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| Early onset or syndromic epilepsy v4.39 | NSF | Achchuthan Shanmugasundram Phenotypes for gene: NSF were changed from Developmental and epileptic encephalopathy 96, OMIM:619340 to Developmental and epileptic encephalopathy 96, OMIM:619340 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.39 | NSF | Achchuthan Shanmugasundram Phenotypes for gene: NSF were changed from Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 96, OMIM:619340 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.38 | NSF | Achchuthan Shanmugasundram Publications for gene: NSF were set to 31675180; 36645181 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.38 | NSF | Achchuthan Shanmugasundram Publications for gene: NSF were set to 31675180 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.37 | NSF | Achchuthan Shanmugasundram edited their review of gene: NSF: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.37 | NSF |
Achchuthan Shanmugasundram changed review comment from: PMID:36645181 describes the two previously reported cases from PMID:31675180. The third case reported had a very mild phenotype and did not present with epilepsy and had normal development. Hence, this gene should remain AMBER.; to: PMID:36645181 describes the two previously reported cases from PMID:31675180. The third case reported had a very mild phenotype and did not present with epilepsy and had normal development. Hence, this gene should remain AMBER. This gene has now been associated with relevant phenotype in OMIM (MIM #619340), but not in Gene2Phenotype. |
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| Early onset or syndromic epilepsy v4.37 | NSF | Achchuthan Shanmugasundram reviewed gene: NSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 36645181; Phenotypes: Developmental and epileptic encephalopathy 96, OMIM:619340; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.518 | DPH5 |
Konstantinos Varvagiannis gene: DPH5 was added gene: DPH5 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DPH5 were set to 35482014 Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck Penetrance for gene: DPH5 were set to unknown Review for gene: DPH5 was set to AMBER Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants. As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date. The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5). WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser). In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2. In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression). ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants. Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice. DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line. The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653). Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added). 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 v2.504 | ATP2B1 |
Konstantinos Varvagiannis gene: ATP2B1 was added gene: ATP2B1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP2B1 were set to 35358416; 33057194 Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck Penetrance for gene: ATP2B1 were set to unknown Review for gene: ATP2B1 was set to AMBER Added comment: At least 12 individuals with NDD due to monoallelic missense/pLoF ATP2B1 variants have been reported to date. Seizures were observed in 5 of them. Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia. Based also on the evidence discussed below, please consider inclusion with amber rating. --- Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants. Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2. All subjects were investigated by singleton/trio exome sequencing. Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder. 9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12). ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function. All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29. The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx). In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues. The nonsense variants occurred in positions predicted to lead to NMD (not studied). Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys). Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD). Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied. Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants. In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala). The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain). Sources: Literature |
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| Early onset or syndromic epilepsy v2.403 | VPS50 |
Konstantinos Varvagiannis gene: VPS50 was added gene: VPS50 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to 34037727 Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum Penetrance for gene: VPS50 were set to Complete Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports. Sources: Literature |
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| Early onset or syndromic epilepsy v2.346 | NSF | Sarah Leigh Classified gene: NSF as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.346 | NSF | Sarah Leigh Gene: nsf has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.345 | NSF | Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.152 | LMNB1 |
Konstantinos Varvagiannis gene: LMNB1 was added gene: LMNB1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LMNB1 were set to 32910914 Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis Penetrance for gene: LMNB1 were set to unknown Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to AMBER Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants. The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some. Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies). LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development. Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development. Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants. Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells). LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu). Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency). Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc. Sources: Literature |
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| Early onset or syndromic epilepsy v2.143 | FAM50A |
Konstantinos Varvagiannis gene: FAM50A was added gene: FAM50A was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943 Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261) Penetrance for gene: FAM50A were set to unknown Review for gene: FAM50A was set to AMBER Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.). Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families). Sources: Literature |
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| Early onset or syndromic epilepsy v2.125 | LIPT1 | Sarah Leigh Added comment: Comment on list classification: This metabolic gene is associated with Lipoyltransferase 1 deficiency 616299 in OMIM and as a probable gene for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. In addition to the six variants that have been reported in five cases Lipoyltransferase 1 deficiency 616299, two further variants have been reported in two unrelated cases of Lipoyltransferase 1 deficiency 616299 who also have epieptic seizures (PMID 29681092; 31042466). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.124 | LIPT1 |
Sarah Leigh gene: LIPT1 was added gene: LIPT1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: LIPT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIPT1 were set to 29681092; 31042466 Phenotypes for gene: LIPT1 were set to Lipoyltransferase 1 deficiency 616299 Review for gene: LIPT1 was set to AMBER Added comment: Sources: Literature |
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| Early onset or syndromic epilepsy v2.0 | NSF | Zornitza Stark reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: 31675180; Phenotypes: Seizures, EEG with burst suppression, Global developmental delay, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.0 | DOLK | Zornitza Stark edited their review of gene: DOLK: Added comment: Early presentation with seizures and demise reported in some individuals. Transferrin isoforms are not a reliable test in the newborn period to guide appropriate genomic analysis towards a CDG/metabolic panel; we also note the 25% recurrence risk, and hence we have included this gene as Green on our panel.; Changed publications: 23890587, 28816422, 24144945 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v2.0 | KAT8 |
Konstantinos Varvagiannis gene: KAT8 was added gene: KAT8 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: KAT8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KAT8 were set to 31794431 Phenotypes for gene: KAT8 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism Penetrance for gene: KAT8 were set to unknown Review for gene: KAT8 was set to GREEN Added comment: Heterozygous pathogenic missense KAT8 variants have been reported in individuals with DD, ID and epilepsy. Variants occurred as de novo events within the chromobarrel or the acetyltransferase domain and were all shown to affect H4K16 acetylation, as would be predicted by the gene's function (lysine acetyltransferase). Evidence from brain specific Kat8 knockout in mouse, supports the role of the gene in brain development. One similarly affected individual compound heterozygous for a nonsense and a missense variant (the former affecting subnuclear localization and the latter H4K16ac) was also reported, with carrier relatives being unaffected. Mutations in genes of the MSL/NSL complexes (with which KAT8 forms multisubunit complexes) or genes in other acetyltransferases of the same subfamily (MYST) as KAT8 cause neurodevelopmental disorders [Details provided below]. ----- Li et al. (2019 - PMID: 31794431) report on 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants, as well as an additional one compound heterozygous for a nonsense and a missense one. Overlapping phenotype consisted of DD/ID (8/8), seizures/epilepsy (6/8), brain MRI anomalies as well as presence of variable facial dysmorphic features. Less frequent features included abnormal vision (5/8), feeding difficulties (3/8), cardiac anomalies (3/8), autism (in 1). The (9th) individual with biallelic variants had similar phenotype of DD/ID, epilepsy, autism and dysmorphic facial features. Heterozygous parents and sister, the latter carrier for the missense variant, were all unaffected. All individuals had undergone exome sequencing, while extensive other investigations for at least 7/9 had only revealed variants of uncertain significance/contribution to the phenotype or were normal. KAT8 encodes lysine acetyltransferase 8, which acetylates histone H4 at lysine 16 (H4K16). It belongs to the MYST subfamily of lysine acetyltransferases, the other members of which include KAT6A, KAT6B (both involved in neurodevelopmental disorders) and KAT5. KAT8 forms two stoichiometric multisubunitcomplexes, one with the MSL complex and the other with the NSL. Mutations in genes encoding for subunits of the NSL or MSL complex (eg. KANSL1 and MSL3) are associated with neurodevelopmental disorders. Overall 6 missense SNVs were reported among the heterozygous patients, p.Tyr90Cys (NM_032188.2:c.269A>G) being a recurrent one seen in 3. The compound heterozygous patient had a missense (c.973C>T / p.Arg325Cys) and a nonsense variant (c.523A>T / p.Lys175*). All missense variants lied either in the chromobarrel domain or the acetyltransferase domain. Variants in the latter domain localized within the KAT8/Mof-specific region or - in the case of the compound heterozygous individual - within the acetyl-CoA binding motif. FLAG-tagged KAT8 (either wt or for all missense SNVs) was transfected in HEK293 cells with vectors for HA-tagged MSL proteins. While the nonsense variant was difficult to express, missense SNVs were expressed to similar levels to wt, promoted expression of MSL proteins but resulted in defective H4K16 acetylation and to a lesser extent H4K5 acetylation. As a result all missense variants impaired acetylation. This was also the case for chromobarrel domain variants, while expression of a KAT8 lacking the chromobarrel domain confirmed its ability to form complex with the MSL proteins and the impairment of H4K16 acetylation. The nonsense variant demonstrated abnormal subnuclear localization. The mouse model provides extensive evidence for the involvement of KAT8 in cerebral development. Cerebrum-specific Kat8 knockout mice presented postnatal growth retardation, hyperactivity/irritability, pre-weaning lethality, and cerebral hypoplasia upon autopsy. Loss of Kat8 reduced the number of neural stem and progenitor cells available for embryonic cerebrocortical development, impaired cell proliferation and stimulated apoptosis. The article also provides additional evidence from mouse model. 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 v1.405 | NSF |
Konstantinos Varvagiannis gene: NSF was added gene: NSF was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NSF were set to 31675180 Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability Penetrance for gene: NSF were set to unknown Review for gene: NSF was set to AMBER Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed). Sources: Literature |
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| Early onset or syndromic epilepsy v1.405 | PCYT2 |
Konstantinos Varvagiannis gene: PCYT2 was added gene: PCYT2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PCYT2 were set to 31637422 Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy Penetrance for gene: PCYT2 were set to Complete Review for gene: PCYT2 was set to GREEN Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations. The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy. Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below): - P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu - P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one. Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID). For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive. All variants were absent from / had extremely low AF in public databases, with no homozygotes. Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway. In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability. Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied: - Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant. - RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls. - Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls. The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping. CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish. Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088). Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life. PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID. As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating. [Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc]. Sources: Literature |
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| Early onset or syndromic epilepsy v1.274 | PIGP |
Konstantinos Varvagiannis changed review comment from: Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies. PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs). PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)]. The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in tranfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants : - mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one. - Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor). - Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation). -------- Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls. ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis). -------- A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to conanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts (NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7). This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090]. -------- ?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry. PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). -------- As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber. (Please consider inclusion in other possibly relevant panels eg. CDGs, etc). Sources: Literature; to: Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies. PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs). PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)]. The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in tranfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants : - mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one. - Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor). - Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation). -------- Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls. ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis). -------- A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to consanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts [NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7)]. This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090]. -------- ?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry. PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). -------- As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber. (Please consider inclusion in other possibly relevant panels eg. CDGs, etc). Sources: Literature |
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| Early onset or syndromic epilepsy v1.272 | PIGP |
Konstantinos Varvagiannis gene: PIGP was added gene: PIGP was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PIGP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGP were set to 28334793; 31139695 Phenotypes for gene: PIGP were set to Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment Penetrance for gene: PIGP were set to Complete Review for gene: PIGP was set to GREEN Added comment: Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies. PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs). PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)]. The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in tranfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants : - mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one. - Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor). - Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation). -------- Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls. ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis). -------- A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to conanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts (NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7). This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090]. -------- ?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry. PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). -------- As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber. (Please consider inclusion in other possibly relevant panels eg. CDGs, etc). Sources: Literature |
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| Early onset or syndromic epilepsy v1.188 | PSAT1 | Tracy Lester reviewed gene: PSAT1: Rating: RED; Mode of pathogenicity: ; Publications: 17436247; Phenotypes: Neu-Laxova syndrome 2, 616038 , ?Phosphoserine aminotransferase deficiency, 610992; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.167 | PIGB |
Konstantinos Varvagiannis gene: PIGB was added gene: PIGB was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGB were set to 31256876 Phenotypes for gene: PIGB were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot Penetrance for gene: PIGB were set to Complete Review for gene: PIGB was set to GREEN Added comment: Murakami et al. (2019 - PMID: 31256876) provide detailed information on 14 individuals from 10 families (4 of which consanguineous) with biallelic pathogenic PIGB variants. Overlapping features included DD/ID (13/13), epilepsy (14/14), deafness (7/14), ophthalmological or brain anomalies, hand and feet anomalies as well as presence of dysmorphic features. ID was common, in those individuals with appropriate age. Some had a previous diagnosis of DOORS syndrome (deafness/onychodystrophy/osteodystrophy,retardation, seizures) and few showed 2-oxoglutatic aciduria which can also be seen in DOORS s. PIGB encodes phosphatidylinositol glycan anchor biosynthesis class B protein. Overall the phenotype was similar to other inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs). As happens to be the case in some other GPI deficiencies alkaline phosphatase was also elevated in those tested (8/9). 8 missense, 1 stopgain as well as an intronic SNV are reported. All variants were either absent or ultra-rare and with no homozygotes in gnomAD. Affected individuals from 4 families, harbored an intronic SNV in the homozygous state. For this variant - with MAF of 0.0001592 or 6.51x10-5 in ExAC and gnomAD - activation of an aberrant splice acceptor site was shown [NM_004855.4:c.847-10A>G or p.Gln282_Trp283insArgCysGln]. Flow cytometric analysis of blood cells or fibroblasts showed decreased levels for various GPI-AP (GPI-anchored protein) markers in affected individuals. These levels were rescued upon transduction with a PIGB-encoding-Lx304 lentiviral vector of fibroblasts from one affected individual, suggesting that the PIGB defect was responsible. The effect of the variants was evaluated using PIGB-deficient CHO cells, transfected with wt or mutant PIGB cDNAs. FACS analysis and immunoblotting demonstrated that variants were able to restore only slightly/partially - if at all - the surface presence of GPI-APs in the case of variants while the levels of mutant protein were reduced. PIGB is not associated with any phenotype in OMIM/G2P. This gene is not commonly included in gene panels for ID offered by diagnostic laboratories. As a result, this gene can be considered for inclusion in the ID and epilepsy panels probably as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v1.57 | KMT5B |
Eleanor Williams gene: KMT5B was added gene: KMT5B was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: KMT5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KMT5B were set to 29276005 Phenotypes for gene: KMT5B were set to Mental retardation, autosomal dominant 51, 617788 Review for gene: KMT5B was set to RED Added comment: KMT5B is associated with Mental retardation, autosomal dominant 51 (#617788) in OMIM and KMT5B syndrome on Gene2phenotype. This syndrome has intellectual disability and overgrowth listed as phenotypes. PMID: 29276005 - Faundes et al 2018 - looked at patients from the Deciphering Developmental Disorders (DDD) study that high-quality-call genetic variants in methyltransferases (KMTs) and demethylases (KDMs) not yet firmly associated with DDs. 4 patients identified with either variants or deletions in KMT5B. 2 had nonsense variants, 2 had deletions encompassing KMT5B (399 kb and 839 kb). All had mild to severe intellectual disability. 2 (1 with nonsense variant, 1 with a deletion) also had seizures. Sources: Literature |
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| Early onset or syndromic epilepsy v1.57 | KMT5B |
Eleanor Williams gene: KMT5B was added gene: KMT5B was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: KMT5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KMT5B were set to 29276005 Phenotypes for gene: KMT5B were set to Mental retardation, autosomal dominant 51, 617788 Review for gene: KMT5B was set to RED Added comment: KMT5B is associated with Mental retardation, autosomal dominant 51 (#617788) in OMIM and KMT5B syndrome on Gene2phenotype. This syndrome has intellectual disability and overgrowth listed as phenotypes. PMID: 29276005 - Faundes et al 2018 - looked at patients from the Deciphering Developmental Disorders (DDD) study that high-quality-call genetic variants in methyltransferases (KMTs) and demethylases (KDMs) not yet firmly associated with DDs. 4 patients identified with either variants or deletions in KMT5B. 2 had nonsense variants, 2 had deletions encompassing KMT5B (399 kb and 839 kb). All had mild to severe intellectual disability. 2 (1 with nonsense variant, 1 with a deletion) also had seizures. 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 v1.31 | KMT2E |
Konstantinos Varvagiannis gene: KMT2E was added gene: KMT2E was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: KMT2E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KMT2E were set to https://doi.org/10.1101/566091 Phenotypes for gene: KMT2E were set to Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size Penetrance for gene: KMT2E were set to unknown Review for gene: KMT2E was set to GREEN Added comment: Gene added in the ID panel (comments below). Epilepsy was a feature in - at least - 11 individuals (with all categories of variants : 4 with truncating, 3 with CNVs, 4 with missense SNVs). As a result this gene can be considered for inclusion in the current panel as green (or amber). From the ID panel : In a collaborative study, O'Donnell-Luria et al. (2019 - https://doi.org/10.1101/566091 - DDD study among the co-authors) report on 38 individuals from 36 families with heterozygous KMT2E variants. Some of these individuals were previously included in previous publications. Developmental delay, intellectual disability, epilepsy and ASD were among the features reported, albeit of variable degree and not universal. 34 of 38 individuals had SNVs or indel variants in KMT2E and 4 individuals had CNVs spanning KMT2E (in one case intragenic, in 3 further as a contiguous gene deletion). For 26 (of 38 individuals) the variant had arisen as a de novo event while in some cases parental sample(s) was/were unavailable to confirm the de novo occurrence or origin (from a reportedly affected parent). The variant in one family was inherited from a parent for whom information on affected/unaffected status was unavailable. As for the variants reported: 30 were protein-truncating (of which 23 predicted to produce transcripts subject to NMD). 4 were missense. 4 were CNVs (de novo deletions, of which 1 intragenic). Truncating variants and deletions of KMT2E suggest haploinsufficiency as the underlying mechanism for this category of variants (KMT2E has a pLI of 1 in gnomAD). However, the somewhat different phenotype related to missense variants (degree of ID, epilepsy in all, microcephaly in some versus macrocephaly in subjects with truncating variants) may suggest a different mechanism for these variants eg. gain of function or dominant negative effect. There was no clustering observed for the missense variants reported. Expressivity of certain features may be variable between males and females. As the authors note : KMT2E encodes a member of the lysine N-methyltransferase 2 family, a family of enzymes with critical role in H3K4 methylation. It is highly expressed in brain, particularly during fetal development. Several monogenic neurodevelopmental disorders due to impaired regulation of H3K4 methylation are known (eg. due to KMT2D/C/B/A mutations, etc). Studies suggest that KMT2E may lack intrinsic methyltransferase activity although it may have an indirect effect on H3K4 methylation. In contrast to other members of the KMT2 family functioning as global activators of open chromatin, KMT2E is believed to be a repressor (although it's function in gene transcription regulation needs to be clarified). A neurological phenotype of Kmt2e (Mll5) deficiency mouse models has not been reported (features included growth restriction, impaired hematopoiesis, etc). KMT2E is not associated with any phenotype in OMIM. The gene is included in the DD panel of G2P, associated with Intellectual disability (disease confidence: confirmed / mutation consequence registered in the db : LoF). KMT2E is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study). As a result, this gene can be considered for upgrade to green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v1.30 | ATN1 |
Konstantinos Varvagiannis gene: ATN1 was added gene: ATN1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATN1 were set to 30827498 Phenotypes for gene: ATN1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney Penetrance for gene: ATN1 were set to unknown Mode of pathogenicity for gene: ATN1 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: ATN1 was set to GREEN Added comment: Apart from CAG repeat expansions (green in the present panel) seizures have been reported in individuals with mutations in the HX repeat motif (5 unrelated individuals, each with a private variant). As a result, ATN1 can be considered for inclusion in the Epilepsy panel as green (or amber). Copied from the ID panel : Palmer et al. (2019 - PMID: 30827498) report on 8 individuals all harboring de novo missense or insertion variants within a 16-amino-acid HX repeat motif (aa 1150-1065 / 8 HX repeats, where H is histidine and X any amino acid) in exon 7 of ATN1. The specific motif is distal to the Gln-rich region involved in Dentatorubro-pallidoluysian atrophy (caused by polyglutamine expansion in exon 5, due to a probable toxic GoF effect - MIM #125370). None of the subjects reported presented features of the latter disorder. Common features included hypotonia (8/8) , DD and/or ID (8/8). Other frequent features included visual or hearing impairment, seizures (5/8 - in most presenting as neonatal/infantile onset dev. encephalopathy), feeding difficulties/functional GI disorders. Some individuals presented with congenital anomalies eg. cardiac, cleft palate, renal anomalies, anteriorly placed anus. Some facial (eg. presence of tall forehead, bitemporal narrowing, deep set eyes, sparse lateral hair, bulbous nose, open mouth appearance ,etc) or features of the extremities (overlapping fingers/toes) were also common. Converging evidence from the literature suggests that ATN1 is a nuclear transcriptional regulator important in the control of brain and other organ development (PMIDs cited: 17150957, 25519973, 10973986). The gene is widely expressed in various tissues incl. brain, heart, lung, kidney, skeletal muscle. Expression is higher in fetal tissues particularly in brain while the gene is broadly expressed in multiple regions of the adult human brain (PMID: 7485154). All 8 variants were missense SNVs or insertions within the HX repeat motif (aa 1150-1065) and had occurred as de novo events: c.3160C>A or p.His1054Asn, c.3172C>T or p.His1058Tyr, c.3177_3178insAACCTG or p.Ser1059_His1060insAsnLeu, c.3177_3178insGACCTG or p.Ser1059_His1060insAspLeu, c.3178C>T or p.His1060Tyr, c.3184C>G or p.His1062Asp, c.3188T>G or p.Leu1063Arg, c.3185A>G or p.His1062Arg [NM_001007026.1]. NMR studies of 2 commercialy synthesized polypeptides containing residues 1046-1067 of ATN1 and the HX motif suggested disruption in the case of His1060Tyr of the spatial and dynamical synchronization of histidines which is favored by the regularly spaced occurrence of histidines in the wild-type sequence. Under specific conditions introduction of His1060Tyr allowed zinc binding, which was not the case for the wild-type peptide, thus conferring the peptide a novel property (the consequences of which are though unknown). Clustering of the variants and presence of LoF in healthy individuals (eg. in gnomAD db) suggests that haploinsufficiency is unlikely. Similar (HX)n repeat motifs exist in other proteins, among others RERE or AUTS2 which are associated with neurodevelopmental disorders. The authors comment that disruption of the HX motif in RERE has been reported in affected individuals and that mutations occurring in this motif are more likely to be associated with congenital anomalies, compared to mutations in the rest of the protein. As for animal models, Atn1 -/- mice are neurologically normal. Knockdown of the gene in rat neuronal progenitor cells led to anomalies in brain development, though these could be rescued by co-transfection with human ATN1 construct (PMIDs cited: 17150957, 25519973). ------- In OMIM, heterozygous pathogenic CAG trinucleotide expansions in ATN1 are associated with DRPLA (MIM #125370). The gene is not associated with any phenotype in G2P. Sources: Literature |
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| Early onset or syndromic epilepsy v1.30 | TRRAP |
Konstantinos Varvagiannis gene: TRRAP was added gene: TRRAP was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TRRAP were set to 30827496 Phenotypes for gene: TRRAP were set to Global developmental delay; Intellectual disability; Autism; Microcephaly; Abnormal heart morphology; Abnormality of the urinary system; Seizures Penetrance for gene: TRRAP were set to unknown Mode of pathogenicity for gene: TRRAP 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: TRRAP was set to AMBER Added comment: Cogné et al. (DDD study among the co-authors - PMID: 30827496) report on 24 individuals with pathogenic TRRAP variants. 17 different variants were reported. All variants were missense SNVs and on most occasions had occurred as de novo or apparently de novo events (paternity and maternity not checked). On one occasion, a parent was not unavailable although the respective grand-parents were not found to harbor the variant. Parental germline mosaicism explained the occurence of a variant in 2 sibs. The authors suggest a strong genotype-phenotype correlation. Individuals whose variant localized within the residues 1031-1159 (NM_001244580.1) presented with a syndromic form of ID with additional malformations. ID was a universal feature in this group (for those subjects evaluated). For variants outside this cluster of residues the phenotype was rather that of ASD without ID or isolated ID with or without ASD, albeit with some exceptions (eg. F860L also associated with a syndromic presentation). ID was a feature in the majority of individuals belonging to the latter group (67% - all with DD) or overall irrespective of the variant localization (85% for those evaluated - all with DD). ** Epilepsy was a feature in 4 individuals (4/24) belonging to either group. ** All 17 variants were absent from gnomAD with CADD scores supporting a deleterious effect (SIFT/PolyPhen2 (both) predicted a tolerated/benign effect for some eg. Ala1043Thr). A few variants were recurrent, namely Ala1043Thr (5 individuals), Glu1106Lys (2), Gly1883Arg (2), Pro1932Leu (in 2 sibs). 6 further subjects (individuals 25-30, reported separately in the supplement) harbored 6 additional variants with lesser evidence for pathogenicity. TRRAP is among the 5 most intolerant genes to missense mutations (z-score of 10.1 in ExAC) while it is also intolerant to LoF variants (pLI of 1). No deletions have been reported in DECIPHER and no LoF were identified in the study. Given type of variants and their clustering rather a gain-of-function effect or dominant-negative effect is suggested. As the authors note a LoF effect of non-clustering variants, associated with a milder phenotype cannot excluded. [Mode of pathogenicity to change if thought to be useful]. TRRAP encodes a protein involved in the recruitment to chromatin of histone acetyltransferases. The latter control the process of acetylation of lysine residues in histones and other DNA-binding proteins thus playing a major role in regulation of gene expression. In line with this, RNA sequencing analysis in skin fibroblasts from affected subjects demonstrated dysregulation of expression for several genes implicated in neuronal function and ion transport. As summarized by the authors: In mice, Trapp knockout is embryonically lethal. Brain-specific knockout leads to premature differentiation of neural progenitors and abnormal brain development. Brain atrophy and microcephaly are observed (microcephaly was a feature in some affected individuals as well, primarily those with variants affecting residues 1031-1159). [PMIDs cited: 11544477, 24792116]. De novo TRRAP variants have been reported also in individuals with neuropsychiatric disorders (PMIDs: 21822266, 23042115, 28392909, 30424743) while TRRAP has been classified among the prenatally-biased genes relevant to its brain expression (PMID:23042115). A de novo missense variant (c.11270G>A or p.R3757Q) was also previously reported in a study of 264 individuals with epileptic encephalopathy (Epi4K Consortium - PMID: 23934111 - indiv. ND29352). ----------- TRRAP is not associated with any phenotype in OMIM, nor in G2P. ----------- As a result, this gene can be considered for inclusion in the epilepsy panel as amber or green. Sources: Literature |
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| Early onset or syndromic epilepsy v1.13 | DHPS |
Konstantinos Varvagiannis gene: DHPS was added gene: DHPS was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHPS were set to 21389784; 21850436 Phenotypes for gene: DHPS were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck Penetrance for gene: DHPS were set to Complete Review for gene: DHPS was set to GREEN Added comment: Ganapathi et al. (doi.org/10.1016/j.ajhg.2018.12.017 - PMID : NA) report on 5 individuals from 4 unrelated families with biallelic pathogenic variants in DHPS. The phenotype consisted of DD/ID (5/5), tone abnormalities (hypotonia/hypertonia/spasticity - 5/5), seizures (5/5 - in one case though unclear staring spells) with EEG abnormalities (5/5). Additionally most individuals displayed behavioral issues, or some common facial features. Several other disorders had been ruled prior to the diagnosis, in all cases by exome sequencing. All individuals harbored a specific missense variant (c.518A>G or p.Asn173Ser) in trans with various other variants incl. a splice site mutation (c.1014+1G>A), an in-frame deletion of 2 amino acids (c.912_917delTTACAT or p.Tyr305_Ile306del) or a variant abolishing the translation initiation codon (c.1A>G or p.Met1?) [All variants using NM_001930.3 as a reference]. Deoxyhypusine synthase (encoded by DHPS) is an enzyme participating in the first step of hypusine synthesis, an amino-acid which is specific to eukaryotic initiation factor 5A (eIF5A) and its homolog (eIF5A2). eIF5A, its hypusinated form and DHPS have all been previously implicated in cellular proliferation/differentiation. eIF5A has also been proposed to be a mRNA translation elongation factor. A role of eIF5A in neuronal growth and survival has been proposed previously (all ref. in present article). Neither eIF5A, nor DHPS or DOHH (an enzyme required for the second step of hypusination) have been associated to any disorders previously. Mutations in genes encoding other eukaryotic elongator factors (eg. EEF1A2, EEF2) have been associated with neurodevelopmental disorders. Concerning the DHPS variants reported: cDNA studies suggested that the c.1014+1G>A variant is translated but results in aberrant splicing and truncation of the protein before its active site. The in-frame deletion as well as the missense variant were shown to have absent or partial (20%) enzyme activity in vitro respectively compared to wild-type (following expression in E.coli BL21(DE3) cells). In line with this, reduced hypusination of eIF5A was observed for these 2 variants when compared to wild-type DHPS, upon co-transfection of constructs overexpressing DHPS (wt or mut.) and eIF5A in HEK293T cells. Absence of homozygous DHPS LoF variants in population databases might suggest that complete deficiency is incompatible with normal embryonic development. Mice heterozygous for Dhps deletion do not demonstrate severe phenotypes, though homozygosity is embryonically lethal (PMIDs: 21389784, 21850436). --------- DHPS is not associated with any phenotype in G2P, nor in OMIM. --------- As a result, DHPS can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v0.1044 | GAMT | Louise Daugherty Phenotypes for gene: GAMT were changed from Cerebral creatine deficiency syndrome 2, 612736; Seizures; Deficiency of guanidinoacetate methyltransferase to Cerebral creatine deficiency syndrome 2, 612736; Seizures; Deficiency of guanidinoacetate methyltransferase; GAMT deficiency | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1039 | GAMT | Louise Daugherty Phenotypes for gene: GAMT were changed from Cerebral creatine deficiency syndrome 2, 612736; Seizures to Cerebral creatine deficiency syndrome 2, 612736; Seizures; Deficiency of guanidinoacetate methyltransferase | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||