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Genetic Epilepsy v1.373 Bryony Thompson Copied gene GAL from panel Mendeliome
Genetic Epilepsy v1.373 GAL Bryony Thompson gene: GAL was added
gene: GAL was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GAL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GAL were set to 25691535
Phenotypes for gene: GAL were set to familial temporal lobe epilepsy 8 MONDO:0014650
Genetic Epilepsy v1.241 RNU6ATAC Lucy Spencer gene: RNU6ATAC was added
gene: RNU6ATAC was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RNU6ATAC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU6ATAC were set to 40975062
Phenotypes for gene: RNU6ATAC were set to Neurodevelopmental disorder (MONDO:0700092), RNU6ATAC-related
Review for gene: RNU6ATAC was set to RED
Added comment: PMID: 40975062 1 patient compound heterozygous for n.36T>G and n.28C>T. Has short stature, microcephaly, hypotonia, neurodevelopmental delay, ID, seizures, ataxia, ventriculomegaly, syndactyly, nystagmus and oculomotor apraxia. Identified in a cohort of individuals with an excess of significant intron retention outliers in minor intron containing genes which are usually removed by the minor spliceosome of which RNU6ATAC is a part (as is RNU4ATAC). Proband had no candidate variants in RNU4ATAC or RNU12. Both RNU6ATAC variants are in a highly conserved 39bp region, and affect nucleotides predicted to be important for binding to U4ATAC.
Sources: Literature
Genetic Epilepsy v1.95 INPP4A Chirag Patel gene: INPP4A was added
gene: INPP4A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to PMID: 39315527
Phenotypes for gene: INPP4A were set to INPP4A-related neurodevelopmental disorder
Review for gene: INPP4A was set to GREEN
Added comment: PMID: 39315527
30 individuals (aged 6 months to 40 years) from 17 unrelated families with biallelic LOF variants in INPP4A gene (11 nonsense or frameshift and 3 missense, mostly exon 4).

Cardinal clinical features include: severe global developmental delay, profound speech impairment, severe-profound intellectual disability, and severe lower limb weakness/paralysis. More variable clinical features include: microcephaly, short stature, cerebellar signs, involuntary movements, axial hypotonia, spasticity, quadriparesis, joint contractures, seizures, visual impairment. Neuroimaging findings vary from normal to features of (ponto)cerebellar hypoplasia, ventriculomegaly, reduced cerebral volume and hypomyelination. A more severe presentation is seen with variants downstream of exon 4.

Preliminary fibroblast cell studies identify disruption of endocytic pathways as the likely mechanism of disease, consistent with previous findings of a role of INPP4A in endocytosis. All mouse models display a phenotype mirroring human INPP4A-related neurodevelopmental disorder entailing a severe movement disorder with inability to walk, a small brain, and poor growth/weight gain.
Sources: Literature
Genetic Epilepsy v1.81 TCP1 Ain Roesley gene: TCP1 was added
gene: TCP1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCP1 were set to 39480921
Phenotypes for gene: TCP1 were set to neurodevelopmental disorder MONDO:0700092, TCP1-related
Penetrance for gene: TCP1 were set to Complete
Review for gene: TCP1 was set to GREEN
gene: TCP1 was marked as current diagnostic
Added comment: previously known as CCT1

8x individuals including 5x de novo
6x PTCs + 2x missense

6/8 DD/ID
2/8 visual impairment
6/8 seizures
6/8 polymicrogyria + 1x Ventriculomegaly, white matter hyperintensities
Sources: Literature
Genetic Epilepsy v1.29 VPS50 Ain Roesley commented on gene: VPS50: 1x proband Chet for a nonsense p.(Lys5*) and a complex structural variant of a 4.3Mb inversion, flanked by 170kb and 428kb deletions, respectively. The 428kb deletion spans the entire VPS50 gene.

Sanger confirmed the Lys5* to be 'homozygous' in the proband.

Phenotypes include:
severe ID, muscular hypotonia, sensorineural hearing impairment, microcephaly, nystagmus, seizures, hypoplastic corpus callous, neonatal low GGT cholesatsis, hepatomegaly, failure to thrive
Genetic Epilepsy v0.2759 WDR73 Ain Roesley Phenotypes for gene: WDR73 were changed from Galloway-Mowat syndrome 1 MIM#251300 to Galloway-Mowat syndrome 1 MIM#251300
Genetic Epilepsy v0.2759 WDR73 Ain Roesley Phenotypes for gene: WDR73 were changed from Galloway-Mowat syndrome 1 MIM#251300 to Galloway-Mowat syndrome 1 MIM#251300
Genetic Epilepsy v0.2758 WDR73 Ain Roesley Phenotypes for gene: WDR73 were changed from to Galloway-Mowat syndrome 1 MIM#251300
Genetic Epilepsy v0.2741 STRADA Zornitza Stark Phenotypes for gene: STRADA were changed from to Polyhydramnios, megalencephaly, and symptomatic epilepsy, OMIM:611087; Polyhydramnios, megalencephaly, and symptomatic epilepsy, MONDO:0012611
Genetic Epilepsy v0.2686 RNASET2 Zornitza Stark Phenotypes for gene: RNASET2 were changed from to Leukoencephalopathy, cystic, without megalencephaly MIM#612951
Genetic Epilepsy v0.2649 PIK3R2 Zornitza Stark Phenotypes for gene: PIK3R2 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, MIM# 603387
Genetic Epilepsy v0.2508 MLC1 Zornitza Stark Phenotypes for gene: MLC1 were changed from to Megalencephalic leukoencephalopathy with subcortical cysts (MIM#604004)
Genetic Epilepsy v0.2458 IKBKG Zornitza Stark changed review comment from: X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature. 6 unrelated boys and a girl reported. All variants resulted in absence of the domain encoded by exon 5 (NEMOdelEx5).

Note variants in this gene are associated with immunodeficiency +/- ectodermal features and with IP.; to: X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature. 6 unrelated boys and a girl reported. All variants resulted in absence of the domain encoded by exon 5 (NEMOdelEx5).

Note variants in this gene are associated with immunodeficiency +/- ectodermal features and with IP.

Seizures reported in the IP phenotype.
Genetic Epilepsy v0.2425 HEPACAM Zornitza Stark Phenotypes for gene: HEPACAM were changed from to Megalencephalic leukoencephalopathy with subcortical cysts 2A, MIM# 613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, MIM# 613926
Genetic Epilepsy v0.2388 GALC Zornitza Stark Marked gene: GALC as ready
Genetic Epilepsy v0.2388 GALC Zornitza Stark Gene: galc has been classified as Green List (High Evidence).
Genetic Epilepsy v0.2388 GALC Zornitza Stark Phenotypes for gene: GALC were changed from to Krabbe disease, MIM# 245200; MONDO:0009499
Genetic Epilepsy v0.2387 GALC Zornitza Stark Publications for gene: GALC were set to
Genetic Epilepsy v0.2386 GALC Zornitza Stark Mode of inheritance for gene: GALC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.2267 TBC1D7 Elena Savva gene: TBC1D7 was added
gene: TBC1D7 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: TBC1D7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D7 were set to 23687350; 24515783
Phenotypes for gene: TBC1D7 were set to Macrocephaly/megalencephaly syndrome, autosomal recessive MIM#248000
Review for gene: TBC1D7 was set to RED
Added comment: PMID: 23687350 - There is no history of seizures in two siblings, but EEG recording showed some epileptic activity in the right temporal lobe

PMID: 24515783 - There is no history of seizures; EEG and brain SPECT were normal.

Gene was listed in the Oliver list
Sources: Literature
Genetic Epilepsy v0.2130 CCND2 Lilian Downie gene: CCND2 was added
gene: CCND2 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: CCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCND2 were set to PMID: 24705253
Phenotypes for gene: CCND2 were set to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 MIM#615938
Review for gene: CCND2 was set to RED
Added comment: seizures not reported in MPPH due to this gene to date
Sources: Expert list
Genetic Epilepsy v0.2060 PEX10 Lauren Rogers gene: PEX10 was added
gene: PEX10 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PEX10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PEX10 were set to 32069232
Phenotypes for gene: PEX10 were set to Peroxisome biogenesis disorder 6A (Zellweger), MIM#614870
Review for gene: PEX10 was set to RED
Added comment: PMID: 32069232: A case report of a 4 month old boy with Zellweger syndrome, with myoclonic seizures, hypotonia and hepatosplenomegaly, who was homozygous for a p.(C296F) variant.
Sources: Literature
Genetic Epilepsy v0.2038 CSF1R Andrew Fennell gene: CSF1R was added
gene: CSF1R was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CSF1R was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CSF1R were set to PMID: 22197934; 24336230; 30982608; 30982609
Phenotypes for gene: CSF1R were set to Brain abnormalities, neurodegeneration, and dysosteosclerosis, (MIM#618476)
Review for gene: CSF1R was set to GREEN
Added comment: Monoallelic disease is onset in 3rd or 4th decades whereas biallelic disease is associated with early-onset disease in infancy or childhood.

Monoallelic association:
PMID: 22197934 - 13/23 individuals from 9 different families reported to have seizures.
PMID: 24336230 - 2/7 individuals with seizures reported from a Japanese cohort.

Biallelic association:
PMID: 30982608 - Two individuals with a seizure history. First was an infant who presented with prenatal structural brain abnormalities, including ACC, ventriculomegaly, and pontocerebellar hypoplasia, and died at 10 months had intractable epilepsy. Second individuals presented with generalized tonic-clonic seizures aged 12 years old associated with regression and loss of all skills.

PMID: 30982609 - Two individuals with seizures were reported from a cohort of 7 individuals. A-III-1 was a male infant who developed seizures in early infancy (after 3 months of age). Individual C-III-4 was a male who developed focal seizures in early infancy.
Sources: Literature
Genetic Epilepsy v0.2030 B3GALNT2 Zornitza Stark Marked gene: B3GALNT2 as ready
Genetic Epilepsy v0.2030 B3GALNT2 Zornitza Stark Gene: b3galnt2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.2030 B3GALNT2 Zornitza Stark Classified gene: B3GALNT2 as Green List (high evidence)
Genetic Epilepsy v0.2030 B3GALNT2 Zornitza Stark Gene: b3galnt2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.2028 B3GALNT2 Lilian Downie gene: B3GALNT2 was added
gene: B3GALNT2 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: B3GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GALNT2 were set to PMID: 29791932, PMID: 29273094, PMID: 35127920
Phenotypes for gene: B3GALNT2 were set to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 11 MIM#615181
Review for gene: B3GALNT2 was set to GREEN
Added comment: Severe congenital muscular dystrophy and ID phenotype. Seizures not consistent feature with early phenotypic reports
PMID: 29791932 epileptic encephalopathy
PMID: 29273094 5 individuals with ID and seizures from single large consanguineous family but they had no or mild muscle symptoms so quite different from previously reported phenotype
PMID: 35127920 not a great article but does have a table summarising the previous cases and 9/21 had seizures.
Sources: Expert list
Genetic Epilepsy v0.1898 USP18 Zornitza Stark gene: USP18 was added
gene: USP18 was added to Genetic Epilepsy. Sources: Expert Review
treatable tags were added to gene: USP18.
Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP18 were set to 12833411; 27325888; 31940699
Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2, MIM#617397
Review for gene: USP18 was set to GREEN
Added comment: - PMID: 27325888 (2016) - Three sibs from a consanguineous Turkish family with a homozygous variant (c.652C>T, p.Q218X) in USP18. Antenatal presentation in one sib led to termination of pregnancy at 22 wk of gestation, and in the remaining two children presentation was neonatal and resulted in death within 2 weeks of life. In the latter two individuals manifestations included severe intracerebral haemorrhages, liver dysfunction, ascites, and lactic acidosis. One sib additionally had severe thrombocytopenia with petechiae, while the other developed seizures.

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

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

- PMID: 31940699 (2020) - One Saudi Arabian boy with a homozygous splice-site variant (c.1073+1G>A) in USP18, presented hydrocephalus with seizures, intraventricular haemorrhage, brain calcifications, necrotizing cellulitis, systemic inflammation, multiple organ failure, and respiratory failure. This was the only patient to survive beyond the perinatal period owing to supportive care and prompt treatment with ruxolitinib. At the time of publication, the child was 3-years-old and was in full remission of clinical manifestations while continuing to receive oral ruxolitinib. He continues to grow normally, however authors note delay in developmental milestones.
Sources: Expert Review
Genetic Epilepsy v0.1879 AQP4 Zornitza Stark Phenotypes for gene: AQP4 were changed from ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448 to Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448
Genetic Epilepsy v0.1877 AQP4 Zornitza Stark reviewed gene: AQP4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1876 AQP4 Lucy Spencer gene: AQP4 was added
gene: AQP4 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: AQP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AQP4 were set to PMID: 37143309
Phenotypes for gene: AQP4 were set to ?Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting MIM#620448
Review for gene: AQP4 was set to AMBER
Added comment: PMID: 37143309
Cohort of 5 patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). Missense variant in AQP4 seen homozygous in 2 siblings and het in the parents. Patients had macrocephaly, developmental delay, hypotonia, epilepsy, and cognitive deficit.

Western blots on generated MDCK cell lines showed no detectable expression of AQP4 protein from the cells with the patients variant. Immunofluorescence also showed no membrane expression. Overexpression studies in HEK293T cells showed WT was seen as mainly monomers or dimers where as variant protein formed large aggregates- likely due to the saturation of protein degradation pathways because of the overexpression.
Sources: Literature
Genetic Epilepsy v0.1876 GPRC5B Lucy Spencer gene: GPRC5B was added
gene: GPRC5B was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: GPRC5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPRC5B were set to 37143309
Phenotypes for gene: GPRC5B were set to Megalencephalic leukoencephalopathy with subcortical cysts 3 MIM#620447
Review for gene: GPRC5B was set to GREEN
Added comment: PMID: 37143309
Cohort of 5 patients with an MRI based diagnosis of megalencephalic leukoencephalopathy with subcortical cysts (MLC). 3 unrelated patients had variants in GPRC5B, 2 have the same inframe dup Ile175dup and the third has an in frame dup of Ala177. All 3 were de novo and unaffected siblings did not have the variants. All patients have macrocephaly, delayed motor development, seizures, all had varying degrees of cognitive deficits. 2 also had spasticity, ataxia and dystonia. MRI showed MLC, abnormal and swollen cerebral white matter.

Patient cell lines showed reduced regulatory volume decrease, and western blot showed a strong increase in GRPC5B levels in patient lymphoblasts. Together, these findings indicate disturbed volume regulation in lymphoblasts from patients with GPRC5B variants, potentially due to increased GPRC5B levels. Transfected cells caused increased volume-regulated anion channel activity.
Sources: Literature
Genetic Epilepsy v0.1836 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Genetic Epilepsy v0.1798 PI4K2A Seb Lunke gene: PI4K2A was added
gene: PI4K2A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 30564627; 35880319; 19581584
Phenotypes for gene: PI4K2A were set to complex neurodevelopmental disorder with motor features, PI4K2A-related, MONDO:0100516
Review for gene: PI4K2A was set to GREEN
Added comment: Two reportedly unrelated, consanguine families with the same hom stop mutation in PI4K2A, p.(Arg309Ter). Probands with seizures, developmental delay, hypotonia/dystonia, myoclonus and developmental delay. MRI showed extensive brain abnormalities including dysgenesis of the corpus callosum, ventriculomegaly, and white matter volume loss.

Functional studies showed cellular mislocalisation of the Arg309Ter truncated protein construct compared to WT and an missense control.

An earlier paper from 2018 described two additional probands with a different stop mutation, p.(Ser22Ter), and overlapping phenotypic presentation.

in 2011, a Pi4k2a knock-out mouse model was described. "Knock-out animals initially appeared normal but later develop a progressive neurological dis-ease characterized by tremor, limb weakness, urinary incontinence and premature mortality. Histological analysis revealed massive axonal degeneration in the spinal cord in the descending corticospinal tracts."
Sources: Literature
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 v0.1317 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 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 v0.1282 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 v0.1165 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 v0.1079 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 v0.982 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 v0.948 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 v0.947 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 v0.676 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 v0.553 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
Genetic Epilepsy v0.551 ST3GAL3 Zornitza Stark Mode of inheritance for gene: ST3GAL3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.550 ST3GAL3 Zornitza Stark Classified gene: ST3GAL3 as Amber List (moderate evidence)
Genetic Epilepsy v0.550 ST3GAL3 Zornitza Stark Gene: st3gal3 has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.548 DHFR Zornitza Stark gene: DHFR was added
gene: DHFR was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: DHFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHFR were set to 21310276; 21310277
Phenotypes for gene: DHFR were set to Megaloblastic anemia due to dihydrofolate reductase deficiency, MIM# 613839
Review for gene: DHFR was set to AMBER
Added comment: Three unrelated families reported, neurological disease in some severe (including seizures), others predominantly haematological presentation.
Sources: Expert Review
Genetic Epilepsy v0.473 ST3GAL3 Zornitza Stark reviewed gene: ST3GAL3: Rating: AMBER; Mode of pathogenicity: None; Publications: 23252400, 31584066; Phenotypes: Epileptic encephalopathy, early infantile, 15 , MIM#615006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.419 PIK3CA Zornitza Stark Phenotypes for gene: PIK3CA were changed from Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, MIM#602501 to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, MIM#602501
Genetic Epilepsy v0.419 PIK3CA Zornitza Stark Phenotypes for gene: PIK3CA were changed from to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, MIM#602501
Genetic Epilepsy v0.416 PIK3CA Zornitza Stark reviewed gene: PIK3CA: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, MIM#602501; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Genetic Epilepsy v0.359 MTR Zornitza Stark Phenotypes for gene: MTR were changed from Homocystinuria-megaloblastic anemia, cblG complementation type, MIM#250940 to Homocystinuria-megaloblastic anemia, cblG complementation type, MIM#250940
Genetic Epilepsy v0.358 MTR Zornitza Stark Phenotypes for gene: MTR were changed from to Homocystinuria-megaloblastic anemia, cblG complementation type, MIM#250940
Genetic Epilepsy v0.356 MTR Zornitza Stark reviewed gene: MTR: Rating: GREEN; Mode of pathogenicity: None; Publications: 25526710, 9683607, 28666289; Phenotypes: Homocystinuria-megaloblastic anemia, cblG complementation type, MIM#250940; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.0 ST3GAL5 Zornitza Stark gene: ST3GAL5 was added
gene: ST3GAL5 was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Australian Genomics Health Alliance Epilepsy Flagship,Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ST3GAL5 was set to Unknown
Genetic Epilepsy v0.0 ST3GAL3 Zornitza Stark gene: ST3GAL3 was added
gene: ST3GAL3 was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Australian Genomics Health Alliance Epilepsy Flagship,Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ST3GAL3 was set to Unknown
Genetic Epilepsy v0.0 GALC Zornitza Stark gene: GALC was added
gene: GALC was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Australian Genomics Health Alliance Epilepsy Flagship,Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: GALC was set to Unknown