Genetic Epilepsy v0.767 NARS Zornitza Stark Classified gene: NARS as Green List (high evidence)
Genetic Epilepsy v0.767 NARS Zornitza Stark Gene: nars has been classified as Green List (High Evidence).
Genetic Epilepsy v0.766 NARS Zornitza Stark Tag new gene name tag was added to gene: NARS.
Genetic Epilepsy v0.766 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
Genetic Epilepsy v0.766 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.766 EEF1A2 Zornitza Stark Marked gene: EEF1A2 as ready
Genetic Epilepsy v0.766 EEF1A2 Zornitza Stark Gene: eef1a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.766 EEF1A2 Zornitza Stark Phenotypes for gene: EEF1A2 were changed from to Epileptic encephalopathy, early infantile, 33, MIM# 616409; Mental retardation, autosomal dominant 38, MIM# 616393
Genetic Epilepsy v0.765 EEF1A2 Zornitza Stark Publications for gene: EEF1A2 were set to
Genetic Epilepsy v0.764 EEF1A2 Zornitza Stark Mode of pathogenicity for gene: EEF1A2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Genetic Epilepsy v0.763 EEF1A2 Zornitza Stark Mode of inheritance for gene: EEF1A2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.762 EEF1A2 Zornitza Stark reviewed gene: EEF1A2: 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: 32160274; Phenotypes: Epileptic encephalopathy, early infantile, 33, MIM# 616409, Mental retardation, autosomal dominant 38, MIM# 616393; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.762 LARS Zornitza Stark Marked gene: LARS as ready
Genetic Epilepsy v0.762 LARS Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is LARS1
Genetic Epilepsy v0.762 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Genetic Epilepsy v0.762 LARS Zornitza Stark Phenotypes for gene: LARS were changed from Infantile liver failure syndrome 1, MIM# 615438 to Infantile liver failure syndrome 1, MIM# 615438; Seizures; Intellectual disability; Encephalopathy
Genetic Epilepsy v0.761 LARS Zornitza Stark Tag new gene name tag was added to gene: LARS.
Genetic Epilepsy v0.761 LARS Zornitza Stark Classified gene: LARS as Green List (high evidence)
Genetic Epilepsy v0.761 LARS Zornitza Stark Gene: lars has been classified as Green List (High Evidence).
Genetic Epilepsy v0.760 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Genetic Epilepsy. 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 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
Genetic Epilepsy v0.760 MDH1 Zornitza Stark Phenotypes for gene: MDH1 were changed from epilepsy; microcephaly; intellectual disability to epilepsy; microcephaly; intellectual disability; Epileptic encephalopathy, early infantile, 88, MIM#618959
Genetic Epilepsy v0.759 MDH1 Zornitza Stark reviewed gene: MDH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31538237,; Phenotypes: Epileptic encephalopathy, early infantile, 88, MIM#618959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.759 NSDHL Zornitza Stark Marked gene: NSDHL as ready
Genetic Epilepsy v0.759 NSDHL Zornitza Stark Gene: nsdhl has been classified as Green List (High Evidence).
Genetic Epilepsy v0.759 NSDHL Zornitza Stark Phenotypes for gene: NSDHL were changed from to CK syndrome (MIM#300831)
Genetic Epilepsy v0.758 NSDHL Zornitza Stark Publications for gene: NSDHL were set to
Genetic Epilepsy v0.757 NSDHL Zornitza Stark Mode of inheritance for gene: NSDHL was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.756 NSDHL Crystle Lee reviewed gene: NSDHL: Rating: GREEN; Mode of pathogenicity: None; Publications: 21129721, 15689440, 25900314; Phenotypes: CK syndrome (MIM#300831); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.756 CUX2 Zornitza Stark Marked gene: CUX2 as ready
Genetic Epilepsy v0.756 CUX2 Zornitza Stark Gene: cux2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.756 CUX2 Zornitza Stark Phenotypes for gene: CUX2 were changed from to Epileptic encephalopathy, early infantile, 67, MIM#618141
Genetic Epilepsy v0.755 CUX2 Zornitza Stark Publications for gene: CUX2 were set to
Genetic Epilepsy v0.754 CUX2 Zornitza Stark Mode of inheritance for gene: CUX2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.753 CUX2 Zornitza Stark reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 2963073, 29795476; Phenotypes: Epileptic encephalopathy, early infantile, 67, MIM#618141; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.753 GRM7 Zornitza Stark Phenotypes for gene: GRM7 were changed from Epilepsy, microcephaly, developmental delay to Epilepsy, microcephaly, developmental delay; neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA), MIM#618922
Genetic Epilepsy v0.752 CNPY3 Zornitza Stark Marked gene: CNPY3 as ready
Genetic Epilepsy v0.752 CNPY3 Zornitza Stark Gene: cnpy3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.752 CNPY3 Zornitza Stark Phenotypes for gene: CNPY3 were changed from to Epileptic encephalopathy, early infantile, 60 (MIM 617929)
Genetic Epilepsy v0.751 CNPY3 Zornitza Stark Publications for gene: CNPY3 were set to
Genetic Epilepsy v0.750 CNPY3 Zornitza Stark Mode of inheritance for gene: CNPY3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.749 TMEM106B Zornitza Stark Marked gene: TMEM106B as ready
Genetic Epilepsy v0.749 TMEM106B Zornitza Stark Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.749 TMEM106B Zornitza Stark Classified gene: TMEM106B as Amber List (moderate evidence)
Genetic Epilepsy v0.749 TMEM106B Zornitza Stark Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.748 TBC1D2B Zornitza Stark Classified gene: TBC1D2B as Green List (high evidence)
Genetic Epilepsy v0.748 TBC1D2B Zornitza Stark Gene: tbc1d2b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.747 ABCA2 Zornitza Stark Marked gene: ABCA2 as ready
Genetic Epilepsy v0.747 ABCA2 Zornitza Stark Gene: abca2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.747 ABCA2 Zornitza Stark Classified gene: ABCA2 as Green List (high evidence)
Genetic Epilepsy v0.747 ABCA2 Zornitza Stark Gene: abca2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.746 HERC2 Zornitza Stark Marked gene: HERC2 as ready
Genetic Epilepsy v0.746 HERC2 Zornitza Stark Gene: herc2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.746 HERC2 Zornitza Stark Classified gene: HERC2 as Green List (high evidence)
Genetic Epilepsy v0.746 HERC2 Zornitza Stark Gene: herc2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.745 CNPY3 Konstantinos Varvagiannis reviewed gene: CNPY3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29394991, 30237576; Phenotypes: Epileptic encephalopathy, early infantile, 60 (MIM 617929); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.745 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.745 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.745 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.745 HERC2 Konstantinos Varvagiannis gene: HERC2 was added
gene: HERC2 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.745 Zornitza Stark removed gene:NAXD from the panel
Genetic Epilepsy v0.744 NAXD Elena Savva gene: NAXD was added
gene: NAXD was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to PMID: 32462209
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, 618321
Review for gene: NAXD was set to GREEN
Added comment: Variable phenotype: one patient reported with neurodevelopmental disorder, autism spectrum disorder and a muscular-dystrophy-like myopathy

Patient reported with progressive encephalopathy with brain edema
Sources: Literature
Genetic Epilepsy v0.744 PLCB1 Zornitza Stark Marked gene: PLCB1 as ready
Genetic Epilepsy v0.744 PLCB1 Zornitza Stark Gene: plcb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.744 PLCB1 Zornitza Stark Phenotypes for gene: PLCB1 were changed from to Epileptic encephalopathy, early infantile, 12 (MIM#613722)
Genetic Epilepsy v0.743 PLCB1 Zornitza Stark Publications for gene: PLCB1 were set to
Genetic Epilepsy v0.742 PLCB1 Zornitza Stark Mode of inheritance for gene: PLCB1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.741 PLCB1 Zornitza Stark Tag SV/CNV tag was added to gene: PLCB1.
Genetic Epilepsy v0.741 PLCB1 Crystle Lee reviewed gene: PLCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24684524, 20833646, 22690784, 26818157; Phenotypes: Epileptic encephalopathy, early infantile, 12 (MIM#613722); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.741 ADPRHL2 Zornitza Stark Marked gene: ADPRHL2 as ready
Genetic Epilepsy v0.741 ADPRHL2 Zornitza Stark Gene: adprhl2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.741 ADPRHL2 Zornitza Stark Phenotypes for gene: ADPRHL2 were changed from to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (MIM#618170)
Genetic Epilepsy v0.740 ADPRHL2 Zornitza Stark Publications for gene: ADPRHL2 were set to
Genetic Epilepsy v0.739 ADPRHL2 Zornitza Stark Mode of inheritance for gene: ADPRHL2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.738 GRN Zornitza Stark Marked gene: GRN as ready
Genetic Epilepsy v0.738 GRN Zornitza Stark Gene: grn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.738 GRN Zornitza Stark Classified gene: GRN as Green List (high evidence)
Genetic Epilepsy v0.738 GRN Zornitza Stark Gene: grn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.737 GRN Elena Savva gene: GRN was added
gene: GRN was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to PMID: 22608501; 31855245
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11 614706
Review for gene: GRN was set to GREEN
Added comment: PMID: 22608501 - 2 siblings with a homozygous PTC and neuronal ceroid lipofuscinosis. Both showed vision deterioration in their mid 20s, with MRI revealing cerebellar atrophy and ataxia

PMID: 31855245 - 6 patients (4 families) with homozygous PTCs and start-loss. 5/6 report vision impairement, 6/6 cognitive deterioration, 3/6 cerebellar involvement, 3/6 seizures. Reviews previous reports, age of onset varies from 7-56 years old and seizures reported in a total of 7/11 patients.
Sources: Literature
Genetic Epilepsy v0.737 ADPRHL2 Crystle Lee reviewed gene: ADPRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30100084, 30401461; Phenotypes: Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (MIM#618170); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.737 SETD1B Zornitza Stark changed review comment from: At least 3, possibly 5, individuals reported with de novo variants in this gene and a neurodevelopmental disorder including seizures.; to: At least 7, possibly 9, individuals reported with de novo variants in this gene and a neurodevelopmental disorder including seizures.
Genetic Epilepsy v0.737 SETD1B Zornitza Stark edited their review of gene: SETD1B: Changed phenotypes: Epilepsy with myoclonic absences, intellectual disability, SETD1B-related neurodevelopmental disorder
Genetic Epilepsy v0.737 SETD1B Zornitza Stark edited their review of gene: SETD1B: Changed publications: 32546566, 29322246, 31440728, 31685013
Genetic Epilepsy v0.737 SETD1B Zornitza Stark Phenotypes for gene: SETD1B were changed from Epilepsy with myoclonic absences; intellectual disability to Epilepsy with myoclonic absences; intellectual disability; SETD1B-related neurodevelopmental disorder
Genetic Epilepsy v0.736 EXOC7 Zornitza Stark Marked gene: EXOC7 as ready
Genetic Epilepsy v0.736 EXOC7 Zornitza Stark Gene: exoc7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.736 EXOC7 Chirag Patel Classified gene: EXOC7 as Green List (high evidence)
Genetic Epilepsy v0.736 EXOC7 Chirag Patel Gene: exoc7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.736 EXOC7 Chirag Patel Classified gene: EXOC7 as Green List (high evidence)
Genetic Epilepsy v0.736 EXOC7 Chirag Patel Gene: exoc7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.735 EXOC7 Chirag Patel Classified gene: EXOC7 as Green List (high evidence)
Genetic Epilepsy v0.735 EXOC7 Chirag Patel Gene: exoc7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.734 EXOC7 Chirag Patel gene: EXOC7 was added
gene: EXOC7 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to PMID: 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
Added comment: 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
Genetic Epilepsy v0.733 GRIA2 Zornitza Stark edited their review of gene: GRIA2: Changed phenotypes: Intellectual disability, autism, Rett-like features, epileptic encephalopathy, Neurodevelopmental disorder with language impairment and behavioral abnormalities, MIM# 618917
Genetic Epilepsy v0.733 GRIA2 Zornitza Stark Phenotypes for gene: GRIA2 were changed from Intellectual disability; autism; Rett-like features; epileptic encephalopathy to Intellectual disability; autism; Rett-like features; epileptic encephalopathy; Neurodevelopmental disorder with language impairment and behavioral abnormalities, MIM# 618917
Genetic Epilepsy v0.732 CDK19 Zornitza Stark Phenotypes for gene: CDK19 were changed from Intellectual disability; epileptic encephalopathy to Intellectual disability; epileptic encephalopathy; Epileptic encephalopathy, early infantile, 87, MIM# 618916
Genetic Epilepsy v0.731 CDK19 Zornitza Stark edited their review of gene: CDK19: Changed phenotypes: Intellectual disability, epileptic encephalopathy, Epileptic encephalopathy, early infantile, 87, MIM# 618916
Genetic Epilepsy v0.731 DALRD3 Zornitza Stark Phenotypes for gene: DALRD3 were changed from Epileptic encephalopathy to Epileptic encephalopathy; Epileptic encephalopathy, early infantile, 86 618910
Genetic Epilepsy v0.730 DALRD3 Zornitza Stark edited their review of gene: DALRD3: Changed phenotypes: Epileptic encephalopathy, Epileptic encephalopathy, early infantile, 86 618910
Genetic Epilepsy v0.730 NEXMIF Zornitza Stark Marked gene: NEXMIF as ready
Genetic Epilepsy v0.730 NEXMIF Zornitza Stark Gene: nexmif has been classified as Green List (High Evidence).
Genetic Epilepsy v0.730 NEXMIF Zornitza Stark Phenotypes for gene: NEXMIF were changed from to Mental retardation, X-linked 98, MIM# 300912
Genetic Epilepsy v0.729 NEXMIF Zornitza Stark Publications for gene: NEXMIF were set to
Genetic Epilepsy v0.728 NEXMIF Zornitza Stark Mode of inheritance for gene: NEXMIF was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.727 NEXMIF Zornitza Stark reviewed gene: NEXMIF: Rating: GREEN; Mode of pathogenicity: None; Publications: 27358180; Phenotypes: Mental retardation, X-linked 98, MIM# 300912; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.727 SV2B Seb Lunke Marked gene: SV2B as ready
Genetic Epilepsy v0.727 SV2B Seb Lunke Gene: sv2b has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.727 SV2B Seb Lunke gene: SV2B was added
gene: SV2B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SV2B was set to Unknown
Publications for gene: SV2B were set to 23617838; 23937191
Phenotypes for gene: SV2B were set to seizures
Review for gene: SV2B was set to RED
Added comment: Multiply described in Epilepsy studies investigating role of SV2 gene family, however no patients directly attributed to variants in this gene and mouse models indicate viability without seizures.
Sources: Literature
Genetic Epilepsy v0.726 SCN3A Zornitza Stark Marked gene: SCN3A as ready
Genetic Epilepsy v0.726 SCN3A Zornitza Stark Gene: scn3a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.726 SCN3A Zornitza Stark Phenotypes for gene: SCN3A were changed from to Epilepsy, familial focal, with variable foci 4, MIM# 617935; Epileptic encephalopathy, early infantile, 62, MIM# 617938; Intellectual disability; Malformations of cortical development
Genetic Epilepsy v0.725 SCN3A Zornitza Stark Publications for gene: SCN3A were set to
Genetic Epilepsy v0.724 SCN3A Zornitza Stark Mode of pathogenicity for gene: SCN3A was changed from to Other
Genetic Epilepsy v0.723 SCN3A Zornitza Stark Mode of inheritance for gene: SCN3A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.722 SCN3A Zornitza Stark reviewed gene: SCN3A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32515017; Phenotypes: Epilepsy, familial focal, with variable foci 4, MIM# 617935, Epileptic encephalopathy, early infantile, 62, MIM# 617938, Intellectual disability, Malformations of cortical development; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.722 SLC6A1 Zornitza Stark Marked gene: SLC6A1 as ready
Genetic Epilepsy v0.722 SLC6A1 Zornitza Stark Gene: slc6a1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.722 SLC6A1 Zornitza Stark Phenotypes for gene: SLC6A1 were changed from to Myoclonic-atonic epilepsy, MIM#616421
Genetic Epilepsy v0.721 SLC6A1 Zornitza Stark Publications for gene: SLC6A1 were set to
Genetic Epilepsy v0.720 SLC6A1 Zornitza Stark Mode of inheritance for gene: SLC6A1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.719 SLC6A1 Zornitza Stark reviewed gene: SLC6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29315614; Phenotypes: Myoclonic-atonic epilepsy, MIM#616421; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.719 SMC1A Zornitza Stark Marked gene: SMC1A as ready
Genetic Epilepsy v0.719 SMC1A Zornitza Stark Gene: smc1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.719 SMC1A Zornitza Stark Phenotypes for gene: SMC1A were changed from to Epileptic encephalopathy, early infantile, 85, with or without midline brain defects, MIM# 301044
Genetic Epilepsy v0.718 SMC1A Zornitza Stark Publications for gene: SMC1A were set to
Genetic Epilepsy v0.717 SMC1A Zornitza Stark Mode of inheritance for gene: SMC1A was changed from Unknown to Other
Genetic Epilepsy v0.716 SMC1A Zornitza Stark reviewed gene: SMC1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31334757, 28166369; Phenotypes: Epileptic encephalopathy, early infantile, 85, with or without midline brain defects, MIM# 301044; Mode of inheritance: Other
Genetic Epilepsy v0.716 GRM7 Zornitza Stark Marked gene: GRM7 as ready
Genetic Epilepsy v0.716 GRM7 Zornitza Stark Gene: grm7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.716 GRM7 Zornitza Stark Classified gene: GRM7 as Green List (high evidence)
Genetic Epilepsy v0.716 GRM7 Zornitza Stark Gene: grm7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.715 GRM7 Zornitza Stark gene: GRM7 was added
gene: GRM7 was added to Genetic Epilepsy. 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
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.
Sources: Literature
Genetic Epilepsy v0.714 OTUD7A Zornitza Stark Marked gene: OTUD7A as ready
Genetic Epilepsy v0.714 OTUD7A Zornitza Stark Gene: otud7a has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.714 OTUD7A Chirag Patel gene: OTUD7A was added
gene: OTUD7A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to PMID: 31997314
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, no OMIM# yet
Review for gene: OTUD7A was set to RED
Added comment: One patient with severe global developmental delay, language impairment and epileptic encephalopathy. 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. We provide evidence that biallelic pathogenic OTUD7A variation is linked to early‐onset epileptic encephalopathy and proteasome dysfunction. 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.
Sources: Literature
Genetic Epilepsy v0.713 DALRD3 Zornitza Stark Marked gene: DALRD3 as ready
Genetic Epilepsy v0.713 DALRD3 Zornitza Stark Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.713 DALRD3 Zornitza Stark Classified gene: DALRD3 as Amber List (moderate evidence)
Genetic Epilepsy v0.713 DALRD3 Zornitza Stark Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.712 DALRD3 Zornitza Stark gene: DALRD3 was added
gene: DALRD3 was added to Genetic Epilepsy. 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 Epileptic encephalopathy
Review for gene: DALRD3 was set to AMBER
Added comment: Two individuals reported with same homozygous nonsense variant, functional data.
Sources: Literature
Genetic Epilepsy v0.711 DHX30 Zornitza Stark Marked gene: DHX30 as ready
Genetic Epilepsy v0.711 DHX30 Zornitza Stark Gene: dhx30 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.711 DHX30 Zornitza Stark Phenotypes for gene: DHX30 were changed from to Neurodevelopmental disorder with severe motor impairment and absent language, MIM#617804
Genetic Epilepsy v0.710 DHX30 Zornitza Stark Publications for gene: DHX30 were set to
Genetic Epilepsy v0.709 DHX30 Zornitza Stark Mode of inheritance for gene: DHX30 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.708 DHX30 Zornitza Stark reviewed gene: DHX30: Rating: GREEN; Mode of pathogenicity: None; Publications: 29100085; Phenotypes: Neurodevelopmental disorder with severe motor impairment and absent language, MIM#617804; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.708 PACS1 Zornitza Stark Marked gene: PACS1 as ready
Genetic Epilepsy v0.708 PACS1 Zornitza Stark Gene: pacs1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.708 PACS1 Zornitza Stark Phenotypes for gene: PACS1 were changed from to Schuurs-Hoeijmakers syndrome (MIM# 615009)
Genetic Epilepsy v0.707 PACS1 Zornitza Stark Publications for gene: PACS1 were set to
Genetic Epilepsy v0.706 PACS1 Zornitza Stark Mode of inheritance for gene: PACS1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.705 PACS1 Zornitza Stark reviewed gene: PACS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26842493, 23159249; Phenotypes: Schuurs-Hoeijmakers syndrome (MIM# 615009); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.705 STARD7 Zornitza Stark Marked gene: STARD7 as ready
Genetic Epilepsy v0.705 STARD7 Zornitza Stark Gene: stard7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.705 STARD7 Zornitza Stark Classified gene: STARD7 as Green List (high evidence)
Genetic Epilepsy v0.705 STARD7 Zornitza Stark Gene: stard7 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.704 STARD7 Zornitza Stark gene: STARD7 was added
gene: STARD7 was added to Genetic Epilepsy. Sources: Literature
STR tags were added to gene: STARD7.
Mode of inheritance for gene: STARD7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STARD7 were set to 11701600; 24114805; 31664034
Phenotypes for gene: STARD7 were set to Epilepsy, familial adult myoclonic, 2, 607876
Mode of pathogenicity for gene: STARD7 was set to Other
Review for gene: STARD7 was set to GREEN
Added comment: 158 individuals from 22 families reported with heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene.
Sources: Literature
Genetic Epilepsy v0.703 NR4A2 Zornitza Stark Marked gene: NR4A2 as ready
Genetic Epilepsy v0.703 NR4A2 Zornitza Stark Gene: nr4a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.703 NR4A2 Zornitza Stark Publications for gene: NR4A2 were set to 31428396
Genetic Epilepsy v0.702 NR4A2 Zornitza Stark reviewed gene: NR4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32366965; Phenotypes: Intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.702 NR4A2 Zornitza Stark Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Genetic Epilepsy v0.701 NR4A2 Zornitza Stark Classified gene: NR4A2 as Green List (high evidence)
Genetic Epilepsy v0.701 NR4A2 Zornitza Stark Gene: nr4a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.700 NR4A2 Konstantinos Varvagiannis gene: NR4A2 was added
gene: NR4A2 was added to Genetic Epilepsy. 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.
---
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.
Sources: Literature
Genetic Epilepsy v0.700 CUL3 Zornitza Stark Marked gene: CUL3 as ready
Genetic Epilepsy v0.700 CUL3 Zornitza Stark Gene: cul3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.700 CUL3 Zornitza Stark 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 Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate
Genetic Epilepsy v0.699 CUL3 Zornitza Stark Classified gene: CUL3 as Amber List (moderate evidence)
Genetic Epilepsy v0.699 CUL3 Zornitza Stark Gene: cul3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.698 CUL3 Konstantinos Varvagiannis gene: CUL3 was added
gene: CUL3 was added to Genetic Epilepsy. 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: 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

Overall, this gene can be considered for inclusion in the ID (amber/green), epilepsy (amber) and/or ASD panels.
Sources: Literature
Genetic Epilepsy v0.698 KCNT1 Zornitza Stark Marked gene: KCNT1 as ready
Genetic Epilepsy v0.698 KCNT1 Zornitza Stark Gene: kcnt1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.698 KCNT1 Zornitza Stark Phenotypes for gene: KCNT1 were changed from to Epilepsy, nocturnal frontal lobe, 5, MIM# 615005; Epileptic encephalopathy, early infantile, 14, MIM# 614959
Genetic Epilepsy v0.697 KCNT1 Zornitza Stark Publications for gene: KCNT1 were set to
Genetic Epilepsy v0.696 KCNT1 Zornitza Stark Mode of inheritance for gene: KCNT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.695 KCNT1 Zornitza Stark reviewed gene: KCNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23086397, 23086396, 31872048, 31532509; Phenotypes: Epilepsy, nocturnal frontal lobe, 5, MIM# 615005, Epileptic encephalopathy, early infantile, 14, MIM# 614959; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.695 UGDH Zornitza Stark Marked gene: UGDH as ready
Genetic Epilepsy v0.695 UGDH Zornitza Stark Gene: ugdh has been classified as Green List (High Evidence).
Genetic Epilepsy v0.695 UGDH Zornitza Stark Classified gene: UGDH as Green List (high evidence)
Genetic Epilepsy v0.695 UGDH Zornitza Stark Gene: ugdh has been classified as Green List (High Evidence).
Genetic Epilepsy v0.694 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.694 SPTBN4 Zornitza Stark Marked gene: SPTBN4 as ready
Genetic Epilepsy v0.694 SPTBN4 Zornitza Stark Gene: sptbn4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.694 SPTBN4 Zornitza Stark Classified gene: SPTBN4 as Green List (high evidence)
Genetic Epilepsy v0.694 SPTBN4 Zornitza Stark Gene: sptbn4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.693 YIF1B Zornitza Stark Marked gene: YIF1B as ready
Genetic Epilepsy v0.693 YIF1B Zornitza Stark Gene: yif1b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.693 YIF1B Zornitza Stark Classified gene: YIF1B as Amber List (moderate evidence)
Genetic Epilepsy v0.693 YIF1B Zornitza Stark Gene: yif1b has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.692 YIF1B Konstantinos Varvagiannis changed review comment from: Abnormality of movement
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; to: 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
Genetic Epilepsy v0.692 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Genetic Epilepsy. 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: Abnormality of movement
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
Genetic Epilepsy v0.692 SPTBN4 Konstantinos Varvagiannis gene: SPTBN4 was added
gene: SPTBN4 was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.692 CDC42BPB Zornitza Stark Marked gene: CDC42BPB as ready
Genetic Epilepsy v0.692 CDC42BPB Zornitza Stark Added comment: Comment when marking as ready: Primarily an ID gene, remains to be seen whether seizures are a prominent part of the phenotype.
Genetic Epilepsy v0.692 CDC42BPB Zornitza Stark Gene: cdc42bpb has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.692 CDC42BPB Zornitza Stark Mode of inheritance for gene: CDC42BPB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.691 CDC42BPB Zornitza Stark Classified gene: CDC42BPB as Amber List (moderate evidence)
Genetic Epilepsy v0.691 CDC42BPB Zornitza Stark Gene: cdc42bpb has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.691 CDC42BPB Zornitza Stark Classified gene: CDC42BPB as Green List (high evidence)
Genetic Epilepsy v0.691 CDC42BPB Zornitza Stark Gene: cdc42bpb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.690 CDC42BPB Konstantinos Varvagiannis gene: CDC42BPB was added
gene: CDC42BPB was added to Genetic Epilepsy. 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
Genetic Epilepsy v0.690 ATP5A1 Zornitza Stark Marked gene: ATP5A1 as ready
Genetic Epilepsy v0.690 ATP5A1 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name: ATP5F1A
Genetic Epilepsy v0.690 ATP5A1 Zornitza Stark Gene: atp5a1 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.690 ATP5A1 Zornitza Stark Tag new gene name tag was added to gene: ATP5A1.
Genetic Epilepsy v0.690 TNK2 Zornitza Stark Classified gene: TNK2 as Amber List (moderate evidence)
Genetic Epilepsy v0.690 TNK2 Zornitza Stark Gene: tnk2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.689 TNK2 Zornitza Stark changed review comment from: Three unrelated families reported.; to: Three unrelated families reported, however report in Hitomi (2013) is questionable due to this variant being present in 6 homozygotes in gnomAD,
Genetic Epilepsy v0.689 TNK2 Zornitza Stark edited their review of gene: TNK2: Changed rating: AMBER
Genetic Epilepsy v0.689 EMX2 Zornitza Stark Marked gene: EMX2 as ready
Genetic Epilepsy v0.689 EMX2 Zornitza Stark Gene: emx2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.689 EMX2 Zornitza Stark Phenotypes for gene: EMX2 were changed from to Schizencephaly, MIM# 269160
Genetic Epilepsy v0.688 EMX2 Zornitza Stark Tag disputed tag was added to gene: EMX2.
Genetic Epilepsy v0.688 EMX2 Zornitza Stark Publications for gene: EMX2 were set to
Genetic Epilepsy v0.687 EMX2 Zornitza Stark Mode of inheritance for gene: EMX2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.686 EMX2 Zornitza Stark Classified gene: EMX2 as Amber List (moderate evidence)
Genetic Epilepsy v0.686 EMX2 Zornitza Stark Gene: emx2 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.685 EMX2 Zornitza Stark reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 8528262, 9359037, 9153481, 9153481, 18409201; Phenotypes: Schizencephaly, MIM# 269160; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.685 CDK19 Zornitza Stark Marked gene: CDK19 as ready
Genetic Epilepsy v0.685 CDK19 Zornitza Stark Gene: cdk19 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.685 CDK19 Zornitza Stark Classified gene: CDK19 as Green List (high evidence)
Genetic Epilepsy v0.685 CDK19 Zornitza Stark Gene: cdk19 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.684 CDK19 Zornitza Stark gene: CDK19 was added
gene: CDK19 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CDK19 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDK19 were set to 32330417
Phenotypes for gene: CDK19 were set to Intellectual disability; epileptic encephalopathy
Review for gene: CDK19 was set to GREEN
Added comment: Three unrelated individuals with de novo missense variants reported, and intellectual disability/epileptic encephalopathy. Supportive functional data.
Sources: Literature
Genetic Epilepsy v0.683 SCN1A Zornitza Stark Marked gene: SCN1A as ready
Genetic Epilepsy v0.683 SCN1A Zornitza Stark Gene: scn1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.683 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from to Epilepsy, generalized, with febrile seizures plus, type 2 604403; Epileptic encephalopathy, early infantile, 6 (Dravet syndrome) 607208; Febrile seizures, familial, 3A 604403
Genetic Epilepsy v0.682 SCN1A Zornitza Stark Mode of inheritance for gene: SCN1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.681 SCN1A Zornitza Stark reviewed gene: SCN1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, generalized, with febrile seizures plus, type 2 604403, Epileptic encephalopathy, early infantile, 6 (Dravet syndrome) 607208, Febrile seizures, familial, 3A 604403; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.681 KCNB1 Zornitza Stark Marked gene: KCNB1 as ready
Genetic Epilepsy v0.681 KCNB1 Zornitza Stark Gene: kcnb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.681 KCNB1 Zornitza Stark Phenotypes for gene: KCNB1 were changed from to Epileptic encephalopathy, early infantile, 26, MIM# 616056
Genetic Epilepsy v0.680 KCNB1 Zornitza Stark Publications for gene: KCNB1 were set to
Genetic Epilepsy v0.679 KCNB1 Zornitza Stark Mode of inheritance for gene: KCNB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.678 KCNB1 Zornitza Stark reviewed gene: KCNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31600826, 31513310; Phenotypes: Epileptic encephalopathy, early infantile, 26, MIM# 616056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.678 GAD1 Zornitza Stark Marked gene: GAD1 as ready
Genetic Epilepsy v0.678 GAD1 Zornitza Stark Gene: gad1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.678 GAD1 Zornitza Stark Classified gene: GAD1 as Green List (high evidence)
Genetic Epilepsy v0.678 GAD1 Zornitza Stark Gene: gad1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.677 GAD1 Zornitza Stark gene: GAD1 was added
gene: GAD1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GAD1 were set to 32282878
Phenotypes for gene: GAD1 were set to Developmental and epileptic encephalopathy
Review for gene: GAD1 was set to GREEN
Added comment: 2020: 11 individuals from 6 consanguineous families reported with bi-allelic LOF variant and a developmental/epileptic encephalopathy. Seizure onset occurred in the first 2 months of life in all. All 10 individuals, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight individuals had joint contractures and/or pes equinovarus. Seven presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four individuals died before 4 years of age.
Sources: Literature
Genetic Epilepsy v0.676 GALNT2 Zornitza Stark Marked gene: GALNT2 as ready
Genetic Epilepsy v0.676 GALNT2 Zornitza Stark Gene: galnt2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.676 GALNT2 Zornitza Stark Classified gene: GALNT2 as Green List (high evidence)
Genetic Epilepsy v0.676 GALNT2 Zornitza Stark Gene: galnt2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.675 GALNT2 Zornitza Stark gene: GALNT2 was added
gene: GALNT2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation
Review for gene: GALNT2 was set to GREEN
Added comment: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities.
Sources: Literature
Genetic Epilepsy v0.674 PLPBP Zornitza Stark Marked gene: PLPBP as ready
Genetic Epilepsy v0.674 PLPBP Zornitza Stark Gene: plpbp has been classified as Green List (High Evidence).
Genetic Epilepsy v0.674 PLPBP Zornitza Stark Phenotypes for gene: PLPBP were changed from to Epilepsy, early-onset, vitamin B6-dependent, MIM# 617290
Genetic Epilepsy v0.673 PLPBP Zornitza Stark Publications for gene: PLPBP were set to
Genetic Epilepsy v0.672 PLPBP Zornitza Stark Mode of inheritance for gene: PLPBP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.671 PLPBP Zornitza Stark reviewed gene: PLPBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 27912044, 31741821, 30668673; Phenotypes: Epilepsy, early-onset, vitamin B6-dependent, MIM# 617290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.671 GRIN2A Zornitza Stark Marked gene: GRIN2A as ready
Genetic Epilepsy v0.671 GRIN2A Zornitza Stark Gene: grin2a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.671 GRIN2A Zornitza Stark Phenotypes for gene: GRIN2A were changed from to Epilepsy, focal, with speech disorder and with or without mental retardation, MIM# 245570
Genetic Epilepsy v0.670 GRIN2A Zornitza Stark Publications for gene: GRIN2A were set to
Genetic Epilepsy v0.669 GRIN2A Zornitza Stark Mode of pathogenicity for gene: GRIN2A was changed from to Other
Genetic Epilepsy v0.668 GRIN2A Zornitza Stark Mode of inheritance for gene: GRIN2A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.668 GRIN2A Zornitza Stark Mode of inheritance for gene: GRIN2A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.667 GRIN2A Zornitza Stark reviewed gene: GRIN2A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30544257; Phenotypes: Epilepsy, focal, with speech disorder and with or without mental retardation, MIM# 245570; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.667 GABRB2 Zornitza Stark Marked gene: GABRB2 as ready
Genetic Epilepsy v0.667 GABRB2 Zornitza Stark Gene: gabrb2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.667 GABRB2 Zornitza Stark Phenotypes for gene: GABRB2 were changed from to Epileptic encephalopathy, infantile or early childhood, 2, MIM# 617829
Genetic Epilepsy v0.666 GABRB2 Zornitza Stark Publications for gene: GABRB2 were set to
Genetic Epilepsy v0.665 GABRB2 Zornitza Stark Mode of inheritance for gene: GABRB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.664 GABRB2 Zornitza Stark reviewed gene: GABRB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27789573, 29100083; Phenotypes: Epileptic encephalopathy, infantile or early childhood, 2, MIM# 617829; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.664 SCN8A Zornitza Stark Publications for gene: SCN8A were set to 31625145; 30842224
Genetic Epilepsy v0.663 SCN8A Zornitza Stark Publications for gene: SCN8A were set to 31625145
Genetic Epilepsy v0.662 GABRA1 Zornitza Stark Marked gene: GABRA1 as ready
Genetic Epilepsy v0.662 GABRA1 Zornitza Stark Gene: gabra1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.662 GABRA1 Zornitza Stark Phenotypes for gene: GABRA1 were changed from to Epileptic encephalopathy, early infantile, 19 615744; Rett syndrome; Rett-like phenotypes; idiopathic generalized Epilepsy; Dravet syndrome
Genetic Epilepsy v0.661 GABRA1 Zornitza Stark Publications for gene: GABRA1 were set to
Genetic Epilepsy v0.660 GABRA1 Zornitza Stark Mode of inheritance for gene: GABRA1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.659 GABRA1 Zornitza Stark reviewed gene: GABRA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11992121, 21714819, 24623842, 30842224; Phenotypes: Epileptic encephalopathy, early infantile, 19 615744, Rett syndrome, Rett-like phenotypes, idiopathic generalized Epilepsy, Dravet syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.659 SAMD12 Zornitza Stark Marked gene: SAMD12 as ready
Genetic Epilepsy v0.659 SAMD12 Zornitza Stark Gene: samd12 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.659 SAMD12 Zornitza Stark Tag deep intronic tag was added to gene: SAMD12.
Genetic Epilepsy v0.659 SAMD12 Zornitza Stark Classified gene: SAMD12 as Green List (high evidence)
Genetic Epilepsy v0.659 SAMD12 Zornitza Stark Gene: samd12 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.658 SAMD12 Zornitza Stark gene: SAMD12 was added
gene: SAMD12 was added to Genetic Epilepsy. 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
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
Genetic Epilepsy v0.657 SCN8A Ain Roesley reviewed gene: SCN8A: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30842224; Phenotypes: Rett syndrome, Rett-like phenotypes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.657 DPYD Zornitza Stark Marked gene: DPYD as ready
Genetic Epilepsy v0.657 DPYD Zornitza Stark Gene: dpyd has been classified as Green List (High Evidence).
Genetic Epilepsy v0.657 DPYD Zornitza Stark Phenotypes for gene: DPYD were changed from to Dihydropyrimidine dehydrogenase deficiency, MIM# 274270
Genetic Epilepsy v0.656 DPYD Zornitza Stark Publications for gene: DPYD were set to
Genetic Epilepsy v0.656 DPYD Zornitza Stark Mode of inheritance for gene: DPYD was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.655 DPYD Zornitza Stark Tag SV/CNV tag was added to gene: DPYD.
Genetic Epilepsy v0.655 DPYD Zornitza Stark reviewed gene: DPYD: Rating: GREEN; Mode of pathogenicity: None; Publications: 19296131, 10071185; Phenotypes: Dihydropyrimidine dehydrogenase deficiency, MIM# 274270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.655 KMT2E Zornitza Stark Phenotypes for gene: KMT2E were changed from Intellectual disability; Autism; Seizures to O'Donnell-Luria-Rodan syndrome, MIM# 618512; Intellectual disability; Autism; Seizures
Genetic Epilepsy v0.654 KMT2E Zornitza Stark edited their review of gene: KMT2E: Added comment: Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. The four individuals with missense variants presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E postulated to explain this divergence in phenotype.; Changed phenotypes: O'Donnell-Luria-Rodan syndrome, MIM# 618512, Intellectual disability, Autism, Seizures
Genetic Epilepsy v0.654 UBA5 Zornitza Stark Marked gene: UBA5 as ready
Genetic Epilepsy v0.654 UBA5 Zornitza Stark Gene: uba5 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.654 UBA5 Zornitza Stark Publications for gene: UBA5 were set to 28965491; 27545674; 27545681
Genetic Epilepsy v0.653 UBA5 Zornitza Stark Phenotypes for gene: UBA5 were changed from to Epileptic encephalopathy, early infantile, 44 (MIM#617132)
Genetic Epilepsy v0.652 UBA5 Zornitza Stark Publications for gene: UBA5 were set to 28965491; 27545674; 27545681
Genetic Epilepsy v0.651 UBA5 Zornitza Stark Publications for gene: UBA5 were set to
Genetic Epilepsy v0.650 UBA5 Zornitza Stark Mode of inheritance for gene: UBA5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.649 UBA5 Zornitza Stark reviewed gene: UBA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 28965491, 27545674, 27545681; Phenotypes: Epileptic encephalopathy, early infantile, 44 (MIM#617132); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.649 AP3B2 Zornitza Stark Marked gene: AP3B2 as ready
Genetic Epilepsy v0.649 AP3B2 Zornitza Stark Gene: ap3b2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.649 AP3B2 Zornitza Stark Phenotypes for gene: AP3B2 were changed from to Early-onset epileptic encephalopathy with optic atrophy, MIM#617276
Genetic Epilepsy v0.648 AP3B2 Zornitza Stark Publications for gene: AP3B2 were set to
Genetic Epilepsy v0.647 AP3B2 Zornitza Stark Mode of inheritance for gene: AP3B2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.646 AP3B2 Zornitza Stark reviewed gene: AP3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27889060; Phenotypes: Early-onset epileptic encephalopathy with optic atrophy, MIM#617276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.646 TFE3 Zornitza Stark Marked gene: TFE3 as ready
Genetic Epilepsy v0.646 TFE3 Zornitza Stark Gene: tfe3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.646 TFE3 Zornitza Stark Classified gene: TFE3 as Green List (high evidence)
Genetic Epilepsy v0.646 TFE3 Zornitza Stark Gene: tfe3 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.645 TFE3 Zornitza Stark gene: TFE3 was added
gene: TFE3 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: TFE3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TFE3 were set to 30595499; 31833172
Phenotypes for gene: TFE3 were set to TFE3-associated neurodevelopmental disorder; Intellectual disability; Epilepsy; Coarse facial features
Review for gene: TFE3 was set to GREEN
Added comment: Seven individuals reported; so far, all have been found to harbour de novo variants affecting exons 3 or 4.
Sources: Expert list
Genetic Epilepsy v0.644 PIGK Zornitza Stark Marked gene: PIGK as ready
Genetic Epilepsy v0.644 PIGK Zornitza Stark Gene: pigk has been classified as Green List (High Evidence).
Genetic Epilepsy v0.644 PIGK Zornitza Stark Classified gene: PIGK as Green List (high evidence)
Genetic Epilepsy v0.644 PIGK Zornitza Stark Gene: pigk has been classified as Green List (High Evidence).
Genetic Epilepsy v0.643 PIGK Zornitza Stark gene: PIGK was added
gene: PIGK was added to Genetic Epilepsy. Sources: Literature
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 Intellectual disability; seizures; cerebellar atrophy
Review for gene: PIGK was set to GREEN
Added comment: 12 individuals from 9 unrelated families reported.
Sources: Literature
Genetic Epilepsy v0.642 ADARB1 Zornitza Stark Classified gene: ADARB1 as Green List (high evidence)
Genetic Epilepsy v0.642 ADARB1 Zornitza Stark Gene: adarb1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.641 ADARB1 Zornitza Stark gene: ADARB1 was added
gene: ADARB1 was added to Genetic Epilepsy. 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 Intellectual disability; microcephaly; seizures
Review for gene: ADARB1 was set to GREEN
Added comment: Four unrelated individuals with bi-allelic variants in this gene.
Sources: Literature
Genetic Epilepsy v0.640 NRROS Zornitza Stark Marked gene: NRROS as ready
Genetic Epilepsy v0.640 NRROS Zornitza Stark Gene: nrros has been classified as Green List (High Evidence).
Genetic Epilepsy v0.640 NRROS Zornitza Stark Classified gene: NRROS as Green List (high evidence)
Genetic Epilepsy v0.640 NRROS Zornitza Stark Gene: nrros has been classified as Green List (High Evidence).
Genetic Epilepsy v0.639 NRROS Zornitza Stark reviewed gene: NRROS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32100099, 32197075; Phenotypes: neurodegeneration, intracranial calcification, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.639 NRROS Sue White gene: NRROS was added
gene: NRROS was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075
Phenotypes for gene: NRROS were set to neurodegeneration; intracranial calcification; epilepsy
Penetrance for gene: NRROS were set to Complete
Genetic Epilepsy v0.638 QARS Zornitza Stark Marked gene: QARS as ready
Genetic Epilepsy v0.638 QARS Zornitza Stark Gene: qars has been classified as Green List (High Evidence).
Genetic Epilepsy v0.638 QARS Zornitza Stark Phenotypes for gene: QARS were changed from to Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MIM# 615760
Genetic Epilepsy v0.637 QARS Zornitza Stark Publications for gene: QARS were set to
Genetic Epilepsy v0.636 QARS Zornitza Stark Mode of inheritance for gene: QARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.635 QARS Zornitza Stark reviewed gene: QARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28620870, 25471517, 25432320, 25041233, 24656866, 32042906; Phenotypes: Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, MIM# 615760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.635 ISCA1 Zornitza Stark Marked gene: ISCA1 as ready
Genetic Epilepsy v0.635 ISCA1 Zornitza Stark Gene: isca1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.635 ISCA1 Zornitza Stark Classified gene: ISCA1 as Green List (high evidence)
Genetic Epilepsy v0.635 ISCA1 Zornitza Stark Gene: isca1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.634 ISCA1 Zornitza Stark gene: ISCA1 was added
gene: ISCA1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122
Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613
Review for gene: ISCA1 was set to GREEN
Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families.
Sources: Expert list
Genetic Epilepsy v0.633 SEMA6B Zornitza Stark Marked gene: SEMA6B as ready
Genetic Epilepsy v0.633 SEMA6B Zornitza Stark Gene: sema6b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.633 SEMA6B Zornitza Stark Classified gene: SEMA6B as Green List (high evidence)
Genetic Epilepsy v0.633 SEMA6B Zornitza Stark Gene: sema6b has been classified as Green List (High Evidence).
Genetic Epilepsy v0.632 SEMA6B Zornitza Stark gene: SEMA6B was added
gene: SEMA6B was added to Genetic Epilepsy. 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
Mode of pathogenicity for gene: SEMA6B was set to Other
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
Genetic Epilepsy v0.630 PURA Zornitza Stark Marked gene: PURA as ready
Genetic Epilepsy v0.630 PURA Zornitza Stark Gene: pura has been classified as Green List (High Evidence).
Genetic Epilepsy v0.630 PURA Zornitza Stark Phenotypes for gene: PURA were changed from to Mental retardation, autosomal dominant 31, MIM# 616158
Genetic Epilepsy v0.629 PURA Zornitza Stark Publications for gene: PURA were set to
Genetic Epilepsy v0.628 PURA Zornitza Stark Mode of inheritance for gene: PURA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.627 PURA Zornitza Stark reviewed gene: PURA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439098, 25342064, 12972605; Phenotypes: Mental retardation, autosomal dominant 31, MIM# 616158; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.627 SYNGAP1 Zornitza Stark Marked gene: SYNGAP1 as ready
Genetic Epilepsy v0.627 SYNGAP1 Zornitza Stark Gene: syngap1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.627 SYNGAP1 Zornitza Stark Phenotypes for gene: SYNGAP1 were changed from to Intellectual disability, autosomal dominant 5, MIM # 612621
Genetic Epilepsy v0.626 SYNGAP1 Zornitza Stark Publications for gene: SYNGAP1 were set to
Genetic Epilepsy v0.625 SYNGAP1 Zornitza Stark Mode of inheritance for gene: SYNGAP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.624 SYNGAP1 Zornitza Stark reviewed gene: SYNGAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26079862; Phenotypes: Intellectual disability, autosomal dominant 5, MIM # 612621; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.624 VARS Zornitza Stark Marked gene: VARS as ready
Genetic Epilepsy v0.624 VARS Zornitza Stark Gene: vars has been classified as Green List (High Evidence).
Genetic Epilepsy v0.624 VARS Zornitza Stark Phenotypes for gene: VARS were changed from to Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy; OMIM #617802
Genetic Epilepsy v0.623 VARS Zornitza Stark Publications for gene: VARS were set to
Genetic Epilepsy v0.622 VARS Zornitza Stark Mode of inheritance for gene: VARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.621 VARS Zornitza Stark reviewed gene: VARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30755616, 30755602, 26539891, 29691655, 30275004; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, OMIM #617802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v0.621 TUBA8 Zornitza Stark Publications for gene: TUBA8 were set to 31481326; 19896110
Genetic Epilepsy v0.620 TUBA8 Zornitza Stark Classified gene: TUBA8 as Red List (low evidence)
Genetic Epilepsy v0.620 TUBA8 Zornitza Stark Gene: tuba8 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.619 TUBA8 Zornitza Stark edited their review of gene: TUBA8: Added comment: However, note that mouse model does not have a brain phenotype and WES in the original families identified homozygous, previously reported as pathogenic, LoF variant in SNAP29, which is much more likely to be causative (28388629).; Changed rating: RED; Changed publications: 31481326, 19896110, 28388629
Genetic Epilepsy v0.619 TRIM8 Zornitza Stark Marked gene: TRIM8 as ready
Genetic Epilepsy v0.619 TRIM8 Zornitza Stark Gene: trim8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.619 TRIM8 Zornitza Stark Phenotypes for gene: TRIM8 were changed from to Intellectual disability; Seizures
Genetic Epilepsy v0.618 TRIM8 Zornitza Stark Publications for gene: TRIM8 were set to
Genetic Epilepsy v0.617 TRIM8 Zornitza Stark Mode of inheritance for gene: TRIM8 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.616 TRIM8 Zornitza Stark reviewed gene: TRIM8: Rating: GREEN; Mode of pathogenicity: None; Publications: 30244534, 27346735, 23934111; Phenotypes: Intellectual disability, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.616 TRAK1 Zornitza Stark reviewed gene: TRAK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, MIM# 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.616 PIGA Zornitza Stark Marked gene: PIGA as ready
Genetic Epilepsy v0.616 PIGA Zornitza Stark Gene: piga has been classified as Green List (High Evidence).
Genetic Epilepsy v0.616 PIGA Zornitza Stark Phenotypes for gene: PIGA were changed from to Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM#300868
Genetic Epilepsy v0.615 PIGA Zornitza Stark Publications for gene: PIGA were set to
Genetic Epilepsy v0.614 PIGA Zornitza Stark Mode of inheritance for gene: PIGA was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.613 PIGA Chern Lim reviewed gene: PIGA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24706016, 24259184, 29159939; Phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM#300868; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.613 TREX1 Zornitza Stark Marked gene: TREX1 as ready
Genetic Epilepsy v0.613 TREX1 Zornitza Stark Gene: trex1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.613 TREX1 Zornitza Stark Phenotypes for gene: TREX1 were changed from to Aicardi-Goutieres syndrome 1, dominant and recessive; Chilblain lupus; {Systemic lupus erythematosus, susceptibility to}; Vasculopathy, retinal, with cerebral leukodystrophy
Genetic Epilepsy v0.612 TREX1 Zornitza Stark Publications for gene: TREX1 were set to
Genetic Epilepsy v0.611 TREX1 Zornitza Stark Mode of inheritance for gene: TREX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.610 TREX1 Zornitza Stark reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937424; Phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive, Chilblain lupus, {Systemic lupus erythematosus, susceptibility to}, Vasculopathy, retinal, with cerebral leukodystrophy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.610 CHD2 Zornitza Stark Marked gene: CHD2 as ready
Genetic Epilepsy v0.610 CHD2 Zornitza Stark Gene: chd2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.610 CHD2 Zornitza Stark Phenotypes for gene: CHD2 were changed from to Epileptic encephalopathy, childhood-onset (MIM # 615369)
Genetic Epilepsy v0.609 CHD2 Zornitza Stark Mode of inheritance for gene: CHD2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.608 RPIA Sebastian Lunke Marked gene: RPIA as ready
Genetic Epilepsy v0.608 RPIA Sebastian Lunke Gene: rpia has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.608 RPIA Sebastian Lunke Classified gene: RPIA as Amber List (moderate evidence)
Genetic Epilepsy v0.608 RPIA Sebastian Lunke Gene: rpia has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.607 RPIA Sebastian Lunke gene: RPIA was added
gene: RPIA was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPIA were set to 14988808; 10589548; 20499043; 28801340; 30088433
Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM 608611
Review for gene: RPIA was set to AMBER
Added comment: 2 of three patients described had seizures.

From GEL: Three patients described in total, one of these with functional data:

Patient 1 with comp het missense and frameshift as well as functional data, early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy

Patient 2 with missense, delayed early development, seizures and regression at the age of 7 with MRI white matter abnormalities

Patient 3 with comp het missense and canonical splice, clinical biochem corroboration ribitol and arabitol in urine demonstrated significant elevations (>20x), neonatal onset leukoencephalopathy and developmental delay
Sources: Expert Review
Genetic Epilepsy v0.606 EML1 Zornitza Stark Marked gene: EML1 as ready
Genetic Epilepsy v0.606 EML1 Zornitza Stark Gene: eml1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.606 EML1 Zornitza Stark Phenotypes for gene: EML1 were changed from to Band heterotopia (MIM# 600348)
Genetic Epilepsy v0.605 EML1 Zornitza Stark Publications for gene: EML1 were set to
Genetic Epilepsy v0.604 EML1 Zornitza Stark Mode of inheritance for gene: EML1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.603 EML1 Zornitza Stark reviewed gene: EML1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31710781; Phenotypes: Band heterotopia (MIM# 600348); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.603 KCNK4 Zornitza Stark Marked gene: KCNK4 as ready
Genetic Epilepsy v0.603 KCNK4 Zornitza Stark Gene: kcnk4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.603 KCNK4 Zornitza Stark Phenotypes for gene: KCNK4 were changed from to Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome 618381
Genetic Epilepsy v0.602 KCNK4 Zornitza Stark Publications for gene: KCNK4 were set to
Genetic Epilepsy v0.601 KCNK4 Zornitza Stark Mode of pathogenicity for gene: KCNK4 was changed from to Other
Genetic Epilepsy v0.601 KCNK4 Zornitza Stark Mode of inheritance for gene: KCNK4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.600 KCNK4 Zornitza Stark reviewed gene: KCNK4: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30290154; Phenotypes: Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome 618381; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.600 GRIN2D Zornitza Stark Marked gene: GRIN2D as ready
Genetic Epilepsy v0.600 GRIN2D Zornitza Stark Gene: grin2d has been classified as Green List (High Evidence).
Genetic Epilepsy v0.600 GRIN2D Zornitza Stark Phenotypes for gene: GRIN2D were changed from to Epileptic encephalopathy, early infantile, 46, MIM# 617162; intellectual disability
Genetic Epilepsy v0.599 GRIN2D Zornitza Stark Publications for gene: GRIN2D were set to
Genetic Epilepsy v0.598 GRIN2D Zornitza Stark Mode of pathogenicity for gene: GRIN2D was changed from to Other
Genetic Epilepsy v0.597 GRIN2D Zornitza Stark Mode of inheritance for gene: GRIN2D was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.596 GRIN2D Zornitza Stark reviewed gene: GRIN2D: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27616483, 30280376; Phenotypes: Epileptic encephalopathy, early infantile, 46, MIM# 617162, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.596 VPS13A Zornitza Stark Marked gene: VPS13A as ready
Genetic Epilepsy v0.596 VPS13A Zornitza Stark Gene: vps13a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.596 VPS13A Zornitza Stark Classified gene: VPS13A as Green List (high evidence)
Genetic Epilepsy v0.596 VPS13A Zornitza Stark Gene: vps13a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.595 VPS13A Bryony Thompson changed review comment from: Epilepsy has been reported as a symptom at onset of the condition in >3 unrelated cases.
Sources: Literature; to: Epilepsy has been reported as a symptom at onset of the condition in at least 8 unrelated cases.
Sources: Literature
Genetic Epilepsy v0.595 VPS13A Bryony Thompson gene: VPS13A was added
gene: VPS13A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: VPS13A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS13A were set to 26813249; 30140251; 31192303
Phenotypes for gene: VPS13A were set to Choreoacanthocytosis MIM#200150
Review for gene: VPS13A was set to GREEN
Added comment: Epilepsy has been reported as a symptom at onset of the condition in >3 unrelated cases.
Sources: Literature
Genetic Epilepsy v0.594 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Rare Disease; Royal Melbourne Hospital
Genetic Epilepsy v0.593 TRAPPC4 Zornitza Stark Marked gene: TRAPPC4 as ready
Genetic Epilepsy v0.593 TRAPPC4 Zornitza Stark Gene: trappc4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.593 TRAPPC4 Zornitza Stark Classified gene: TRAPPC4 as Green List (high evidence)
Genetic Epilepsy v0.593 TRAPPC4 Zornitza Stark Gene: trappc4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.592 TRAPPC4 Zornitza Stark gene: TRAPPC4 was added
gene: TRAPPC4 was added to Genetic Epilepsy. Sources: Expert Review
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 intellectual disability; epilepsy; spasticity; microcephaly
Review for gene: TRAPPC4 was set to GREEN
Added comment: Seven individuals from three unrelated families reported; recurrent splice site variant (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G), not a founder variant.
Sources: Expert Review
Genetic Epilepsy v0.591 TMX2 Zornitza Stark Marked gene: TMX2 as ready
Genetic Epilepsy v0.591 TMX2 Zornitza Stark Gene: tmx2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.591 TMX2 Zornitza Stark Classified gene: TMX2 as Green List (high evidence)
Genetic Epilepsy v0.591 TMX2 Zornitza Stark Gene: tmx2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.590 TMX2 Zornitza Stark gene: TMX2 was added
gene: TMX2 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31735293; 31586943
Phenotypes for gene: TMX2 were set to Microcephaly; ID; brain malformations; seizures
Review for gene: TMX2 was set to GREEN
Added comment: 14 individuals from 10 unrelated families with bi-allelic variants in this gene (31735293) and another four families with recurrent variant (31586943).
Sources: Expert Review
Genetic Epilepsy v0.589 SNX27 Zornitza Stark Marked gene: SNX27 as ready
Genetic Epilepsy v0.589 SNX27 Zornitza Stark Gene: snx27 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.589 SNX27 Zornitza Stark Classified gene: SNX27 as Green List (high evidence)
Genetic Epilepsy v0.589 SNX27 Zornitza Stark Gene: snx27 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.588 SNX27 Zornitza Stark gene: SNX27 was added
gene: SNX27 was added to Genetic Epilepsy. Sources: Expert Review
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 intellectual disability; seizures
Review for gene: SNX27 was set to GREEN
Added comment: Three unrelated families and animal model.
Sources: Expert Review
Genetic Epilepsy v0.587 PUM1 Zornitza Stark Marked gene: PUM1 as ready
Genetic Epilepsy v0.587 PUM1 Zornitza Stark Gene: pum1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.587 PUM1 Zornitza Stark Phenotypes for gene: PUM1 were changed from ataxia; intellectual disability; epilepsy to intellectual disability; epilepsy; Spinocerebellar ataxia 47, MIM# 617931
Genetic Epilepsy v0.586 PUM1 Zornitza Stark Classified gene: PUM1 as Green List (high evidence)
Genetic Epilepsy v0.586 PUM1 Zornitza Stark Gene: pum1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.585 PUM1 Zornitza Stark gene: PUM1 was added
gene: PUM1 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUM1 were set to 29474920; 25768905; 30903679; 31859446
Phenotypes for gene: PUM1 were set to ataxia; intellectual disability; epilepsy
Review for gene: PUM1 was set to GREEN
Added comment: More than 10 families reported. Individuals with either PUM1 deletions or de novo missense variants have a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). One family with milder missense variant and adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA)
Sources: Expert Review
Genetic Epilepsy v0.584 PMPCB Zornitza Stark Marked gene: PMPCB as ready
Genetic Epilepsy v0.584 PMPCB Zornitza Stark Gene: pmpcb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.584 PMPCB Zornitza Stark Classified gene: PMPCB as Green List (high evidence)
Genetic Epilepsy v0.584 PMPCB Zornitza Stark Gene: pmpcb has been classified as Green List (High Evidence).
Genetic Epilepsy v0.583 PMPCB Zornitza Stark gene: PMPCB was added
gene: PMPCB was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMPCB were set to 29576218
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954
Review for gene: PMPCB was set to GREEN
Added comment: Five individuals from four families; seizures in 4/5 individuals reported, onset in infancy.
Sources: Expert list
Genetic Epilepsy v0.582 PCYT2 Zornitza Stark Marked gene: PCYT2 as ready
Genetic Epilepsy v0.582 PCYT2 Zornitza Stark Gene: pcyt2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.582 PCYT2 Zornitza Stark Classified gene: PCYT2 as Green List (high evidence)
Genetic Epilepsy v0.582 PCYT2 Zornitza Stark Gene: pcyt2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.581 PCYT2 Zornitza Stark gene: PCYT2 was added
gene: PCYT2 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to intellectual disability; regression; spastic para-/tetraparesis; epilepsy; progressive cerebral and cerebellar atrophy
Review for gene: PCYT2 was set to GREEN
Added comment: Five individuals from four families.
Sources: Expert list
Genetic Epilepsy v0.580 OXR1 Zornitza Stark Marked gene: OXR1 as ready
Genetic Epilepsy v0.580 OXR1 Zornitza Stark Gene: oxr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.580 OXR1 Zornitza Stark Classified gene: OXR1 as Green List (high evidence)
Genetic Epilepsy v0.580 OXR1 Zornitza Stark Gene: oxr1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.579 OXR1 Zornitza Stark gene: OXR1 was added
gene: OXR1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXR1 were set to 31785787; 22028674
Phenotypes for gene: OXR1 were set to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay, MIM# 213000
Review for gene: OXR1 was set to GREEN
Added comment: Five individuals from three unrelated families, supportive animal models.
Sources: Literature
Genetic Epilepsy v0.578 NSF Zornitza Stark Marked gene: NSF as ready
Genetic Epilepsy v0.578 NSF Zornitza Stark Gene: nsf has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.578 NSF Zornitza Stark Classified gene: NSF as Amber List (moderate evidence)
Genetic Epilepsy v0.578 NSF Zornitza Stark Gene: nsf has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.577 NSF Zornitza Stark gene: NSF was added
gene: NSF was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NSF were set to 31675180
Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Review for gene: NSF was set to AMBER
Added comment: Two individuals reported with de novo missense variants in this gene.
Sources: Literature
Genetic Epilepsy v0.576 KAT8 Zornitza Stark Marked gene: KAT8 as ready
Genetic Epilepsy v0.576 KAT8 Zornitza Stark Gene: kat8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.576 KAT8 Zornitza Stark Classified gene: KAT8 as Green List (high evidence)
Genetic Epilepsy v0.576 KAT8 Zornitza Stark Gene: kat8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.575 KAT8 Zornitza Stark gene: KAT8 was added
gene: KAT8 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KAT8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KAT8 were set to 31794431
Phenotypes for gene: KAT8 were set to Intellectual disability; seizures; autism; dysmorphic features
Review for gene: KAT8 was set to GREEN
Added comment: Eight unrelated individuals reported with de novo variants in this gene and a mouse model. All variants missense, in the chromobarrel domain or the acetyltransferase domain; three individuals had the same variant p.Tyr90Cys . One more individual reported with bi-allelic variants: one missense and one frameshift; carrier parents were normal suggesting that may be haploinsuffiency is not the mechanism.
Sources: Literature
Genetic Epilepsy v0.574 SCN9A Zornitza Stark Marked gene: SCN9A as ready
Genetic Epilepsy v0.574 SCN9A Zornitza Stark Gene: scn9a has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.574 SCN9A Zornitza Stark Phenotypes for gene: SCN9A were changed from to {Dravet syndrome, modifier of} MIM#607208; Epilepsy, generalized, with febrile seizures plus, type 7 MIM#613863; Febrile seizures, familial, 3B MIM#613863
Genetic Epilepsy v0.573 SCN9A Zornitza Stark Publications for gene: SCN9A were set to
Genetic Epilepsy v0.572 SCN9A Zornitza Stark Mode of inheritance for gene: SCN9A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.571 SCN9A Zornitza Stark Classified gene: SCN9A as Amber List (moderate evidence)
Genetic Epilepsy v0.571 SCN9A Zornitza Stark Gene: scn9a has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.570 SCN9A Zornitza Stark reviewed gene: SCN9A: Rating: AMBER; Mode of pathogenicity: None; Publications: 19763161, 29500686, 30834459, 23895530; Phenotypes: {Dravet syndrome, modifier of} MIM#607208, Epilepsy, generalized, with febrile seizures plus, type 7 MIM#613863, Febrile seizures, familial, 3B MIM#613863; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.570 HNRNPU Zornitza Stark Marked gene: HNRNPU as ready
Genetic Epilepsy v0.570 HNRNPU Zornitza Stark Gene: hnrnpu has been classified as Green List (High Evidence).
Genetic Epilepsy v0.570 HNRNPU Zornitza Stark Phenotypes for gene: HNRNPU were changed from to Epileptic encephalopathy, early infantile, 54, MIM#617391
Genetic Epilepsy v0.569 HNRNPU Zornitza Stark Publications for gene: HNRNPU were set to Epileptic encephalopathy, early infantile, 54, MIM#617391
Genetic Epilepsy v0.568 HNRNPU Zornitza Stark Publications for gene: HNRNPU were set to
Genetic Epilepsy v0.567 HNRNPU Zornitza Stark Mode of inheritance for gene: HNRNPU was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.566 HNRNPU Zornitza Stark reviewed gene: HNRNPU: Rating: GREEN; Mode of pathogenicity: None; Publications: Epileptic encephalopathy, early infantile, 54, MIM#617391; Phenotypes: 28944577, 28393272; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.566 SERPINI1 Zornitza Stark Marked gene: SERPINI1 as ready
Genetic Epilepsy v0.566 SERPINI1 Zornitza Stark Gene: serpini1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.566 SERPINI1 Zornitza Stark Classified gene: SERPINI1 as Green List (high evidence)
Genetic Epilepsy v0.566 SERPINI1 Zornitza Stark Gene: serpini1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.565 NEU1 Zornitza Stark Marked gene: NEU1 as ready
Genetic Epilepsy v0.565 NEU1 Zornitza Stark Gene: neu1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.565 NEU1 Zornitza Stark Classified gene: NEU1 as Green List (high evidence)
Genetic Epilepsy v0.565 NEU1 Zornitza Stark Gene: neu1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.564 CERS1 Zornitza Stark Marked gene: CERS1 as ready
Genetic Epilepsy v0.564 CERS1 Zornitza Stark Gene: cers1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.564 CERS1 Zornitza Stark Classified gene: CERS1 as Green List (high evidence)
Genetic Epilepsy v0.564 CERS1 Zornitza Stark Gene: cers1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.563 AFG3L2 Zornitza Stark Marked gene: AFG3L2 as ready
Genetic Epilepsy v0.563 AFG3L2 Zornitza Stark Added comment: Comment when marking as ready: The two families reported with ballelic variants appear distantly related. One family with mono-allelic variant.
Genetic Epilepsy v0.563 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.563 SERPINI1 Bryony Thompson gene: SERPINI1 was added
gene: SERPINI1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: SERPINI1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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
Added comment: >3 unrelated families with progressive myoclonus epilepsy.
Sources: Expert list
Genetic Epilepsy v0.562 NEU1 Bryony Thompson gene: NEU1 was added
gene: NEU1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: NEU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEU1 were set to 25401298; 14517945
Phenotypes for gene: NEU1 were set to Sialidosis, type I/II MIM#256550
Review for gene: NEU1 was set to GREEN
Added comment: >3 unrelated cases/families reported with progressive myoclonic epilepsy
Sources: Expert list
Genetic Epilepsy v0.561 CERS1 Bryony Thompson gene: CERS1 was added
gene: CERS1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: CERS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CERS1 were set to 24782409; 21625621; 30800706
Phenotypes for gene: CERS1 were set to Epilepsy, progressive myoclonic, 8 MIM#616230
Review for gene: CERS1 was set to GREEN
Added comment: Two unrelated families with PME identified, and functional assays in vitro and in patient cells demonstrating impaired ceramide biosynthesis. Mouse model shows neurodegeneration and lipofuscin accumulation.
Sources: Expert list
Genetic Epilepsy v0.560 AFG3L2 Bryony Thompson gene: AFG3L2 was added
gene: AFG3L2 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: AFG3L2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AFG3L2 were set to 25401298; 22022284; 25927548
Phenotypes for gene: AFG3L2 were set to Spastic ataxia 5, autosomal recessive MIM#614487; Spinocerebellar ataxia 28 MIM#610246
Review for gene: AFG3L2 was set to AMBER
Added comment: Currently two clear-cut reports of PME associated with biallelic variants in this gene. Two Italian patients with the same homozygous variant (found to be related through identity by decent analysis), who presented with severe progressive myoclonus at age 10 years after normal early development. Progressive myoclonic epilepsy found to be a feature of the phenotype in a consanguineous family with a homozygous variant. Family with a homozygous SETX variant and a heterozygous AFG3L2 variant with ataxia with postural/intentional myoclonus and involuntary movements, where the myoclonus phenotype appears to be segregating with the AFG3L2 variant.
Sources: Expert list
Genetic Epilepsy v0.559 RALGAPA1 Zornitza Stark Marked gene: RALGAPA1 as ready
Genetic Epilepsy v0.559 RALGAPA1 Zornitza Stark Gene: ralgapa1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.559 RALGAPA1 Zornitza Stark Classified gene: RALGAPA1 as Green List (high evidence)
Genetic Epilepsy v0.559 RALGAPA1 Zornitza Stark Gene: ralgapa1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.558 RALGAPA1 Zornitza Stark gene: RALGAPA1 was added
gene: RALGAPA1 was added to Genetic Epilepsy. Sources: Literature
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
Added comment: Four unrelated individuals reported.
Sources: Literature
Genetic Epilepsy v0.557 GNAO1 Zornitza Stark Marked gene: GNAO1 as ready
Genetic Epilepsy v0.557 GNAO1 Zornitza Stark Gene: gnao1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.557 GNAO1 Zornitza Stark Phenotypes for gene: GNAO1 were changed from to Epileptic encephalopathy, early infantile, 17; Neurodevelopmental disorder with involuntary movements
Genetic Epilepsy v0.556 GNAO1 Zornitza Stark Publications for gene: GNAO1 were set to
Genetic Epilepsy v0.555 GNAO1 Zornitza Stark Mode of inheritance for gene: GNAO1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.554 GNAO1 Zornitza Stark reviewed gene: GNAO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28747448, 30682224; Phenotypes: Epileptic encephalopathy, early infantile, 17, Neurodevelopmental disorder with involuntary movements; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.554 ALKBH8 Zornitza Stark Classified gene: ALKBH8 as Green List (high evidence)
Genetic Epilepsy v0.554 ALKBH8 Zornitza Stark Gene: alkbh8 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.553 ST3GAL3 Zornitza Stark Marked gene: ST3GAL3 as ready
Genetic Epilepsy v0.553 ST3GAL3 Zornitza Stark Gene: st3gal3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.553 ST3GAL3 Zornitza Stark Phenotypes for gene: ST3GAL3 were changed from to Epileptic encephalopathy, early infantile, 15 , MIM#615006
Genetic Epilepsy v0.552 ST3GAL3 Zornitza Stark Publications for gene: ST3GAL3 were set to