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| Genetic Epilepsy v0.2195 | LMNB2 |
Elena Savva gene: LMNB2 was added gene: LMNB2 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: LMNB2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LMNB2 were set to PMID: 33783721; 25954030; 34466237 Phenotypes for gene: LMNB2 were set to ?Epilepsy, progressive myoclonic, 9 MIM#616540 Review for gene: LMNB2 was set to AMBER Added comment: PMID: 33783721 - hom missense p.(Arg158Trp) in a proband with Progressive myoclonus epilepsies. No functional studies to validate the missense variant PMID: 25954030 - hom missense p.(His157Tyr) in a proband with Progressive myoclonus epilepsies. In vitro assembly analysis of mutant lamin B2 protein revealed a distinct defect in the assembly of the highly ordered fibrous arrays typically formed by wild-type lamin B2, variant segregated in the affected sister PMID: 34466237 - Hom missense p.(Arg158Leu) in a 5yo boy with progressive wide-based ataxic gait and intractable myoclonic seizure. All unaffected relatives (13) were het or wildtype Association to epilepsy is amber and biallelic Seizures noted as a rare feature of dominant disease in OMIM Sources: Literature |
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| Genetic Epilepsy v0.2060 | LRPPRC |
Rylee Peters gene: LRPPRC was added gene: LRPPRC was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: LRPPRC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRPPRC were set to 21266382; 26510951; 38046674; 29152527 Phenotypes for gene: LRPPRC were set to Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) (MIM#220111) Review for gene: LRPPRC was set to AMBER Added comment: PMID: 21266382 - Cohort of patients with French-Canadian Leigh disease (MIM#220111). 55 of 56 patients were homozygous for the A354V mutation in LRPPRC. - Condition is distinct for metabolic crises. 6/44 affected patients experienced seizures. - During presentation of metabolic crises, 5 patients presented seizures. During neurological crises, 9 patients presented seizures. - 10 patients were living at the time of the study and have had a stable clinical course (since puberty), with mild ID and seizures (3/6 patients). PMID: 26510951 - 10 individuals (7 unrelated families) with recessive LRPPRC variants (identified via WES and candidate gene sequencing) with phenotypes resembling French-Canadian Leigh syndrome patients. - 1/10 patients compound heterozygous for premature termination variants, experienced several brief generalised seizures and developed a severe encephalopathy and persistent metabolic acidosis. - Functional characterisation of patients' fibroblasts and skeletal muscle homogenates (homozygous p.Arg1276_Lys1300del and compound heterozygous p.Glu497*; p.Gly1050Argfs*4 individuals) showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. PMID: 38046674 - Case report; 1 individual with novel homozygous splice donor variant (c.469+2T>A) in LRPPRC causing Leigh syndrome with epilepsy. Parents are consanguineous and are unaffected carriers. The affected child had intrauterine developmental delays, absence of the corpus callosum and was suspected of exhibiting neurodevelopmental disorder, specifically experiencing seizures. PMID: 29152527 - 1 individual with novel compound heterozygous missense variants with mild French-Canadian Type Leigh Syndrome. Developed refractory multifocal epilepsy at 3 years of age requiring multiple antiepileptics and ketogenic diet to control his seizures. Sources: Literature |
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| Genetic Epilepsy v0.1814 | ASH1L |
Zornitza Stark gene: ASH1L was added gene: ASH1L was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: ASH1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ASH1L were set to 34373061; 25961944; 34782621; 32469098 Phenotypes for gene: ASH1L were set to Mental retardation, autosomal dominant 52, MIM#617796 Review for gene: ASH1L was set to GREEN Added comment: Liu et al 2021 - twin sisters with mild intellectual disability and seizures. WES identified a de novo nonsense variant in exon 3. In this paper they look at previously reported variants and others reported in patients presenting with a seizure phenotype -Table 2: p.Glu2143* - autism spectrum disorder (seizure) - ref 7 p.Arg2391His - Intellectual disability (seizure) - ref 7 p.Arg2421* - intellectual disability/developmental delay (seizure) - ref 7 (Ref 7 - Krumm et al, 2015, Nat Genet, 47:582-88). Krumm et al, 2015 - cohort of patients with myoclonic atonic seizures (MAE) - table 2 shows that 1 patient idenitifed in this cohort (de novo) and that two additional patients were identified in the Iossifov proband (family 13678 - nonsense - can't see anything re epilepsy phenotype) and de rubeis proband (no mention in this paper that they had epilepsy pheno - PMID 25363760) - all de novo (2 nonsense 1 fs) Qin et al 2021 - The elevated PFC pyramidal neuronal excitability, increased E/I ratio, and excessive synchronised cortical network activity of Ash1L-deficient mice is linked to seizures, which recapitulates the phenotype of some autistic children carrying ASH1L variants. Tang et al, 2020 - table 3 candidate variants - ASH1L - de novo variant p.Arg1342* - 7 year old male with seizure onset at 6 months refractory to treatment, also mod- severe ID, ASD and ADHD. 3 definite families where de novo nonsense/fs variants have been reported in individuals with an epilepsy phenotype as well as ASD/ ID in the literature, patients reported in decipher with seizure phenotype and ASHIL variant (2 de novo nonsense, 1 de novo fs reported as pathogenic), and mouse studies support role for ASHIL in epeilepsy phenotype. Sources: Literature |
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| 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 |
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| Genetic Epilepsy v0.1675 | ARG1 | Zornitza Stark Tag treatable tag was added to gene: ARG1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| 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. ----- 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. ----- 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*)]. ----- 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 |
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| 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 |
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| Genetic Epilepsy v0.167 | ARG1 | Zornitza Stark Marked gene: ARG1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.167 | ARG1 | Zornitza Stark Gene: arg1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.167 | ARG1 | Zornitza Stark Classified gene: ARG1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.167 | ARG1 | Zornitza Stark Gene: arg1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.166 | ARG1 |
Zornitza Stark gene: ARG1 was added gene: ARG1 was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Expert list Mode of inheritance for gene: ARG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARG1 were set to 2365823; 29726057 Phenotypes for gene: ARG1 were set to Argininemia, 207800 Review for gene: ARG1 was set to GREEN Added comment: Seizures are part of the phenotype of this metabolic condition. Sources: Expert list |
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| Genetic Epilepsy v0.163 | AP2M1 |
Zornitza Stark gene: AP2M1 was added gene: AP2M1 was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Expert list Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AP2M1 were set to 31104773 Phenotypes for gene: AP2M1 were set to Intellectual developmental disorder 60 with seizures, MIM# 618587 Review for gene: AP2M1 was set to GREEN Added comment: Four unrelated individuals reported, recurrent variant, NM_004068.3:c.508C>T or p.Arg170Trp. Sources: Expert list |
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| Genetic Epilepsy v0.46 | KCNT2 |
Elizabeth Palmer gene: KCNT2 was added gene: KCNT2 was added to Genetic Epilepsy_AustralianGenomics_VCGS. Sources: Literature Mode of inheritance for gene: KCNT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNT2 were set to (PMID: 29069600; 29740868) Phenotypes for gene: KCNT2 were set to Developmental and epileptic encephalopathy Penetrance for gene: KCNT2 were set to Complete Mode of pathogenicity for gene: KCNT2 was set to Other Review for gene: KCNT2 was set to GREEN Added comment: A. Ambrosino et al described 2 unrelated females with de novo variants in KCNT2. The first patient had the variant p.(Arg190His) had with West syndrome followed by Lennox-Gastaut syndrome , the second patient had the variant p.(Arg190Pro) and DEE with migrating focal seizures. Both variants were absent gnomad and had supportive in silico support for pathogenicity. In an electrophisological model both KCNT2 R190P and KCNT2 R190H increased maximal current density and shifted toward more negative membrane potential values the activation curve of KCNT2 channels, consistent with gain of function effects. PMID: 29740868. Gururaj et al describe one male with de novo variant in KCNT2 p. (Phe240Leu) and early infantile epileptic encephalopathy. he variant was absent gnomad and supportive evidence of pathogenicity This variant was electrophysiologically modelled and revealed that the variant resulted in a 'change in function' demonstrating unusual altered selectivity in KNa channels.PMID: 29069600. Sources: Literature |
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