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| Early onset or syndromic epilepsy v4.5 | MED11 |
Sarah Leigh gene: MED11 was added gene: MED11 was added to Early onset or syndromic epilepsy. Sources: Literature Q2_23_promote_green tags were added to gene: MED11. 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 MED11-associated neurodevelopmental disorder Review for gene: MED11 was set to GREEN Added comment: Not associated with a phenotype in OMIM, but is associated with MED11-associated neurodevelopmental disorder in Gen2Phen. PMID: 36001086 reports a single MED11 variant (NM_001001683.4: c.325C>T, p.Arg109*), that segregates with the condition in five unrelated families, however, there is homozygosity between two of these families, idicating that they may be related. Global delay was observed in three individuals from three unrelated familes and seizures were evident in four individuals from four unrelated families. Severe microcephaly was apparent in the two unrelated familes where this parameter was recorded. Overall, the MED11-associated neurodevelopmental disorder appeared to result in profound effects and proved fatal at birth and 10 days in two of the cases reported. Sources: Literature |
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| Early onset or syndromic epilepsy v2.524 | DROSHA |
Konstantinos Varvagiannis gene: DROSHA was added gene: DROSHA was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DROSHA were set to 35405010 Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot Penetrance for gene: DROSHA were set to unknown Mode of pathogenicity for gene: DROSHA 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: DROSHA was set to AMBER Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09). There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one). Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ] ----- Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants. Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features. Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq. DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse. As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided): - in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity - in Drosophila playing a role in the development of ovary, eye, nervous system etc. - in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects. Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes. miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s. Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs). Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided). Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly. Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele. The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction. Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs. Sources: Literature |
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| Early onset or syndromic epilepsy v2.518 | GLRA2 |
Konstantinos Varvagiannis gene: GLRA2 was added gene: GLRA2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: GLRA2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GLRA2 were set to 20531469; 20479760; 26370147; 28588452; 35294868 Phenotypes for gene: GLRA2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Microcephaly; Abnormality of eye movement Penetrance for gene: GLRA2 were set to unknown Mode of pathogenicity for gene: GLRA2 was set to Other Review for gene: GLRA2 was set to AMBER Added comment: Heterozygous or hemizygous pathogenic GLRA2 variants cause Intellectual developmental disorder, X-linked, syndromic, Pilorge type (# 301076) as summarized in a recent OMIM entry. The phenotype is characterized by DD with variably impaired intellectual development, behavioral abnormalities (autistic features in some), variable ocular findings (nystagmus, strabismus, oculomotor apraxia) and seizures in some [ 6/13 in Ref4 ]. GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth. Animal models support the role of the gene in CNS. Studies have been performed for several of the variants reported to date (in all cases missense and a htz deletion of the last 2 exons). As summarized by OMIM, most affected females carry de novo htz missense GoF variants, and most affected males inherited hemizygous LoF ones. XCI has not been studied in most htz (affected/unaffected) females (with the exception of the del in Ref2, see also Ref3). Details provided below. (Note: Most articles refer to variants using HGVS nomenclature while few without incl. the signal peptide eg. p.Arg350Leu corresponding to Arg323Leu). Consider inclusion in the current panel with amber/green rating. [1]---- Piton et al (2011 - PMID: 20479760) sequenced 111 X-linked synaptic genes in a cohort of 142 individuals with ASD and identified a female (S00125) harboring Arg350Leu (NM_002063 chrX:14618871 G/T), inherited from her mother (no clinical information provided). Functional evaluation of the variant was performed in a later publication (Ref3), providing additional clinical details on the proband. [2]---- Pilorge et al (2016 - PMID: 26370147) review the role of glycine receptors (GlyRs). These typically consist of pentameric combinations of alpha (α1-α4) and beta (β) subunits and form a pore that controls transmembrane flux of chloride. GlyRs can be formed either as homomers comprising five α subunits or as heteromers of α and β subunits (in 2:3 or 3:2 stoichiometry). Each subunit has an N-terminal extracellular domain with the ligand-binding site and 4 transmembrane domains. GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth. The authors discuss the role of glycine as inhibitory neurotransmitter in adult CNS and depolarizing/excitatory action in immature neurons, as well as the role of GlyR α2 in proliferation and neuronal migration during cortical development. The authors previously (2010 - PMID: 20531469) identified a boy with ASD, language delay and low average IQ (verbal 93, performance 75, full-scale IQ 82) harboring a 142 kb microdeletion spanning the last 2 exons of GRLA2 (hg19 - chrX:14693216-14836199). This CNV was confirmed with qPCR and the breakpoints localized to intron 7 after sequencing. Reverse transcription of mRNA from blood revealed presence of a truncated transcript in the child suggestive of little or no NMD. In the mother, the non-truncated transcript was amplified. Further it was shown that the product leaded to incorporation of intron 7, with inclusion of 5 residues followed by a stop codon. The mother had a normal, non-skewed XCI. Previous testing had excluded an FMR1 expansion. Screening of 400 males with ASD identified a further male with de novo missense SNV (NM_002063.3:c.458G>A / p.Arg153Gln). This child had non-syndromic autism, severe language delay, mild ID (fs IQ 63) and GTC seizures with onset at 18y. Previous testing incl. a normal karyotype, FMR1 analysis, and CMA. The boy had an older sister with ASD, not harboring the same GLRA2 variant (interpreted in the context of intrafamilial genetic heterogeneity for ASD). The authors also studied a dn missense variant (NM_001118886.1:c.407A>G / p.Asn136Ser) previously reported in a proband with autism (11842.p2 - Iossifov et al, 2014 - PMID: 25363768). In vitro studies demonstrated that the 3 aforementioned variants impaired GlyR2 α2 function: - The authors generated constructs for wt, the deletion (of last 2 exons) and Arg153Gln and performed co-transfection with EGFP cDNA in Chinese hamster ovary (CHO) cells. While wt and Arg153Gln were observed at the plasma membrane of transfected cells, the del was undetectable at the cell surface and was mislocalized in the cytoplasm (as also expected by loss of the transmembrane domains). - Upon isolation of biotinylated surface receptors and western blot, Arg153Gln was shown to result to 56% decreased surface expression compared to wt, while the intracellular fragment was also reduced by 32% suggesting impaired synthesis or degradation. Asn136Ser had 67% lower surface (and 15% lower intracellular) expression. - Whole-cell patch clamp recordings of transfected CHO cells suggested that the minimum concentration of glycine to evoke whole-cell current was ~100 higher for Arg153Gln compared to wt. High concentrations of glycine were unable to evoke any current in the case of the deletion (due to loss of surface expression). Asn136Ser also reduced glycine sensitivity (14x increase in EC50). Zebrafish studies for glra2 and the del or Arg153Gln variants: Morpholino mediated knockdown of glra2 led to hyperbranching of spinal motor axons compared to ctrls. Co-injection of human wt mRNA with glra2 morpholino, rescued the aberrant branching phenotype which was not the case for the 2 variants. Glra2 ko mouse model (also on chrX): - Mutant mice (Glra2-/Y) had normal adult body, brain weight, were fertile and had a normal lifespan. They displayed no differences in locomotor activity, or social behavior compared to wt. They however exhibited impaired learning and memory in the novel object recognition task (spatial learning and memory in the novel location recognition task and Morris water maze were N). - Long-term potentiation in prefrontal cortex after high frequency stimulation was significantly impaired in mutant mice compared to wt, overall supporting that impaired glycinergic signaling results in abnormal synaptic plasticity in this relevant for ASD region. [3]---- Zhang et al (2017 - PMID: 28588452) determined the functional effects of Arg350Leu which was reported by Piton et al (Arg323Leu without the signal peptide). The authors provide further clinical details on this female with autism, macrocephaly, loss of acquired words, seizures, mild motor delay and hypothyroidism. The mother of the, also carrier of the SNV, was reportedly unaffected. The potency of glycine in activating recombinant homomeric α2 and heteromeric α2β receptors was examined by whole-cell patch-clamp recording (HEK293 cells). In homo-/ and heteromeric receptors this variant resulted in small decrease in glycine sensitivity with peak currents not significantly different compared to wt (the latter suggestive of normal surface expression). This variant resulted in prolonged inhibitory postsynaptic currents (IPSCs) with ~2-fold slower rise and decay times, while IPSC amplitude did not differ significantly. Overall, the slowed decay times, prolongation of active periods and small but significantly increased conductance of mutant channels suggested that this variant exerts a gain-of-function effect. The authors briefly cite a study by Cotton et al (2015, PMID: 25381334) providing evidence that GLRA2 escapes XCI in the vast majority of tissues and brain. [4]---- Marcogliese et al (2022 - PMID: 35294868) functionally tested the effects of missense DNM observed in individuals with ASD diagnosis in Drosophila. The authors generated TG4 (MiMIC cassette) fly mutants for candidate ASD genes (creating LoF alleles for the respective genes). Using a GAL4/UAS system with human cDNA constructs for reference/variants they performed the rescue/overexpression assays to study the functional consequences. Flies expressing human ref GLRA2 cDNA failed to copulate but exhibited normal movement. Flies for Asn136Ser (a variant reported by Iossifov et al, 2014 - PMID: 25363768) copulated similar to the TG4 mutant providing evidence for a LoF effect of this variant. Upon GAL4/UAS expression and co-staining with neuronal (Elav) and glial (Repo) nuclear markers, GLRA2 was shown to be expressed in CNS with expression in a subset of neurons and in some glia. Upon ubiquitous overexpression of human reference or variant cDNA, Asn136Ser also behaved as a LoF allele. Based on the evidence on this gene, and following re-analyses of exome data, GeneMatcher collaborations etc, the authors identified 13 additional unrelated subjects harboring GLRA2 variants (8 females/5 males). These had DD/ID of variable severity (13/13) w/wo autistic features (in 4 or 5), microcephaly (4-5/13 all females), epilepsy (6/13 - both sexes) and ocular manifestations (10/13 - incl. nystagmus, strabismus, etc). Hypotonia/incoordination was observed in 7/13. All females had dn missense variants (8/8, NM_001118886.1:c.887C>T/p.Thr296Met in 6/8, others: c.140T>C/p.Phe47Ser, c.777C>G/p.Ile259Met), while all males had inherited missense SNVs from their unaffected mothers (p.Arg252Cys, p.Ala288Thr, p.Pro396Thr, p.Pro400Leu, p.Arg445Gln). The authors studied an variant which was recurrent in females (Thr296Met) and another found in a male (Arg252Cys). Upon overexpression, the latter behaved - similarly to Asn136Ser - as LoF allele, while Thr296Met did not differ significantly from reference. Structural modeling suggested that Thr296 is adjacent to a residue important for keeping the ion pore in closed conformation. Upon pnr-GAL4 (over)expression in the dorsolateral stripe in the notum, Thr296Met caused lethality, which was not the case for the reference. When expressed at lower levels, Thr296Met formation of melanized nodules in thorax, a phenotype not previously observed upon overexpression of ref/other variants. The authors performed ERGs in fly eyes. They first used a pan-neuronal driver (nSyb-GAL) leading to GLRA2 ref / variant expression in pre-synaptic photoreceptors and post-synaptic neurons. A significant increase of "OFF" transients was observed for Thr296Met, suggesting increase in synaptic transmission and a GoF effect. Expression limited to pre-synaptic photoreceptors (Rh1-GAL4 driver) did not lead to significant differences compared to ref allele, while Arg252Cys was associated with decreased amplitudes of "OFF" transients, suggestive of decreased synaptic transmission and confirming a LoF effect. Marcogliese et al conclude that reduced GLRA2 activity can lead to disease in males but can be tolerated in htz females (as was the case for asymptomatic mothers), while GoF variants leading to overactivation of the channel could be overrepresented in affected females. Sources: Literature |
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| Early onset or syndromic epilepsy v2.489 | CHKA |
Konstantinos Varvagiannis gene: CHKA was added gene: CHKA was added to Genetic epilepsy syndromes. 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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| Early onset or syndromic epilepsy v2.405 | ARG1 | Arina Puzriakova Phenotypes for gene: ARG1 were changed from Argininemia 207800 to Argininemia, OMIM:207800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.143 | MADD |
Konstantinos Varvagiannis gene: MADD was added gene: MADD was added to Genetic epilepsy syndromes. 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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| Early onset or syndromic epilepsy v2.122 | HERC2 |
Konstantinos Varvagiannis gene: HERC2 was added gene: HERC2 was added to Genetic epilepsy syndromes. 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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| Early onset or syndromic epilepsy v2.69 | TIMM50 | Rebecca Foulger commented on gene: TIMM50: PMID:31058414 (Tort et al., 2019) report compound het TIMM50 variants in a boy with 3-MGA-uria (p.Arg114Gln, p.Gly269Ser). At 3.5 months, a diagnosis of West syndrome was made, and he showed a good response to ACTH and antiepileptic treatment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.0 | PUM1 |
Konstantinos Varvagiannis gene: PUM1 was added gene: PUM1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PUM1 were set to 29474920; 30903679; 31859446 Phenotypes for gene: PUM1 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism Penetrance for gene: PUM1 were set to unknown Review for gene: PUM1 was set to GREEN Added comment: 5 unrelated individuals with de novo pathogenic PUM1 variants have been reported in the literature. DD (5/5), ID (4/5 - relevant severity to the current panel), seizures (4/4 - absence/tonic-clonic, abnormal EEG) and variable other features (incl. facial dysmorphism, ataxia, cryptorchidism) appear to be part of the phenotype. 9 individuals with deletions spanning PUM1 and proximal genes presented similar features. [1] PMID: 29474920 - Gennarino et al (2018) [2] PMID: 30903679 - Bonnemason-Carrere et al (2019) [3] PMID: 31859446 - Voet et al (2019) [with review of the literature] SNVs in relevant individuals were identified by exome sequencing and were in all cases de novo. Arg1147Trp was a recurrent variant reported in 3 unrelated subjects with ID and seizures (Refs 1,2,3 / NM_001020658.1:c.3439C>T). A nonsense variant was reported in an additional one with DD, ID, seizures and additional features (c.2509C>T / p.Arg837* - Ref3). One individual with a de novo missense variant (c.3416G>A / p.Arg1139Trp) with DD and ataxia, though without ID was reported in Ref1. Details on 9 individuals with 0.3 - 5.6 Mb deletions spanning PUM1 and other genes are provided in Ref1. Features also included DD, ID, seizures, ataxia, etc. Extensive initial investigations were reported for individuals in Refs 2 and 3 (various investigations incl. karyotype, SNP-array, targeted sequencing of OPHN1, KANSL1 or of a small panel of ID genes, biopsies and/or metabolic work-up) to rule out alternative causes. These only revealed a likely benign CNV and a GRIA3 SNV of uncertain significance in the case of an individual harboring the recurrent Arg1147Trp variant [Ref2]. Role of the gene (from OMIM): Pumilio proteins, such as PUM1, negatively regulate gene expression by repressing translation of mRNAs to which they bind (Lee et al., 2016). A clinically significant PUM1 target is ataxin (ATXN1; 601556), mutation in which causes spinocerebellar ataxia-1 (SCA1; 601556). Variant studies: - Arg1147Trp was shown to be associated with normal PUM1 mRNA levels, but reduced (to ~43%) PUM1 protein levels in patient fibroblasts. ATXN1 mRNA and protein levels, as well as protein and/or mRNA levels of other PUM1 targets were shown to be increased (Ref1). - In Ref1, in vitro transfection assays with wt or mt PUM1 were performed in HEK293T cells to evaluate repression of ATXN1 and E2F3. While overexpression of wt and Arg1147Trp were able to reduce ATXN1 and E2F3 levels, Arg1139Trp was not able to repress ATXN1 or E2F3. - Upon overexpression in mouse hippocampal neurons, PUM1 missense mutations (among others Arg1139Trp and Arg1147Trp) were shown to alter neuronal morphology. Overall haploinsufficiency is the proposed mechanism for the disorder for which the acronym PADDAS is used (Pumilio1-associated developmental disability, ataxia and seizure). Milder mutations reducing PUM1 levels by 25% are associated with adult-onset ataxia without ID (PRCA or Pumilio1-related cerebellar ataxia) [Ref1]. Mouse models: The role of PUM1 was first suggested in mouse models where Pum1 mutations were shown to lead to a SCA1-like phenotype (PMID cited : 12086639 - Watase et al 2002) further shown to be caused by increased Atxn1 mRNA and protein levels (PMID cited : 25768905 - Gennarino et al 2015). The mouse model seems to recapitulate several of the features observed in affected individuals : Pum1 homozygous ko mice display among others hyperactivity, progressive cerebellar signs, spontaneous seizures as also observed in affected individuals (PMID cited : 25768905 - Gennarino et al 2015). Cryptorchidism was observed in 2 patients similar to testicular hypoplasia reported in Pum1 ko mice (PMID cited : 22342750 - Chen et al 2012). - Heterozygous mice were evaluated in Ref1 with 69% or 75% exhibiting spontaneous seizures by the end of 30 or 35 wks respectively, with abnormal EEG activity already by 16 wks. Additional individuals with PUM1 variants and a relevant phenotype of ID with or without seizures have been reported as part of the DDD study or as external submissions to Decipher and ClinVar : https://decipher.sanger.ac.uk/search?q=PUM1#research-variants/results [ DDD4K.01387 participant ] https://decipher.sanger.ac.uk/search?q=pum1#consented-patients/results [ external submission(s) ] https://www.ncbi.nlm.nih.gov/clinvar/variation/431110/ [ splice-site variant in an individual with ID submitted prior to the 1st publication on the disorder ] Sources: Literature |
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| Early onset or syndromic epilepsy v1.475 | TMX2 |
Konstantinos Varvagiannis gene: TMX2 was added gene: TMX2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMX2 were set to 31586943; 31735293; 31270415 Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration Penetrance for gene: TMX2 were set to Complete Review for gene: TMX2 was set to GREEN Added comment: This gene was reviewed for the intellectual disability panel. Epilepsy is part of the phenotype. Therefore green rating should be considered. From the ID panel : A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy. As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating. Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc. All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below]. The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6. *To the best of my understanding : Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding. Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life. As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival. Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase. Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity. TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions. --------- Created: 26 Nov 2019, 11:21 p.m. | Last Modified: 26 Nov 2019, 11:21 p.m. Panel Version: 2.1122 [Previous review] PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI. All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones. Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families). Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks. The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals). This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven. TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article. As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging). ------- Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism). ------- There is no associated phenotype in OMIM/G2P/SysID. ------- Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence. Sources: Literature Sources: Literature |
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| Early onset or syndromic epilepsy v1.351 | TDP2 |
Konstantinos Varvagiannis gene: TDP2 was added gene: TDP2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TDP2 were set to 24658003; 30109272; 31410782 Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949 Penetrance for gene: TDP2 were set to unknown Review for gene: TDP2 was set to GREEN Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder. TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity. The gene is expressed in fetal and adult human brain. Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role. Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes. Published studies are summarized below. TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID. Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model). ------------ [1] - PMID: 24658003 (Gómez-Herreros et al. 2014): Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3). A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study). The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity). The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject. As also commented: - TDP2 has relevant expression in human (particularly adult) brain. - Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated. - Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968). [2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018): A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle). [3] - PMID: 31410782 (Ciaccio et al. 2019): A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing. Sources: Literature |
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| Early onset or syndromic epilepsy v1.342 | PMPCB |
Konstantinos Varvagiannis changed review comment from: Review from the ID panel: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954). 5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218). Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset. Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2): - c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B] - c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C] - c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs] The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel). Extensive studies demonstrated (perhaps a better summary provided by OMIM): - Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells. - Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity. - Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters. - Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue. Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested). PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable). As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber). Sources: Literature; to: Review from the ID panel: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954). 5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218). Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset. Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2): - c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B] - c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C] - c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs] The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel). Extensive studies demonstrated (perhaps a better summary provided by OMIM): - Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells. - Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity. - Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters. - Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue. Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested). PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable). As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v1.336 | PMPCB |
Konstantinos Varvagiannis gene: PMPCB was added gene: PMPCB was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PMPCB were set to 29576218 Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954 Penetrance for gene: PMPCB were set to Complete Review for gene: PMPCB was set to GREEN Added comment: Review from the ID panel: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954). 5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218). Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset. Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2): - c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B] - c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C] - c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs] The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel). Extensive studies demonstrated (perhaps a better summary provided by OMIM): - Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells. - Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity. - Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters. - Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue. Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested). PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable). As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v1.191 | ARG1 | Rebecca Foulger Source Wessex and West Midlands GLH was added to ARG1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | ARG1 | Rebecca Foulger Source NHS GMS was added to ARG1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | ARG1 | Rebecca Foulger reviewed gene: ARG1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | ARG1 | Tracy Lester reviewed gene: ARG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 2365823, 29726057 ; Phenotypes: Argininemia, 207800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.152 | PRICKLE1 | Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from biallelic to BOTH monoallelic and biallelic based on PMID:21276947. Tao et al. 2011 sequenced PRICKLE1 (and PRICKLE2) in 88 unrelated patients with myoclonus epilepsy and found two patients with heterozygous missense mutations in PRICKLE1: p.Arg144His and p.Tyr472His. The variants were not found in control data sets. The authors therefore suggest that the heterozygous PRICKLE1 variants are also associated with myoclonus epilepsy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.80 | CSNK2A1 |
Rebecca Foulger gene: CSNK2A1 was added gene: CSNK2A1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: CSNK2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CSNK2A1 were set to 30655572 Phenotypes for gene: CSNK2A1 were set to seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome Review for gene: CSNK2A1 was set to AMBER Added comment: Added CSNK2A1 to the epilepsy panel based on PMID:30655572. Nakashima et al, 2019 describe 4 patients with DD and seizures. Two of the patients (both Japanese) had de novo variants in CSNK2A1: c.593A>G, p.Lys198Arg in Patient 1, c.571C>T, p.Arg191* in Patient 2. Although both shared global DD and seizures, patient 1 showed later onset (4 yrs old) seizures which were less frequent. Additional features in Patient 1 include facial dysmorphisms, short stature and muscle weakness. Patient 2 had a more severe phenotype with seizures starting in the early infantile stage (5 months) with acute encephalopathy and death age 1 yr, 7 months. Note that Patient 1 had 3 candidate de novo deleterious variants (ATAD2B, TOPORS, CSNK2A1): ACMG variant guidelines were used to evaluate the pathogenicity of the variants. ATAD2B and TOPORS variants were likely pathogenic, and CSNK2A1 variant was pathogenic. In Patient 2, no further likely de novo variants were found. Sources: Literature |
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| Early onset or syndromic epilepsy v1.52 | AP2M1 |
Konstantinos Varvagiannis gene: AP2M1 was added gene: AP2M1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: AP2M1 were set to 31104773 Phenotypes for gene: AP2M1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Ataxia; Autistic behavior Penetrance for gene: AP2M1 were set to Complete Review for gene: AP2M1 was set to GREEN Added comment: Helbig et al. (2019 - PMID: 31104773) report on 4 individuals with developmental and epileptic encephalopathy due to a recurrent de novo AP2M1 missense variant (NM_004068.3:c.508C>T or p.Arg170Trp). Seizure types included atonic, myoclonic-atonic, absence seizures (with or without eyelid myoclonia), tonic-clonic etc. Hypotonia, developmental delay (prior to the onset of seizures at 1y 3m to 4y) and intellectual disability were observed in all four. Other features included ataxia (3/4) or autism spectrum disorder (2/4). AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2). AP2M1 is highly expressed in the CNS. The AP-2 complex is involved in clathrin-mediated endocytosis at the plasma mebrane of neurons and non-neuronal cells. This mechanism is important for recycling synaptic vesicle components at mammalian central synapses. Previous evidence suggests regulation of GABA and/or glutamate receptors at the neuronal surface by AP-2 (several references provided by Helbig et al.). The authors provide evidence for impaired (reduced) clathrin-mediated endocytosis of transferrin in AP-2μ-depleted human HeLa cells upon plasmid-based re-expression of the Arg170Trp variant compaired to re-expression of WT. A similar defect was demonstrated upon comparison of the same process when WT and Arg170Trp re-expression was studied in primary astrocytes from conditional AP-2μ knockout mice. Expression levels, protein stability, membrane recruitment and localization of the AP-2 complex in clathrin-coated pits were similar for the Arg170Trp variant and WT. As a result, the effect of the specific variant is suggested to be mediated by alteration of the AP-2 complex function (/impaired recognition of cargo membrane proteins) rather than haploinsufficiency. AP2M1 is highly intolerant to missense / LoF variants with z-score and pLI in ExAC of 5.82 and 0.99 respectively. As the authors discuss, heterozygous Ap2m1 mutant mice do not have an apparent phenotype. Homozygous mutant mice die before day 3.5 postcoitus, suggesting a critical role in early embryonic development (PMID 16227583 cited) AP2M1 is currently not associated with any phenotype in OMIM / G2P. As a result, this gene can be considered for inclusion in the epilepsy and ID panels probably as green (4 individuals with highly similar phenotype of DEE, relevance of phenotype and/or degree of ID, functional studies, etc) rather than amber (single recurrent variant - although this is also the case for other genes rated green). Sources: Literature |
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| Early onset or syndromic epilepsy v1.35 | ZNF142 |
Konstantinos Varvagiannis gene: ZNF142 was added gene: ZNF142 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF142 were set to 31036918 Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia Penetrance for gene: ZNF142 were set to Incomplete Review for gene: ZNF142 was set to AMBER Added comment: Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants. Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs. Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects. 6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out. ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1). As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)]. ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P. As a result, this gene can be considered for inclusion in the current panel as probably as amber (seizures in 5/7 individuals, though many had a single occurrence) or green. Sources: Literature |
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| Early onset or syndromic epilepsy v0.824 | FGF12 | Louise Daugherty Added comment: Comment on publications: Added publications that support the association with the phenotype suggested by external reviewer and recent publication PMID:29699863 that describes two unrelated cases, 1 Japanese patient diagnosed with early infantile epileptic encephalopathy (EIEE) and another diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). Both patients had an identical heterozygous missense mutation [c.341G>A:p.(Arg114His)] in FGF12 , which was identified with whole-exome sequencing. The mutation is identical to previously reported mutations in cases with early onset epileptic encephalopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.470 | ARG1 | Sarah Leigh Marked gene: ARG1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.470 | ARG1 | Sarah Leigh Gene: arg1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.470 | ARG1 | Sarah Leigh Classified gene: ARG1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.470 | ARG1 | Sarah Leigh Gene: arg1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.469 | ARG1 |
Sarah Leigh gene: ARG1 was added gene: ARG1 was added to Genetic Epilepsy Syndromes. Sources: Literature Mode of inheritance for gene: ARG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARG1 were set to 26310552; 1463019 Phenotypes for gene: ARG1 were set to Argininemia 207800 Review for gene: ARG1 was set to GREEN Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. Seizures reported in at least three unrelated cases carrying different variants. Sources: Literature |
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