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Genetic Epilepsy v2.21 PREP chirag patel Marked gene: PREP as ready
Genetic Epilepsy v2.21 PREP chirag patel Gene: prep has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v2.21 chirag patel Copied gene PREP from panel Mendeliome
Genetic Epilepsy v2.21 PREP chirag patel gene: PREP was added
gene: PREP was added to Genetic Epilepsy. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: PREP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PREP were set to 42362369
Phenotypes for gene: PREP were set to Neurodevelopmental disorder (MONDO:0700092), PREP-related
Genetic Epilepsy v1.216 AP2S1 Zornitza Stark gene: AP2S1 was added
gene: AP2S1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AP2S1 were set to 31981491; 33057194; 35982160; 35982159
Phenotypes for gene: AP2S1 were set to Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Review for gene: AP2S1 was set to GREEN
Added comment: Several isolated cases with de novo missense variants in large NDD cohorts PMID: 31981491;33057194;35982160;35982159.

26 unrelated NDD in a preprint with 5 recurring de novo missenses p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His https://doi.org/10.1101/2024.07.22.24310683. 70% had epilepsy, 50% brain anomalies.
Sources: Literature
Genetic Epilepsy v1.190 RNF2 Zornitza Stark edited their review of gene: RNF2: Added comment: PMID 40831499 is a preprint which identifies additional individuals with de novo variants. p.S82R is recurrent. Functional data to support gene-disease association.; Changed rating: GREEN; Changed publications: 33864376, 40831499
Genetic Epilepsy v1.186 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Genetic Epilepsy v1.172 BLOC1S1 Rylee Peters gene: BLOC1S1 was added
gene: BLOC1S1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to https://www.medrxiv.org/content/10.1101/2025.07.17.25331211v1
Phenotypes for gene: BLOC1S1 were set to Neurodevelopmental disorder (MONDO:0700092), BLOC1S1-related
Review for gene: BLOC1S1 was set to GREEN
Added comment: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Sources: Literature
Genetic Epilepsy v0.2028 PRUNE1 Chris Ciotta gene: PRUNE1 was added
gene: PRUNE1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PRUNE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRUNE1 were set to PMID: 28334956; 26539891; 30556349; 29940663; 29797509
Phenotypes for gene: PRUNE1 were set to Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MIM#617481
Review for gene: PRUNE1 was set to GREEN
Added comment: PRUNE1 is associated with neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (MIM#617481). Seizures are a listed phenotype in OMIM in some patients.
- Seizures were seen in 6/13 individuals (PMID:28334956) from Oman, Iran, India and Italy, the variants identified in individuals with seizures were absent from gnomAD besides the commonly reported Asp109Asn variant (41 hets, 0 Homs in V4) which has also been extensively reported in ClinVar (10x pathogenic reports).
- Seizures were also reported in 7/9 Cree children from the Canadian province of Manitoba (PMID:30556349), they all shared a likely founder homozygous c.521-2A>G splicing variant. The normally spliced product was absent in RNA prepared from two individuals with exon 5 skipping or multiple exon skipping leading to a frameshift and premature termination observed as outcomes of this variant.
- Epilepsy was reported in 11/12 unrelated individuals (paediatric patients with neurological symptoms from Munich) with bi-allelic variants in PRUNE1 (PMID:29940663).
Sources: Literature
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 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 v0.776 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 v0.155 AFF3 Zornitza Stark gene: AFF3 was added
gene: AFF3 was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Expert list
Mode of inheritance for gene: AFF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: AFF3 were set to Intellectual disability; seizures; hypertrichosis
Review for gene: AFF3 was set to GREEN
Added comment: Voisin et al, 2019 (preprint) - New AD disorder associated with de novo missense variants in AFF3. 10 unrelated affected individuals with de novo missense variants. 10/11 had epilepsy. Functional data including animal model.
Sources: Expert list