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| Genetic Epilepsy v0.2287 | TLK2 |
Elena Savva gene: TLK2 was added gene: TLK2 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: TLK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TLK2 were set to 37662408; 31558842 Phenotypes for gene: TLK2 were set to Intellectual developmental disorder, autosomal dominant 57 MIM#618050 Review for gene: TLK2 was set to AMBER Added comment: Seizures (13%) in OMIM PMID: 37662408 - NOT PEER REVIEWED. Patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency. De novo missense found, but also another de novo PTC in MDM1. Functional studies support missense pathogenicity PMID: 31558842 - HOM missense patient with a severe neurodev disorder, parents are clinically unaffected. She presented with epileptic spasms at the age of 6 months. Her EEG showed hypsarrhythmia suggesting West syndrome. She has been seizure-free since 3 years of age. Sources: Literature |
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| Genetic Epilepsy v0.2182 | KAT6A |
Elena Savva gene: KAT6A was added gene: KAT6A was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: KAT6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KAT6A were set to PMID: 34748993 Phenotypes for gene: KAT6A were set to Arboleda-Tham syndrome MIM#616268 Review for gene: KAT6A was set to GREEN Added comment: PMID: 34748993 - 2 new probands with KAT6A syndrome and epilepsy. Proband 1 - Epilepsy onset was at 3 months of age when daily right hemiclonic seizures appeared in sleep. Had a de novo missense, previously reported as pathogenic. Proband 2 - Seizures onset was at 5 months with daily clusters of symmetric spasms characterized by flexion of the arms, extension of the legs and eyes’ rolling. Had a de novo PTC Paper then reviews literature, notes 17/90 probands had epilepsy Sources: Literature |
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| Genetic Epilepsy v0.2172 | IARS2 |
Elena Savva gene: IARS2 was added gene: IARS2 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: IARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IARS2 were set to PMID: 30041933 Phenotypes for gene: IARS2 were set to Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia MIM#616007 Review for gene: IARS2 was set to RED Added comment: PMID: 30041933 - Japanese sibling pair presented with Leigh syndrome and infantile spasms. The siblings were identified with compound heterozygous missense mutations p.[(Phe227Ser)];[(Arg817His)]. No functional studies to support the pathogenicity of the missense variants Sources: Literature |
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| Genetic Epilepsy v0.2149 | DHX16 |
Andrew Fennell gene: DHX16 was added gene: DHX16 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DHX16 were set to PMID: 31256877; 36211162 Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, MIM# 618733 Review for gene: DHX16 was set to GREEN Added comment: PMID: 31256877 - two of the four reported individuals had seizures (infantile spasms in one & GTC in one) PMID: 36211162 - single case report of an 18-month old child with infantile spasms, likely for several months prior to presentation. Sources: Literature |
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| Genetic Epilepsy v0.2112 | RAI1 |
Belinda Chong gene: RAI1 was added gene: RAI1 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: RAI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAI1 were set to 36256819; 11404004; 12652298; 15788730 Phenotypes for gene: RAI1 were set to Smith-Magenis syndrome MIM#182290 Review for gene: RAI1 was set to GREEN gene: RAI1 was marked as current diagnostic Added comment: PMID 36256819: Spontaneous seizures have been detected in 30% of Rai1−/− mice and SMS patients PMID: 16566870: Considering that close to one third of individuals with Smith-Magenis syndrome with epileptiform abnormalities also had a history of clinical seizures, cortical hyperexcitability and epilepsy should be considered an important component of the Smith-Magenis syndrome clinical phenotype. Sources: Literature |
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| Genetic Epilepsy v0.2096 | CAMTA1 |
Lilian Downie gene: CAMTA1 was added gene: CAMTA1 was added to Genetic Epilepsy. Sources: Expert list Mode of inheritance for gene: CAMTA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CAMTA1 were set to PMID: 31957018 Phenotypes for gene: CAMTA1 were set to Cerebellar dysfunction with variable cognitive and behavioral abnormalities MIM#614756 Review for gene: CAMTA1 was set to RED Added comment: PMID: 31957018 sequencing in an epilepsy cohort - if negative looked at 'candidate epilepy genes', variant identified in CAMTA1 in patient with infantile spasms, refractory epilepsy, dev delay and corticovisual impairment. Sources: Expert list |
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| Genetic Epilepsy v0.2060 | NR2F1 |
Rylee Peters gene: NR2F1 was added gene: NR2F1 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: NR2F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NR2F1 were set to 32275123 Phenotypes for gene: NR2F1 were set to Bosch-Boonstra-Schaaf optic atrophy syndrome, MIM# 615722 Review for gene: NR2F1 was set to GREEN Added comment: PMID: 32275123 - Cohort of 54 individuals with a deletion of or likely pathogenic variant in NR2F1, including previously published individuals with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). -24/46 (52%) individuals described with seizures, some of which include infantile spasms. - Rech et al. (2020) also described that mutations in the DBD were associated with a higher prevalence of motor delay, the inability to walk unassisted, the absence of speech, seizures, and sensitivity to touch compared to other types of mutations. Sources: Literature |
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| Genetic Epilepsy v0.1987 | COL4A1 | Zornitza Stark Phenotypes for gene: COL4A1 were changed from to Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps MIM#611773; Brain small vessel disease with or without ocular anomalies MIM#175780; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant MIM#618564 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.1984 | COL4A1 | Zornitza Stark reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps MIM#611773, Brain small vessel disease with or without ocular anomalies MIM#175780, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant MIM#618564; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.1900 | ZNF335 |
Zornitza Stark gene: ZNF335 was added gene: ZNF335 was added to Genetic Epilepsy. Sources: Expert Review Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF335 were set to 23178126; 27540107; 29652087 Phenotypes for gene: ZNF335 were set to Microcephaly 10, primary, autosomal recessive (MIM#615095) Review for gene: ZNF335 was set to GREEN Added comment: At least 6 unrelated families reported in literature with different biallelic variants in ZNF335. Microcephaly is the primary feature, but also commonly in association with a variable epilepsy phenotype. Stouffs et al. (PMID:29652087) report 2 unrelated cases: patient A, demonstrating refractory seizures leading to death at age 5 days, whereas patient B lacked any clinical seizures, but had frequent spasms that have yet to be recorded by EEG. The proband in Sato et al. (PMID:27540107) had rare focal seizures controlled by treatment. Although not noted by Yang et al. (PMID:231781260), affected individuals in that family had seizures described as paroxysmal myoclonic jerks (personal communication with Stouffs et al). The case by Rana et al. (PMID:31187448) presented multifocal drug-resistant epilepsy, and while details were limited in McSherry et al. (PMID:30500859), authors did also note seizures. Sources: Expert Review |
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| Genetic Epilepsy v0.1824 | EIF4A2 |
Dean Phelan gene: EIF4A2 was added gene: EIF4A2 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: EIF4A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: EIF4A2 were set to PMID: 36528028 Phenotypes for gene: EIF4A2 were set to Neurodevelopmental disorder (MONDO:0700092), EIF4A2-related Mode of pathogenicity for gene: EIF4A2 was set to Other Review for gene: EIF4A2 was set to GREEN Added comment: PMID: 36528028 - EIF4A2 variants were observed in 15 individuals from 14 families. Affected individuals had a range of symptoms including global developmental delay (9/15), ID (7/15), epilepsy (11/15) and structural brain alterations (10/15). Monoallelic and biallelic variants were reported and functional studies showed both LOF and GOF disease mechanisms. Sources: Literature |
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| 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 |
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| 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 v0.1317 | 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 v0.951 | 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 |
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| 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 v0.698 | 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 |
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| 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 |
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| 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 |
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| Genetic Epilepsy v0.471 | SMS | Zornitza Stark Marked gene: SMS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.471 | SMS | Zornitza Stark Gene: sms has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.471 | SMS | Zornitza Stark Classified gene: SMS as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.471 | SMS | Zornitza Stark Gene: sms has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.470 | SMS |
Zornitza Stark gene: SMS was added gene: SMS was added to Genetic Epilepsy. Sources: Expert list Mode of inheritance for gene: SMS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SMS were set to 30237987 Phenotypes for gene: SMS were set to Mental retardation X-linked Snyder-Robinson type, 309583 Review for gene: SMS was set to GREEN gene: SMS was marked as current diagnostic Added comment: Seizures reported in some affected individuals. Sources: Expert list |
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