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Genetic epilepsy syndromes 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].
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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
Genetic epilepsy syndromes v2.0 RARS Konstantinos Varvagiannis gene: RARS was added
gene: RARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RARS were set to 31814314; 28905880; 24777941
Phenotypes for gene: RARS were set to Leukodystrophy, hypomyelinating, 9 616140
Penetrance for gene: RARS were set to Complete
Review for gene: RARS was set to GREEN
Added comment: Biallelic pathogenic RARS1 variants cause Leukodystrophy, hypomyelinating, 9 (# 616140).

The current review was based primarily on PMID: 31814314 (Mendes et al, 2019) providing details on 20 affected individuals from 15 families. 5 of these patients were included in a previous publication (Wolf et al, 2014 - PMID: 24777941) sharing authors with this study.

Clinical presentation and severity can be highly variable. However, among the 15 patients of relevant age (5/20 deceased at an early age), ID was observed in 13 (in 6/13 mild-moderate, in 7/13 severe/profound). Epilepsy was reported in half (10/20) with seizures being refractory to treatment in most and the phenotype corresponding to an infantile epileptic encephalopathy. DD and seizures were the presenting feature in 7 and 5 patients respectively, while in other cases presenting features were less specific (eg. failure to thrive in 1/20, irritabilty in 2/20). As a result the gene appears to be relevant to both DD/ID and epilepsy panels.

RARS1 encodes the cytoplasmic arginyl-tRNA synthetase 1, which is a component of the aminoacyl-tRNA synthetase complex (OMIM and Wolf et al, 2014 - PMID: 24777941). Aminoacyl-tRNA synthetases catalyze the aminoacylation ('charging') of tRNA by (with) their cognate amino acid.

Utilisation of alternative initiation codons, from a single mRNA transcript, results in translation of a long and a short protein isoform (Zheng et al 2006 - PMID: 16430231). The long isoform is needed for the formation of the multi-synthetase complex (MSC), while the short is free in the cytoplasm and does not have any interaction with the MSC. The long isoform appears to be essential for protein synthesis (discussed with several refs provided in PMID: 28905880 - Nafisinia et al, 2017).

The role of variants has been supported in several patients by additional studies - among others :
[PMID 31814314] Impaired Arginyl-tRNA synthetase activity was demonstrated in fibroblasts from 3 patients. Activity was normal in one additional individual compound heterozygous for a variant affecting initiation codon and a missense one. Western blot however demonstrated presence mainly of the short protein isoform. The authors suggest that this isoform possibly contributed to enzymatic activity. The long isoform which is needed for the MSC complex was only represented by a faint band in the Western Blot of the same individual.
[PMID: 28905880] Using fibroblasts from an affected subject homozygous for a missense variant (NM_002887.3:c.5A>G / p.Asp2Gly) and controls, a 75% reduction of the long isoform was shown upon WB. The short isoform was present at similar levels. As the N-terminus (of the long isoform) mediates interaction with the MSC (and AIMP1), assembly of the latter was 99% reduced in patient fibroblasts. Proliferation of patient fibroblasts was significantly reduced when cultured in a medium with limited arginine, a finding which was thought to reflect inefficient protein synthesis.

Mutations in other genes encoding for aminoacyl-tRNA synthetases (eg. AARS1, VARS1) or scaffolding proteins of the multisynthetase complex (eg. AIMP1 and AIMP2) lead to neurodevelopmental disorders with overlapping phenotype [most genes rated green in both the ID and epilepsy panel].
Sources: Literature
Genetic epilepsy syndromes v2.0 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
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In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
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As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

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Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
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In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
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As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

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Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
Genetic epilepsy syndromes v2.0 Rebecca Foulger promoted panel to version 2.0
Genetic epilepsy syndromes v1.498 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Genetic epilepsy syndromes v1.497 TRAPPC4 Konstantinos Varvagiannis gene: TRAPPC4 was added
gene: TRAPPC4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC4 were set to 31794024
Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment
Penetrance for gene: TRAPPC4 were set to Complete
Review for gene: TRAPPC4 was set to GREEN
Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant.

Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy).

Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc).

Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members.

Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G].

mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls).

Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift).

TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article].

Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel).

Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals.

Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing).

TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts.
Sources: Literature
Genetic epilepsy syndromes v1.497 SNX27 Konstantinos Varvagiannis gene: SNX27 was added
gene: SNX27 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SNX27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX27 were set to 25894286; 31721175; 21300787; 23524343
Phenotypes for gene: SNX27 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: SNX27 were set to Complete
Review for gene: SNX27 was set to AMBER
Added comment: (From the ID panel)

Evidence from 2 publications suggests that DD, ID and seizures are part of the phenotype of individuals with biallelic SNX27 pathogenic variants :
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Damseh, Danson et al (2015 - PMID: 25894286) first reported on a consanguineous family with 4 affected sibs, homozygous for an SNX27 pathogenic variant. Features incl. hypotonia soon after birth, failure to thrive, severely delayed psychomotor development with no milestone acquisition, occurrence of myoclonic seizures with 3 individuals deceased early. Exome sequencing in one revealed a few candidate variants, with an SNX27 frameshift one [NM_030918.6:c.515_516del - p.(His172Argfs*6) / absent from ExAC] being the only retained following Sanger segregation studies. Using fibroblasts from an affected individual, Western blot with an antibody which would also bind prior to the truncation site, was consistent with dramatically reduced/absent SNX27 truncated mutant protein. Protein levels of VPS35, a component of the retromer responsible for direct cargo binding (not mediated by a cargo adaptor as SNX27), were normal.
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Parente et al (2019 - PMID: 31721175) reported on a 13-year-old male with motor and language delay, ADHD, ID (kindergarten academic level at the age of 13) and seizures with onset at the age of 9 years (GTC, with abnormal EEG and postical SV tachycardia). Variable physical findings were reported. White matter hyperintesities were noted upon initial brain MRI (but were less marked in subsequent ones). Initial genetic testing (Alexander's disease, CMA, FMR1) was normal. Exome revealed compound heterozygosity for 2 SNX27 variants (NM_030918.5/NM_001330723.1 both apply c.510C>G - p.Tyr170* and c.1295G>A - p.Cys432Tyr) each inherited from healthy carrier parents. There were no other potentially causative variants. A parental history of - isolated - late onset seizures was reported (so this individual may not be considered for the seizure phenotype here).

The authors also reported on a further 31-year old affected male. This individual had infantile hypotonia, poor eye contact with subsequent significant DD, seizures (febrile/afebrile T-C with onset at the age of 14m) and ID estimated in the severe range. Variable - though somewhat different - physical findings were reported. Initial work-up included basic metabolic testing, standard karyotype, FISH for 15q11 and subtelomeric regions and PHF6 genetic testing - all normal. Exome (and subsequent Sanger confirmation/parental studies) revealed compound heterozygosity for a missense and a frameshift variant (c.989G>A / p.Arg330His and c.782dupT / p.Leu262Profs*6 same in NM_001330723.1, NM_030918.6).
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SNX27 encodes sorting nexin 27, a cargo adaptor for the retromer. The latter is a multi-protein complex essential for regulating the retrieval and recycling of transmembrane cargos from endosomes to the trans-Golgi network or the plasma membrane [Lucas et al 2016 - PMID: 27889239 / McNally et al 2018 - PMID: 30072228].

As summarized by Parente et al, the encoded protein by regulating composition of the cell surface influences several processes eg. neuronal excitability, synaptic plasticity, Wnt signaling etc. It has been shown to interact with surface receptors and their ligands including GIRK channels, 5-HT4, ionotropic glutamate receptors (incl. NMDA- and AMPA-type receptors) and mGluR5 [several refs. provided].

Knockout of Snx27 in mice resulted in embryonic lethality (16% hmz of the 25% expected), severe postnatal growth retardation and death within the first 3 weeks. Snx27(+/-) mice have normal neuroanatomy but exhibit cognitive deficits (in learning and memory) and defects in synaptic function/plasticity with reduced amounts of NMDA and AMPA receptors (Cai et al - PMID: 21300787, Wang et al - PMID: 23524343).
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There is no associated phenotype in OMIM/G2P.
Sources: Literature
Genetic epilepsy syndromes v1.497 OXR1 Konstantinos Varvagiannis gene: OXR1 was added
gene: OXR1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Phenotypes for gene: OXR1 were set to Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum
Penetrance for gene: OXR1 were set to Complete
Review for gene: OXR1 was set to GREEN
Added comment: Wang et al (2019 - https://doi.org/10.1016/j.ajhg.2019.11.002 ) report on 5 individuals (from 3 families) with biallelic OXR1 LoF variants.

Common features included hypotonia (4/5), severe global DD (5/5) and speech delay (5/5), ID (5/5), epilepsy (5/5) with cerebellar dysplasia/atrophy (5/5) and in some scoliosis.

All were investigated by exome sequencing and were found to harbor biallelic loss-of-function variants (2 splice-site, a stopgain and a frameshift one) either in homozygosity (2 consanguineous families) or in compound heterozygosity. In all cases parental segregation studies were compatible and in one family, an unaffected sib shown to be carrier.

Althouhgh OXR1 has been shown to affect several processes (among others DNA lesions induced by oxidative stress in E.coli, neuronal maintenance, mitochondrial morphology and DNA maintenance, etc), its mechanism of action is still not well defined. There are 6 RefSeq transcripts, the longest (NM_018002.3) encoding 3 protein domains (LysM, GRAM, TLDc). The TLDc domain is encoded by all transcripts.

Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1.

Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families.

The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd.

Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function.

The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes).

Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction).

Overall the data presented suggest a critical role for OXR1 in lysosomal biology.

Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects.
Sources: Literature
Genetic epilepsy syndromes v1.497 PCYT2 Ellen McDonagh reviewed gene: PCYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.497 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Genetic epilepsy syndromes v1.496 WWOX Rebecca Foulger Publications for gene: WWOX were set to Tabarki (2015) Ben-Salam (2015) Mignot (2015)
Genetic epilepsy syndromes v1.495 WWOX Rebecca Foulger Phenotypes for gene: WWOX were changed from to Epileptic encephalopathy, early infantile, 28, 616211
Genetic epilepsy syndromes v1.494 WDR45 Rebecca Foulger Phenotypes for gene: WDR45 were changed from to Neurodegeneration with brain iron accumulation 5, 300894
Genetic epilepsy syndromes v1.493 WDR45 Rebecca Foulger Publications for gene: WDR45 were set to Saitsu et al (2013) Nat Genet. 45(4):445-9
Genetic epilepsy syndromes v1.492 STX1B Rebecca Foulger Phenotypes for gene: STX1B were changed from to Generalized epilepsy with febrile seizures plus, type 9, 616172
Genetic epilepsy syndromes v1.491 STX1B Rebecca Foulger Mode of inheritance for gene: STX1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.490 SLC6A1 Rebecca Foulger Phenotypes for gene: SLC6A1 were changed from to Myoclonic-atonic epilepsy, 616421
Genetic epilepsy syndromes v1.489 SLC6A1 Rebecca Foulger Publications for gene: SLC6A1 were set to Carvill et al (2015) Am J Hum Genet 96(5): 808-15
Genetic epilepsy syndromes v1.488 PNPO Rebecca Foulger Phenotypes for gene: PNPO were changed from to Pyridoxamine 5'-phosphate oxidase deficiency, 610090
Genetic epilepsy syndromes v1.487 NDUFS8 Rebecca Foulger Phenotypes for gene: NDUFS8 were changed from Mitochondrial complex I deficiency, nuclear type 2, 618222 to Mitochondrial complex I deficiency, nuclear type 2, 618222; Leigh syndrome due to mitochondrial complex I deficiency
Genetic epilepsy syndromes v1.486 NDUFS8 Rebecca Foulger Phenotypes for gene: NDUFS8 were changed from to Mitochondrial complex I deficiency, nuclear type 2, 618222
Genetic epilepsy syndromes v1.485 DNM1 Rebecca Foulger Mode of inheritance for gene: DNM1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.484 DNM1 Rebecca Foulger Publications for gene: DNM1 were set to EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11
Genetic epilepsy syndromes v1.483 DNM1 Rebecca Foulger Phenotypes for gene: DNM1 were changed from to Epileptic encephalopathy, early infantile, 31, 616346
Genetic epilepsy syndromes v1.482 CYFIP2 Rebecca Foulger Mode of pathogenicity for gene: CYFIP2 was changed from None to Other
Genetic epilepsy syndromes v1.481 CYFIP2 Rebecca Foulger Publications for gene: CYFIP2 were set to 29534297
Genetic epilepsy syndromes v1.480 CYFIP2 Rebecca Foulger Phenotypes for gene: CYFIP2 were changed from to Epileptic encephalopathy, early infantile, 65, 618008
Genetic epilepsy syndromes v1.479 CSTB Rebecca Foulger Publications for gene: CSTB were set to
Genetic epilepsy syndromes v1.478 CSTB Rebecca Foulger Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800
Genetic epilepsy syndromes v1.477 PNPT1 Konstantinos Varvagiannis gene: PNPT1 was added
gene: PNPT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PNPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPT1 were set to 31752325
Phenotypes for gene: PNPT1 were set to Combined oxidative phosphorylation deficiency 13, MIM 614932
Penetrance for gene: PNPT1 were set to Complete
Review for gene: PNPT1 was set to GREEN
Added comment: Reviewed for the intellectual disability panel. Seizures may be observed in affected individuals (details below). Please consider inclusion with amber / green rating.

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Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.
Sources: Literature
Genetic epilepsy syndromes v1.477 SCAMP5 Ellen McDonagh Added comment: Comment on mode of pathogenicity: A dominant negative effect is predicted.
Genetic epilepsy syndromes v1.477 SCAMP5 Ellen McDonagh Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other
Genetic epilepsy syndromes v1.476 SCAMP5 Ellen McDonagh Classified gene: SCAMP5 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.476 SCAMP5 Ellen McDonagh Added comment: Comment on list classification: Gene added by external Reviewer, and promoted to Amber due to review and overall evidence.
Genetic epilepsy syndromes v1.476 SCAMP5 Ellen McDonagh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes 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.

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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).
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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).
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There is no associated phenotype in OMIM/G2P/SysID.
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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
Genetic epilepsy syndromes v1.475 IDH2 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green.Refers to glioma patients: not a seizure disorder. Demoted from Green to RED.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Refers to glioma patients- not a seizure disorder. Demoted from Green to RED.
Genetic epilepsy syndromes v1.475 CYP27A1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.475 SCN9A Rebecca Foulger Publications for gene: SCN9A were set to 19763161; 29500686
Genetic epilepsy syndromes v1.474 FLNA Rebecca Foulger changed review comment from: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was notes that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.; to: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was noted that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.
Genetic epilepsy syndromes v1.474 PEX6 Rebecca Foulger Classified gene: PEX6 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.474 PEX6 Rebecca Foulger Gene: pex6 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.473 PEX6 Rebecca Foulger commented on gene: PEX6: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Genetic epilepsy syndromes v1.473 PEX3 Rebecca Foulger Classified gene: PEX3 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.473 PEX3 Rebecca Foulger Gene: pex3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.472 PEX3 Rebecca Foulger commented on gene: PEX3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Genetic epilepsy syndromes v1.472 PEX2 Rebecca Foulger Classified gene: PEX2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.472 PEX2 Rebecca Foulger Gene: pex2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.471 PEX2 Rebecca Foulger commented on gene: PEX2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Genetic epilepsy syndromes v1.471 PEX19 Rebecca Foulger Classified gene: PEX19 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.471 PEX19 Rebecca Foulger Gene: pex19 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.470 PEX19 Rebecca Foulger commented on gene: PEX19: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Genetic epilepsy syndromes v1.470 PEX13 Rebecca Foulger Classified gene: PEX13 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.470 PEX13 Rebecca Foulger Gene: pex13 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.469 PEX13 Rebecca Foulger commented on gene: PEX13: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Genetic epilepsy syndromes v1.469 BSCL2 Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should change from 'BOTH monoallelic and biallelic' to 'BIALLELIC': just one monoallelic case so far, which could be a false positive.
Genetic epilepsy syndromes v1.469 BSCL2 Rebecca Foulger Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.468 NDUFA1 Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should be updated from XLR to XLD.
Genetic epilepsy syndromes v1.468 NDUFA1 Rebecca Foulger Mode of inheritance for gene: NDUFA1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.467 NSDHL Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should remain as XLR.
Genetic epilepsy syndromes v1.467 NSDHL Rebecca Foulger Mode of inheritance for gene: NSDHL was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.466 ADAR Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should remain as BIALLELIC: No current evidence for seizures in monoallelic cases.
Genetic epilepsy syndromes v1.466 ADAR Rebecca Foulger Mode of inheritance for gene: ADAR was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.465 DNAJC5 Rebecca Foulger Classified gene: DNAJC5 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.465 DNAJC5 Rebecca Foulger Gene: dnajc5 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.464 DNAJC5 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures present later. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.464 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.464 SGSH Rebecca Foulger commented on gene: SGSH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.
Genetic epilepsy syndromes v1.464 EXT2 Rebecca Foulger Classified gene: EXT2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.464 EXT2 Rebecca Foulger Gene: ext2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.463 EXT2 Rebecca Foulger commented on gene: EXT2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures not a presenting feature. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.463 CLPB Rebecca Foulger Classified gene: CLPB as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.463 CLPB Rebecca Foulger Gene: clpb has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.462 CLPB Rebecca Foulger commented on gene: CLPB: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Although there are three cases, most patients don't have seizures. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.462 TMEM70 Rebecca Foulger Classified gene: TMEM70 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.462 TMEM70 Rebecca Foulger Gene: tmem70 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.461 TMEM70 Rebecca Foulger commented on gene: TMEM70: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Insufficient seizure evidence. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.461 SLC6A19 Rebecca Foulger Classified gene: SLC6A19 as Red List (low evidence)
Genetic epilepsy syndromes v1.461 SLC6A19 Rebecca Foulger Gene: slc6a19 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.460 SLC6A19 Rebecca Foulger commented on gene: SLC6A19: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Epilepsy is not a key feature. Demoted from Green to Red.
Genetic epilepsy syndromes v1.460 SLC35A1 Rebecca Foulger Publications for gene: SLC35A1 were set to 23873973; 15576474; 28856833; 30115659
Genetic epilepsy syndromes v1.459 SLC35A1 Rebecca Foulger Classified gene: SLC35A1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.459 SLC35A1 Rebecca Foulger Gene: slc35a1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.458 SLC35A1 Rebecca Foulger commented on gene: SLC35A1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.458 SCO2 Rebecca Foulger Publications for gene: SCO2 were set to 10545952; 10749987; 18924171
Genetic epilepsy syndromes v1.457 SCO2 Rebecca Foulger Classified gene: SCO2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.457 SCO2 Rebecca Foulger Gene: sco2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.456 SCO2 Rebecca Foulger commented on gene: SCO2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.456 SCO1 Rebecca Foulger Classified gene: SCO1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.456 SCO1 Rebecca Foulger Gene: sco1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.455 SCO1 Rebecca Foulger commented on gene: SCO1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.455 QDPR Rebecca Foulger Classified gene: QDPR as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.455 QDPR Rebecca Foulger Gene: qdpr has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.454 QDPR Rebecca Foulger commented on gene: QDPR: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.454 PRODH Rebecca Foulger Classified gene: PRODH as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.454 PRODH Rebecca Foulger Gene: prodh has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.453 PRODH Rebecca Foulger commented on gene: PRODH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.453 PEX7 Rebecca Foulger Classified gene: PEX7 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.453 PEX7 Rebecca Foulger Gene: pex7 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.452 PEX7 Rebecca Foulger commented on gene: PEX7: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.452 PEX12 Rebecca Foulger Classified gene: PEX12 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.452 PEX12 Rebecca Foulger Gene: pex12 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.451 PEX12 Rebecca Foulger commented on gene: PEX12: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted all PEX genes from Green to Amber.
Genetic epilepsy syndromes v1.451 PEX10 Rebecca Foulger Publications for gene: PEX10 were set to 20695019
Genetic epilepsy syndromes v1.450 PEX10 Rebecca Foulger Classified gene: PEX10 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.450 PEX10 Rebecca Foulger Gene: pex10 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.449 PEX10 Rebecca Foulger commented on gene: PEX10: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted all PEX genes from Green to Amber.
Genetic epilepsy syndromes v1.449 PEX1 Rebecca Foulger Classified gene: PEX1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.449 PEX1 Rebecca Foulger Gene: pex1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.448 PEX1 Rebecca Foulger commented on gene: PEX1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted all PEX genes from Green to Amber.
Genetic epilepsy syndromes v1.448 MTR Rebecca Foulger Classified gene: MTR as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.448 MTR Rebecca Foulger Gene: mtr has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.447 MTR Rebecca Foulger commented on gene: MTR: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Metabolic phenotype with failure to thrive, with seizures presenting later. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.447 IDH2 Rebecca Foulger Classified gene: IDH2 as Red List (low evidence)
Genetic epilepsy syndromes v1.447 IDH2 Rebecca Foulger Gene: idh2 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.446 IDH2 Rebecca Foulger commented on gene: IDH2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green.Refers to glioma patients: not a seizure disorder. Demoted from Green to RED.
Genetic epilepsy syndromes v1.446 HLCS Rebecca Foulger Classified gene: HLCS as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.446 HLCS Rebecca Foulger Gene: hlcs has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.445 HLCS Rebecca Foulger commented on gene: HLCS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.445 GSS Rebecca Foulger Classified gene: GSS as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.445 GSS Rebecca Foulger Gene: gss has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.444 GSS Rebecca Foulger commented on gene: GSS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.444 GLYCTK Rebecca Foulger Classified gene: GLYCTK as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.444 GLYCTK Rebecca Foulger Gene: glyctk has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.443 GLYCTK Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Bordeline cases from literature, variable phenotype and needs better genotype:phenotype correlation. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.443 GLYCTK Rebecca Foulger commented on gene: GLYCTK: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.443 GFM1 Rebecca Foulger Classified gene: GFM1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.443 GFM1 Rebecca Foulger Gene: gfm1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.442 GFM1 Rebecca Foulger commented on gene: GFM1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.442 GCH1 Rebecca Foulger Classified gene: GCH1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.442 GCH1 Rebecca Foulger Gene: gch1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.441 GCH1 Rebecca Foulger commented on gene: GCH1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.441 FH Rebecca Foulger Classified gene: FH as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.441 FH Rebecca Foulger Gene: fh has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.440 FH Rebecca Foulger commented on gene: FH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.440 FAR1 Rebecca Foulger Classified gene: FAR1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.440 FAR1 Rebecca Foulger Gene: far1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.439 FAR1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Borderline evidence and variable phenotype. Requires better genotype:phenotype correlation. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.439 FAR1 Rebecca Foulger commented on gene: FAR1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Borderline evidence and variable phenotype. Requires better genotype:phenotype correlation. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.439 DOLK Rebecca Foulger Classified gene: DOLK as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.439 DOLK Rebecca Foulger Gene: dolk has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.438 DOLK Rebecca Foulger commented on gene: DOLK: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.438 CYP27A1 Rebecca Foulger Classified gene: CYP27A1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.438 CYP27A1 Rebecca Foulger Gene: cyp27a1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.437 CYP27A1 Rebecca Foulger commented on gene: CYP27A1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.437 PTS Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Seizures may present before 9 months, and could be the primary presentation in these cases. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Seizures may present before 9 months, and could be the primary presentation in these cases. Since the last group review, PTS has also been promoted to Green on the 'Inborn errors of metabolism' panel (v 1.407). Promoted PTS from Amber to Green on the epilepsy panel.
Genetic epilepsy syndromes v1.437 PTS Rebecca Foulger Classified gene: PTS as Green List (high evidence)
Genetic epilepsy syndromes v1.437 PTS Rebecca Foulger Gene: pts has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.436 PTS Rebecca Foulger commented on gene: PTS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Seizures may present before 9 months, and could be the primary presentation in these cases. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.436 RRM2B Rebecca Foulger commented on gene: RRM2B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.
Genetic epilepsy syndromes v1.436 PEX5 Rebecca Foulger commented on gene: PEX5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.
Genetic epilepsy syndromes v1.436 GTPBP3 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Kept rating as Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.
Genetic epilepsy syndromes v1.436 GTPBP3 Rebecca Foulger commented on gene: GTPBP3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Kept rating as Amber.
Genetic epilepsy syndromes v1.436 DPM2 Rebecca Foulger commented on gene: DPM2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Kept rating as Amber.
Genetic epilepsy syndromes v1.436 SCN9A Rebecca Foulger Classified gene: SCN9A as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.436 SCN9A Rebecca Foulger Gene: scn9a has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.435 SCN9A Rebecca Foulger commented on gene: SCN9A: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted SCN9A from Green to Amber.
Genetic epilepsy syndromes v1.435 KCNA1 Rebecca Foulger Classified gene: KCNA1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.435 KCNA1 Rebecca Foulger Gene: kcna1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.434 KCNA1 Rebecca Foulger commented on gene: KCNA1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted KCNA1 from Green to Amber.
Genetic epilepsy syndromes v1.434 FLNA Rebecca Foulger Added comment: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was notes that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.
Genetic epilepsy syndromes v1.434 FLNA Rebecca Foulger Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.433 FLNA Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy, and following Green ratings by Alisdair McNeill and Alison Callaway: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.
Genetic epilepsy syndromes v1.433 FLNA Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.
Genetic epilepsy syndromes v1.433 FLNA Rebecca Foulger commented on gene: FLNA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.
Genetic epilepsy syndromes v1.433 CACNA2D2 Rebecca Foulger Phenotypes for gene: CACNA2D2 were changed from Absence epilepsy to Absence epilepsy; Cerebellar atrophy with seizures and variable developmental delay, 618501
Genetic epilepsy syndromes v1.432 CACNA2D2 Rebecca Foulger Classified gene: CACNA2D2 as Green List (high evidence)
Genetic epilepsy syndromes v1.432 CACNA2D2 Rebecca Foulger Gene: cacna2d2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.431 CACNA2D2 Rebecca Foulger commented on gene: CACNA2D2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.431 ALG8 Rebecca Foulger commented on gene: ALG8: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although there is inconsistency amongst patients, there are sufficient cases for a Green rating. Kept rating as Green.
Genetic epilepsy syndromes v1.431 TDP2 Rebecca Foulger commented on gene: TDP2
Genetic epilepsy syndromes v1.431 GOT2 Rebecca Foulger Classified gene: GOT2 as Green List (high evidence)
Genetic epilepsy syndromes v1.431 GOT2 Rebecca Foulger Gene: got2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.430 GOT2 Rebecca Foulger commented on gene: GOT2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.430 HNRNPR Rebecca Foulger Mode of inheritance for gene: HNRNPR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.429 HNRNPR Rebecca Foulger Classified gene: HNRNPR as Green List (high evidence)
Genetic epilepsy syndromes v1.429 HNRNPR Rebecca Foulger Gene: hnrnpr has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.428 HNRNPR Rebecca Foulger commented on gene: HNRNPR: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although obvious dysmoprhism is associated with the phenotype, it meets the criteria for a Green rating. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.428 ZNF142 Rebecca Foulger Classified gene: ZNF142 as Green List (high evidence)
Genetic epilepsy syndromes v1.428 ZNF142 Rebecca Foulger Gene: znf142 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.427 ZNF142 Rebecca Foulger commented on gene: ZNF142: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Sufficient cases for inclusion. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.427 TRRAP Rebecca Foulger commented on gene: TRRAP: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures aren't a prominent feature. Kept rating as Amber.
Genetic epilepsy syndromes v1.427 NPRL2 Rebecca Foulger Classified gene: NPRL2 as Green List (high evidence)
Genetic epilepsy syndromes v1.427 NPRL2 Rebecca Foulger Gene: nprl2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.426 NPRL2 Rebecca Foulger commented on gene: NPRL2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Sufficient cases to support gene:disease association, although unaffected carriers/incomplete penetrance may make variant interpretation difficult. Promoted from Amber to Green with the option to review on subsequent versions.
Genetic epilepsy syndromes v1.426 HCN2 Rebecca Foulger Marked gene: HCN2 as ready
Genetic epilepsy syndromes v1.426 HCN2 Rebecca Foulger Gene: hcn2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.426 HCN2 Rebecca Foulger commented on gene: HCN2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although this is a borderline case with questions over phenotype segregation, there are sufficient cases to support inclusion. Although seizures aren’t one of the cardinal phenotypes, most cases will be trios and therefore there will be less issues in being inclusive. Kept rating of HCN2 as Green with the option of review on subsequent panel versions.
Genetic epilepsy syndromes v1.426 AFF3 Rebecca Foulger Classified gene: AFF3 as Green List (high evidence)
Genetic epilepsy syndromes v1.426 AFF3 Rebecca Foulger Gene: aff3 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.425 AFF3 Rebecca Foulger commented on gene: AFF3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: Sufficient evidence in pre-print Voisin et al., 2019 article. Promoted AFF3 from Amber to Green.
Genetic epilepsy syndromes v1.425 SCN9A Alison Callaway reviewed gene: SCN9A: Rating: AMBER; Mode of pathogenicity: None; Publications: 30834459, 29500686; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.425 ALG8 Rebecca Foulger changed review comment from: 26066342 (Hock et al., 2015) describe 3 new patients with ALG8-CDG, provide an update on 2 previous patients and summarise 10 previous patients. The 15 patients total included 4 pairs of siblings. Brain involvement (psychomotor disability or seizures or ataxia or structural anomalies) were seen in 12/13 patients.; to: 26066342 (Hock et al., 2015) describe 3 new patients with ALG8-CDG, provide an update on 2 previous patients and summarise 10 previous patients. The 15 patients total included 4 pairs of siblings. Brain involvement (psychomotor disability or seizures or ataxia or structural anomalies) was seen in 12/13 patients.
Genetic epilepsy syndromes v1.425 DMXL2 Konstantinos Varvagiannis changed review comment from: This gene can be considered for inclusion in both ID and epilepsy panels probably with green (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc) or amber rating.

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be constant features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1).
This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Sources: Literature; to: This gene can be considered for inclusion in both ID and epilepsy panels probably with green (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc) or amber rating.

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be constant features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1).
This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Sources: Literature
Genetic epilepsy syndromes v1.425 DMXL2 Konstantinos Varvagiannis gene: DMXL2 was added
gene: DMXL2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DMXL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DMXL2 were set to 25248098; 30237576; 31688942; 30732576
Phenotypes for gene: DMXL2 were set to Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113
Penetrance for gene: DMXL2 were set to unknown
Review for gene: DMXL2 was set to GREEN
Added comment: This gene can be considered for inclusion in both ID and epilepsy panels probably with green (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc) or amber rating.

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be constant features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1).
This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
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[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
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[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Sources: Literature
Genetic epilepsy syndromes v1.425 ALG8 Rebecca Foulger commented on gene: ALG8: PMID:19688606 (Vesela et al., 2009) present a girl with neonatal onset of CDG. Seizures were present from the first day and the girl died age 2 months from progressive oedema, bleeding and cardio-respiratory insufficiency. She had compound het variants in ALG8 (p.T47P and p.R364X).
Genetic epilepsy syndromes v1.425 ALG8 Rebecca Foulger commented on gene: ALG8: PMID:23430830 (Millon et al., 2011) report 2 siblings with a congenital glycosylation disorder. Their clinical presentation included seizures. The authors could not identify the genetic deficiency in these patients yet.
Genetic epilepsy syndromes v1.425 ALG8 Rebecca Foulger commented on gene: ALG8: 26066342 (Hock et al., 2015) describe 3 new patients with ALG8-CDG, provide an update on 2 previous patients and summarise 10 previous patients. The 15 patients total included 4 pairs of siblings. Brain involvement (psychomotor disability or seizures or ataxia or structural anomalies) were seen in 12/13 patients.
Genetic epilepsy syndromes v1.425 FLNA Alison Callaway reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.425 CACNA2D2 Zerin Hyder reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30410802, PMID: 31402629, PMID: 24358150, PMID: 23339110, PMID: 29997391; Phenotypes: epilepsy, ataxia, developmental delay, cerebellar atrophy; Mode of inheritance: None
Genetic epilepsy syndromes v1.425 SLC6A19 Rebecca Foulger Phenotypes for gene: SLC6A19 were changed from to Hartnup disorder, 234500
Genetic epilepsy syndromes v1.424 SLC6A19 Rebecca Foulger Publications for gene: SLC6A19 were set to
Genetic epilepsy syndromes v1.423 SLC6A19 Rebecca Foulger commented on gene: SLC6A19: PMID:20399395 (Cheon et al 2010) report a Korean boy age 8 years and 5 months with Hartnup disorder. He had seizures, ADHD and mental retardation. Genetic analysis revealed novel compound het variants in SLC6A19: p.Thr596fsX73 and p.Ser303Leu.
Genetic epilepsy syndromes v1.423 SCO2 Rebecca Foulger commented on gene: SCO2: PMID:18924171 (Verdijk et al, 2008) report compound het SOC2 variants (E140K and W36X) in 2 siblings with fatal infantile cardioencephalomyopathy. The index patient had convulsions age 1 day and died of heart failure age 25 days. The sibling fetus was terminated at 23 weeks following genetic testing.
Genetic epilepsy syndromes v1.423 SCO2 Rebecca Foulger commented on gene: SCO2: PMID:10749987 (Jaksch et al., 2000) report 10 patients with fatal hypertrophic cardiomyopathy from 9 families. Mutations in SCO2 (E140K, R171W) were found in 3 patients (2 unrelated families) all of whom had seizures: Table 1.
Genetic epilepsy syndromes v1.423 SCO2 Rebecca Foulger commented on gene: SCO2: PMID:10545952 (Papadopoulou et al 1999) identified variants in SCO2 in 3 unrelated infants with fatal cardioencephalomyopathy and COX deficiency. Patient 2 had focal epileptiform discharges on an EEG.
Genetic epilepsy syndromes v1.423 SCO1 Rebecca Foulger commented on gene: SCO1: PMID:22231385 (Honzik et al., 2012) summarise 461 patients with mitochondrial disorders. One patient had a variant in SCO1: seizures were not a feature (Table 2, Stiburek et al., 2009).
Genetic epilepsy syndromes v1.423 SCO1 Rebecca Foulger changed review comment from: PMID:15023375 report an 8-week old infant who presented with neonatal seizures and limb malformations. There were multiple seizure types, including multifocal myoclonus, complex partial events and generalised tonic–clonic episodes. Treatment of seizures was of limited success. The specific defect seen in the patient was a complex IV deficiency. Although no known variants were identified, the clinical picture overlaps with the SCO1 presentation.; to: PMID:15023375 (Kurian et al., 2004) report an 8-week old infant who presented with neonatal seizures and limb malformations. There were multiple seizure types, including multifocal myoclonus, complex partial events and generalised tonic–clonic episodes. Treatment of seizures was of limited success. The specific defect seen in the patient was a complex IV deficiency. Although no known variants were identified, the clinical picture overlaps with the SCO1 presentation.
Genetic epilepsy syndromes v1.423 SCO1 Rebecca Foulger Publications for gene: SCO1 were set to 23878101; 11013136; 19295170
Genetic epilepsy syndromes v1.422 SCO1 Rebecca Foulger changed review comment from: PMID:23878101 (Leary et al., 2013) report compound het variants in SCO1 in a patient with fatal encephalopathy. The patient developed seizures age 4 months which were difficult to control. He died age 5 months (Supporting information).; to: PMID:23878101 (Leary et al., 2013) report compound het variants in SCO1 in a patient with fatal encephalopathy. The patient developed seizures age 4 months which were difficult to control. He died age 5 months (seizure information and extended clinical phenotype is the supporting information).
Genetic epilepsy syndromes v1.422 SCO1 Rebecca Foulger commented on gene: SCO1: PMID:15023375 report an 8-week old infant who presented with neonatal seizures and limb malformations. There were multiple seizure types, including multifocal myoclonus, complex partial events and generalised tonic–clonic episodes. Treatment of seizures was of limited success. The specific defect seen in the patient was a complex IV deficiency. Although no known variants were identified, the clinical picture overlaps with the SCO1 presentation.
Genetic epilepsy syndromes v1.422 SCO1 Rebecca Foulger commented on gene: SCO1: PMID:23878101 (Leary et al., 2013) report compound het variants in SCO1 in a patient with fatal encephalopathy. The patient developed seizures age 4 months which were difficult to control. He died age 5 months (Supporting information).
Genetic epilepsy syndromes v1.422 QDPR Rebecca Foulger Phenotypes for gene: QDPR were changed from Hyperphenylalaninemia, BH4-deficient, C, 261630 to Hyperphenylalaninemia, BH4-deficient, C, 261630; DHPR deficiency
Genetic epilepsy syndromes v1.421 QDPR Rebecca Foulger Publications for gene: QDPR were set to 9341885; 26006720
Genetic epilepsy syndromes v1.420 QDPR Rebecca Foulger commented on gene: QDPR: Seizures listed in the OMIM Clinical synopsis for 'Hyperphenylalaninemia, BH4-deficient, C' (MIM:261630).
Genetic epilepsy syndromes v1.420 QDPR Rebecca Foulger commented on gene: QDPR: Ikeda et al. (1997, PMID:9341885) report a Japanese boy with hyperphenylalaninemia and a splicing error variant in QDPR. He was the offspring of first-cousin parents. The patient showed intractable seizures and developmental delay.
Genetic epilepsy syndromes v1.420 PRODH Rebecca Foulger Publications for gene: PRODH were set to 12217952
Genetic epilepsy syndromes v1.419 PRODH Rebecca Foulger commented on gene: PRODH: PMID:17412540 (Afenjar et al 2007) report 4 unrelated children and biallelic variants in PRODH. The authors note that 4 previous patients had been reported (Jacquet et al, 2002, 2003 and Raux et al 2007) and of the 8 total patients, 5 had epilepsy (plus febrile case), often severe with status epilepticus.
Genetic epilepsy syndromes v1.419 PRODH Rebecca Foulger commented on gene: PRODH: PMID:18197084 (Di Rosa et al., 2008) screened 4 unrelated Italian children all of whom presented with epilepsy and ID, and compound het/homozygous variants in PRODH. Functional tests to confirm the pathogenicity were not performed.
Genetic epilepsy syndromes v1.419 PRODH Rebecca Foulger Publications for gene: PRODH were set to
Genetic epilepsy syndromes v1.418 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:16141001 (Rosewich et al 2005) studied 33 patients with PEX1 variants. Seizures are a feature in Table 3 for 6 patients.
Genetic epilepsy syndromes v1.418 PEX1 Rebecca Foulger Publications for gene: PEX1 were set to 12402331; 26387595; 9398847
Genetic epilepsy syndromes v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:15098231 (Poll-The BT et al 2004) surveyed 31 patients with a generalized peroxisomal disorder from 27 families. 7/31 patients (23%) developed seizures from 0 - 2.7 years. Most patients (60-70%) had variants in the PEX1 gene. Most frequent variants include G843D and frameshift c.2097insT.
Genetic epilepsy syndromes v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:15301838 (Michelakakis et al, 2004) decribe a female patient of healthy unrelated patients. Her diagnosis of Leber congenital amaurosis was subsequently demonstrated to be a PEX1 defect. Myoclonic seizures began age 2. The patient is heterozygous for G843D variant and an additional second variant that is not yet identified.
Genetic epilepsy syndromes v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:28432012 (Ge et al., 2017) report 2 Chinese newborns with Zellweger phenotypes and compound het variants in PEX1 (Arg577Thrfs*15 and Asn830Thrfx*61). Although the authors note that seizures are in the clinical spectrum of ZS patients, seizures were not reported for the Chinese newborns.
Genetic epilepsy syndromes v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:21844578 (Cho et al., 2011) report a Korean patient who was compound het for variants in the PEX1 gene (p.H678QfsX3 and p.R949W) inherited from the parents. He had typical features of ZS including seizures (starting 4 days old), dysmorphic face and a poor suck.
Genetic epilepsy syndromes v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:28666289 (Komulainen-Ebrahim et al., 2017) describe a homozygous MTR p.P1173L variant in a patient with drug-resistant seizures associated with hyperhomocysteinemia and hypomethioninemia.
Genetic epilepsy syndromes v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:9683607 (Wilson et al., 1998) report 3 cblG patients, including 2 siblings who presented with neonatal seizures.
Genetic epilepsy syndromes v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:25526710 (Huemer et al., 2015) summarise clinical features of 13 patients with the cblG defect (caused by defects in MTR): 5/13 had seizures.
Genetic epilepsy syndromes v1.417 IDH2 Rebecca Foulger commented on gene: IDH2: A number of papers note that IDH1 and IDH2 variants have an established association with preoperative seizures in patients with grade II-IV diffuse gliomas (PMID:29172136, 29288860, 22217666).
Genetic epilepsy syndromes v1.417 IDH2 Rebecca Foulger Publications for gene: IDH2 were set to 20847235
Genetic epilepsy syndromes v1.416 IDH2 Rebecca Foulger commented on gene: IDH2: PMID:24049096 (Nota et al., 2013) report 3 cases, with seizures reported in 2/3. Case 2 was a 9 year old Caucasian girl with tonic-clonic seizures and mosaic IDH2 variants. Case 3 was a Caucasian girl with seizures age 3 months- her seizures responded well to anticonvulsants. The patient died from sudden cardiac arrest age 8, and was found to have a heterozygous IDH2 c.419G>A variant. Germline mosaicism in the mother was suggested to explain the inheritance pattern in this family.
Genetic epilepsy syndromes v1.416 HLCS Rebecca Foulger commented on gene: HLCS: PMID:27114915 (Donti et al., 2016) describe a cohort of 5 patients. Case 5 had focal seizures age 5 months which have continued since. He has compound het variants in HLCS (N570K and c.1519+5G>A). The authors note that the phenotypic spectrum of HCLS is broad, from intractable seizures and ID to normal growth and development.
Genetic epilepsy syndromes v1.416 GSS Rebecca Foulger Publications for gene: GSS were set to 26984560
Genetic epilepsy syndromes v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:26669244 (Gunduz et al., 2016) report 4 patients with GS deficiency. Case I and Case IV had seizures noted together with homozygous variants (splicing variant in I and p.R125H in IV): Table 1.
Genetic epilepsy syndromes v1.415 GSS Rebecca Foulger commented on gene: GSS: Seizures are recorded in OMIM Clinical synopsis for MIM:266130 based on Marstein et al., 1976 (no PubMed).
Genetic epilepsy syndromes v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:15990954 (Njallson et al 2005) summarise the phenotypes of patients with glutathione synthetase deficiency, but don't mention seizures or epilepsy (as noted in review by Tracy Lester).
Genetic epilepsy syndromes v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:11445798 (Ristoff et al,. 2001) examined 28 patients with Glutathione synthetase deficiency (GSSD). Diagnosis was based on metabolic tests. 16/28 had neurological symptoms such as seizures/psychomotor retardation. In 16 patients with severe GS deficiency, 7 had seizures.
Genetic epilepsy syndromes v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:26984560 (Atwal et al. 2016) present a 19 year old female with Glutathione synthetase deficiency (GSSD). She was diagnosed with a mild seizure disorder age 10, and treated with the antiepileptic lamotrigine, which was discontinued once she was seizure free for 5 years. The authors note it is possible her seizures were unrelated to the underlying GSSD.
Genetic epilepsy syndromes v1.415 GSS Rebecca Foulger Publications for gene: GSS were set to
Genetic epilepsy syndromes v1.414 GLYCTK Rebecca Foulger Publications for gene: GLYCTK were set to 3588091; 30637540; 28462797; 20949620
Genetic epilepsy syndromes v1.413 GLYCTK Rebecca Foulger Publications for gene: GLYCTK were set to 3588091
Genetic epilepsy syndromes v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:30637540 (Zehavi et al., 2019) report a male from a consanguineous Arab family with intractable seizures and a homozygous missense pathogenic variant in GLYCTK (p.Leu152Pro).
Genetic epilepsy syndromes v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:28462797 (Swanson et al., 2017) reviewed the Serbian patient from Sass et al., 2010. In addition to p.Phe483SerfsX2 variant in GLYCTK, the patient had an additional Ser117Leu variant in AMT highlighting the co-occurence of two metabolic conditions (D-glyceric aciduria and nonketotic hyperglycinemia).
Genetic epilepsy syndromes v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:20949620 (Sass et al., 2010) report 3 patients of Serbian, Mexican and Turkish origin, including the original 1974 (Serbian) patient. All had homozygous variant in GLYTCK:
Patient A was a Serbian boy with generalized seizures beginning age 8 weeks (p.Phe483SerfsX2 variant).
Patient B was a Mexican girl with focal clonic seizures and a Phe493Cys variant.
Patient C was a Turkish boy where seizures were not noted (p.Leu520CysfsX108 variant).
Genetic epilepsy syndromes v1.412 GFM1 Rebecca Foulger Publications for gene: GFM1 were set to 25852744; 26937387; 28216230; 23430926; 21986555
Genetic epilepsy syndromes v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:28216230 (Simon et al., 2017) report 2 brothers with compound het variants in GFM1 (maternally-inherited p.Arg250Trp and paternally-inherited p.Gly230_231Glnins19). The younger brother (P1) developed seizures by 4.5 months, characterised as infantile spasms. He has remained seizure free on treatment with topiramate. No seizures were noted for the brother who died age 10 months from multiple organ failure. The authors suggest additional modifier genes may be responsible for the different in severity between the brothers.
Genetic epilepsy syndromes v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:26937387 (Ravn et al., 2015) describe 3 patients with novel GFM1 variants. Patient 3 (a girl of non-consanguineous parents) had epileptic seizures beginning at 2 months old. She died at 3 months during a febrile episode.
Genetic epilepsy syndromes v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:21986555. Galmiche et al., 2012 report two unrelated patients with homozygous GFM1 variants (R671C). The parents were both heterozygous for this variant For the first patient (an Algerian boy from consanguineous parents), no clinical seizures were noted but EEG showed burst of multifocal spikes.
Genetic epilepsy syndromes v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:25852744. Brito et al., 2015 report an infant born to unrelated Caucasian parents with seizures amongst her phenotype (starting age 7 months) and compound het variants in GFM1 (Gly469Valfs*84 and Arg671Cys). The authors summarise clinical features of previous GFM1-deficient patients and note seizures in 5/12 patients.
Genetic epilepsy syndromes v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:21119709. In a girl, born of consanguineous parents, with combined oxidative phosphorylation deficiency, Smits et al. (2011) identified a homozygous R250W variant in GFM1. The patient had refractory seizures amongst her phenotypes. This paper is referred to in the review by Tracy Lester.
Genetic epilepsy syndromes v1.411 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057; 7730309; 31202265
Genetic epilepsy syndromes v1.410 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057; 7730309
Genetic epilepsy syndromes v1.409 GCH1 Rebecca Foulger commented on gene: GCH1: Additional evidence for seizures being part of the metabolic disorder comes from PMID:31202265 (Dayasiri et al, 2019) who report a S. Asian child with AR GTPCH (GCH1) deficiency, diagnosed from metabolic testing and family consanguinity. Features included recurrent seizures since 3 months old.
Genetic epilepsy syndromes v1.409 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057
Genetic epilepsy syndromes v1.408 HCN2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept MOI as 'BOTH monoallelic and biallelic' as supported by reviews from Helen Lord and Alison Callaway, and literature (PMID:22131395).
Genetic epilepsy syndromes v1.408 HCN2 Rebecca Foulger Mode of inheritance for gene: HCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.407 Ellen McDonagh Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS Rare Disease Virtual
Genetic epilepsy syndromes v1.406 Ellen McDonagh List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; R59
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v1.405 SCAMP5 Konstantinos Varvagiannis gene: SCAMP5 was added
gene: SCAMP5 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAMP5 were set to 31439720; 20071347
Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Penetrance for gene: SCAMP5 were set to unknown
Mode of pathogenicity for gene: SCAMP5 was set to Other
Review for gene: SCAMP5 was set to AMBER
Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures, behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
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PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
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SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
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Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v1.405 FDFT1 Konstantinos Varvagiannis gene: FDFT1 was added
gene: FDFT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face
Penetrance for gene: FDFT1 were set to Complete
Review for gene: FDFT1 was set to AMBER
Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below].
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Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias).

FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis.

A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites.

Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis).

WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included:
- Minigene splice assay demonstrating retention of 22 bp in intron 8.
- Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts)
- Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot.
Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected).

As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant :
- cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect.
- Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity.

Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure.

In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories.
Sources: Literature
Genetic epilepsy syndromes v1.405 GOT2 Rebecca Foulger commented on gene: GOT2
Genetic epilepsy syndromes v1.405 HNRNPR Rebecca Foulger commented on gene: HNRNPR
Genetic epilepsy syndromes v1.405 HLCS Rebecca Foulger Publications for gene: HLCS were set to
Genetic epilepsy syndromes v1.404 HLCS Rebecca Foulger Phenotypes for gene: HLCS were changed from to Holocarboxylase synthetase deficiency, 253270
Genetic epilepsy syndromes v1.403 PLA2G6 Rebecca Foulger Classified gene: PLA2G6 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.403 PLA2G6 Rebecca Foulger Added comment: Comment on list classification: Although PLA2G6 is Green on the 'Inborn errors of metabolism' panel, have added to the Epilepsy panel as Amber as unclear if seizures are a consistent feature. Requires clinical review (and review of the MOI in PMID:27513994) before promotion to Green.
Genetic epilepsy syndromes v1.403 PLA2G6 Rebecca Foulger Gene: pla2g6 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.402 PLA2G6 Rebecca Foulger Added comment: Comment on mode of inheritance: Selected 'BIALLELIC' inheritance to match the metabolism PanelApp panels (including Inborn errors of metabolism, V1.392), all OMIM disorders and both G2P disorders. However, PMID:27513994 report autosomal dominant inheritance for Familial cortical myoclonic tremor with epilepsy (FCMTE).
Genetic epilepsy syndromes v1.402 PLA2G6 Rebecca Foulger Mode of inheritance for gene: PLA2G6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:27513994 (Gao et al., 2016) report a family (41 members) which included 6 individuals affected with Familial cortical myoclonic tremor with epilepsy (FCMTE). All 6 individuals had tremors while 5 individuals had seizures. Genomic sequencing was performed on 3 affected and 2 unaffected individuals. A novel missense variant c.475C>T (p.A159T) in PLA2G6 with AD inheritance was identified in this family which segregated with the disease. Note that a variant in SNRNP200 gene also segregated with the disease but is within the untranslated region and the functional effect is unclear.
Genetic epilepsy syndromes v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:30772976. Ma et al., 2019 analyse a Chinese Han pedigree with seizures amongst the phenotype. Compound het variants in PLA2G6 were found (p.A80T and p.D331Y) (full English text not available).
Genetic epilepsy syndromes v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:30340910. Darling et al., 2019 investigated 16 patients from 13 families with PLA2G6-associated neurodegeneration (an autosomal recessive disorder). Epilepsy was observed in 8/16 patients (7 families, 2 patients had been previously reported, Table 1). All patients harboured missense, nonsense and frameshift variants in PLA2G6.
Genetic epilepsy syndromes v1.401 PLA2G6 Rebecca Foulger gene: PLA2G6 was added
gene: PLA2G6 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: PLA2G6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLA2G6 were set to 30340910; 27513994; 30772976
Phenotypes for gene: PLA2G6 were set to PLA2G6-associated neurodegeneration (PLAN); Familial cortical myoclonic tremor with epilepsy (FCMTE); Infantile neuroaxonal dystrophy 1, 256600; Neurodegeneration with brain iron accumulation 2B, 610217
Added comment: Added to epilepsy panel based on a Green rating on the 'Inborn errors of metabolism panel'- seizures are a reported feature of MIM:256600 and MIM:610217.
Sources: Literature, Other
Genetic epilepsy syndromes v1.400 DNAJC5 Rebecca Foulger Classified gene: DNAJC5 as Green List (high evidence)
Genetic epilepsy syndromes v1.400 DNAJC5 Rebecca Foulger Added comment: Comment on list classification: Added to panel as a Green gene as seizures are a symptom of the metabolic disorder, and sufficient epilepsy cases from literature.
Genetic epilepsy syndromes v1.400 DNAJC5 Rebecca Foulger Gene: dnajc5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:22235333: Velinov et al., 2012. The authors previously described the Parry family in the 1970s. All affected individuals from the family had a history of progressive seizure disorder. They identified a pLeu116del variant in DNAJC5 which segregated with the disease. 8 additional families were studied for this paper, with seizures amongst the phenotypes. In one affected individual, pLeu115Arg was identified (proband BD-319) who had seizures and gradual dementia beginning in the mid 30s.
Genetic epilepsy syndromes v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:29506599: Jarrett et al., 2018 report a family with Kufs disease in which the proband and 3/4 children presented with cognitive impariment, seizures and myoclonus. Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) variant in the DNAJC5 gene. EEG on the asymptomatic fourth child showed moderatley severe slowing. The proband's father was deceased but had a history of epileptic seizures.
Genetic epilepsy syndromes v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:22978711: Cadieux-Dion et al., 2013. report a p.L116del variant in DNAJC5 in two distinct American families, and a p.L115R variant in an additional family. All individuals showed generalized tonic-clonic seizures.
Genetic epilepsy syndromes v1.399 DNAJC5 Rebecca Foulger gene: DNAJC5 was added
gene: DNAJC5 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: DNAJC5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DNAJC5 were set to 22978711; 29506599; 22235333
Phenotypes for gene: DNAJC5 were set to Ceroid lipofuscinosis, neuronal, 4, Parry type, 162350; autosomal dominant Kufs disease; generalized tonic–clonic seizures
Added comment: Added DNAJC5 to the Epilepsy panel based on a Green rating on the 'Inborn errors of metabolism' panel: seizures are listed as a symptom of MIM:162350 in OMIM.
Sources: Literature, Other
Genetic epilepsy syndromes v1.398 CLN6 Rebecca Foulger commented on gene: CLN6: PMID:30561534. Berkovic et al., 2019 report phenotypes of patients with CLN6 pathogenic variants from 13 unrelated families (homozygous in 4 families and compound het in 9 families). The typical presentation was progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures.
Genetic epilepsy syndromes v1.398 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341; 31029456; 31216804
Genetic epilepsy syndromes v1.397 SETD5 Rebecca Foulger Phenotypes for gene: SETD5 were changed from Mental retardation, autosomal dominant 23 to Mental retardation, autosomal dominant 23, 615761
Genetic epilepsy syndromes v1.396 SETD5 Rebecca Foulger Publications for gene: SETD5 were set to
Genetic epilepsy syndromes v1.395 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341; 31029456
Genetic epilepsy syndromes v1.394 CLN6 Rebecca Foulger changed review comment from: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not avaialble).; to: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not available).
Genetic epilepsy syndromes v1.394 CLN6 Rebecca Foulger commented on gene: CLN6: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not avaialble).
Genetic epilepsy syndromes v1.394 CLN6 Rebecca Foulger commented on gene: CLN6: Additional case in PMID:31029456 (Matsumoto et al., 2019) of Japanese boy with a homozygous C.794_976del variant p. (Ser265del) in CLN6. Symptoms include focal seizures.
Genetic epilepsy syndromes v1.394 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341
Genetic epilepsy syndromes v1.393 SGSH Rebecca Foulger Classified gene: SGSH as Green List (high evidence)
Genetic epilepsy syndromes v1.393 SGSH Rebecca Foulger Added comment: Comment on list classification: Added SGSH to the panel with a Green rating: Green on the 'Inborn errors of metabolism' panel, and seizures are part of the MPS IIIA phenotype. Sufficient cases from the literature for inclusion on the panel.
Genetic epilepsy syndromes v1.393 SGSH Rebecca Foulger Gene: sgsh has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.392 SGSH Rebecca Foulger commented on gene: SGSH: PMID: 30593151 (Li et al., 2018) report an 8 year old female with developmental regression and seizures amongst her symptoms. She was diagnosed with autosomal recessive (AR) MPS IIIA with compound het variants in SGSH (c.1298G>A p.Arg433Gln and c.630 G>T p.Trp210Cys), inherited from each parent. The pathogenicity of c.630G>T has not been reported yet. c.1298G>A has been associated with MPS-IIIA previously.
Genetic epilepsy syndromes v1.392 SGSH Rebecca Foulger commented on gene: SGSH: PMID:21061399: Valstar et al. 2010 retrospectively reviewed the clinical features of 92 patients with MPS IIIA, including 32 living and 60 deceased individuals. There was wide phenotypic variability but Epilepsy was reported in 53/80 patients with a median seizure age of 11 years (range, 1-43 years). Patients with a severe MPS IIIA phenotype developed epilepsy at a significantly earlier age compared to patients suffering from a more attenuated form of the disease.
Genetic epilepsy syndromes v1.392 SGSH Rebecca Foulger gene: SGSH was added
gene: SGSH was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: SGSH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSH were set to 21061399; 30593151
Phenotypes for gene: SGSH were set to Mucopolysaccharidosis type IIIA (Sanfilippo A), 252900; seizures
Review for gene: SGSH was set to GREEN
Added comment: Added SGSH to the panel based on Green rating on the 'Inborn errors of metabolism' panel: seizures are a part of the Mucopolysaccharidosis phenotype.
Sources: Literature, Other
Genetic epilepsy syndromes v1.391 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease
Genetic epilepsy syndromes v1.389 Rebecca Foulger List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy
Genetic epilepsy syndromes v1.388 APC2 Catherine Snow reviewed gene: APC2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.388 BSCL2 Rebecca Foulger Phenotypes for gene: BSCL2 were changed from Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Intractable epilepsy and neurological regression; Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685
Genetic epilepsy syndromes v1.387 BSCL2 Rebecca Foulger Publications for gene: BSCL2 were set to 24896178; 26503795; 23564749; 15181077; 30767895; 23564749
Genetic epilepsy syndromes v1.386 BSCL2 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:31369919 (Fernandez-Marmiesse et al., 2019) report 2 siblings with profound refractory epilepsy and neurological regression. A de novo Met189Lys variant in BSCL2 was detected that was absent in the parents and unaffected sibling. This is the first evidence of an association between a heterozygous BSCL2 variant and EIEE, and supports an AD+AR Mode of inheritance.
Genetic epilepsy syndromes v1.386 BSCL2 Rebecca Foulger Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.385 BSCL2 Rebecca Foulger Publications for gene: BSCL2 were set to 24896178; 26503795; 23564749; 15181077; 30767895
Genetic epilepsy syndromes v1.384 CYP27A1 Rebecca Foulger Publications for gene: CYP27A1 were set to 18227423; 22336472; 24442603; 29484516
Genetic epilepsy syndromes v1.383 EXT2 Rebecca Foulger changed review comment from: Comment on list classification: Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).; to: Comment on list classification: Added EXT2 to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Genetic epilepsy syndromes v1.383 EMX2 Rebecca Foulger Classified gene: EMX2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.383 EMX2 Rebecca Foulger Gene: emx2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.382 EMX2 Rebecca Foulger Classified gene: EMX2 as Green List (high evidence)
Genetic epilepsy syndromes v1.382 EMX2 Rebecca Foulger Added comment: Comment on list classification: Demoted EMX2 from Green to Amber based on the Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy, and the post-Webex review by Helen Lord. The Schizencephaly phenotype is more appropriate for the ID/Cortical malformations panel, and EMX2 has now been added as a Green gene to 'Malformations of cortical development' (#96) panel.
Genetic epilepsy syndromes v1.382 EMX2 Rebecca Foulger Gene: emx2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.381 TDP2 Catherine Snow changed review comment from: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green; to: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. All individuals reported to have seizures, although age of onset varied from 2 months to 12 years. There are sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green.
Genetic epilepsy syndromes v1.381 TDP2 Catherine Snow Classified gene: TDP2 as Green List (high evidence)
Genetic epilepsy syndromes v1.381 TDP2 Catherine Snow Added comment: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green
Genetic epilepsy syndromes v1.381 TDP2 Catherine Snow Gene: tdp2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.380 TDP2 Catherine Snow Mode of inheritance for gene: TDP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.379 TANC2 Rebecca Foulger Classified gene: TANC2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.379 TANC2 Rebecca Foulger Added comment: Comment on list classification: Set rating of TANC2 to Amber. Not yet associated with a disorder in OMIM or Gene2Phenotype. One 2019 paper linking TANC2 with epilepsy in 11/20 cases: sufficient unrelated cases in PMID:31616000 but the pathogenicity of the variants has not been confirmed.
Genetic epilepsy syndromes v1.379 TANC2 Rebecca Foulger Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.378 TANC2 Rebecca Foulger gene: TANC2 was added
gene: TANC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TANC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TANC2 were set to 31616000
Phenotypes for gene: TANC2 were set to NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Seizures; Epilepsy
Added comment: Added TANC2 to panel following curation of TANC2 on the Intellectual disability panel. PMID:31616000 (Guo et al, 2019) report 11/20 individuals with a TANC2 variant who had a formal diagnosis of epilepsy (n=9) or who suffered recurrent seizures (n=2).
Sources: Literature
Genetic epilepsy syndromes v1.377 CLN6 Rebecca Foulger Classified gene: CLN6 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.377 CLN6 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on Amber review by Tracy Lester and PMID:21549341 (Arsov et al., 2011) where seizures are a consistent feature across families.
Genetic epilepsy syndromes v1.377 CLN6 Rebecca Foulger Gene: cln6 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.376 NDUFS7 Rebecca Foulger Phenotypes for gene: NDUFS7 were changed from to Mitochondrial complex I deficiency, nuclear type 3, 618224
Genetic epilepsy syndromes v1.375 CLN6 Rebecca Foulger Mode of inheritance for gene: CLN6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.374 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to
Genetic epilepsy syndromes v1.373 ALG2 Rebecca Foulger Phenotypes for gene: ALG2 were changed from to ?Congenital disorder of glycosylation type Ii, 607906; Myasthenic syndrome congenital 14 with tubular aggregates, 616228
Genetic epilepsy syndromes v1.372 ALG2 Rebecca Foulger Mode of inheritance for gene: ALG2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger changed review comment from: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).; to: Comment on list classification: Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Genetic epilepsy syndromes v1.371 TXN2 Rebecca Foulger commented on gene: TXN2
Genetic epilepsy syndromes v1.371 MT-CO3 Rebecca Foulger commented on gene: MT-CO3
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger Classified gene: EXT2 as Green List (high evidence)
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger Added comment: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Genetic epilepsy syndromes v1.371 EXT2 Rebecca Foulger Gene: ext2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.370 CLPB Rebecca Foulger commented on gene: CLPB
Genetic epilepsy syndromes v1.370 TXN2 Rebecca Foulger gene: TXN2 was added
gene: TXN2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene: TXN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TXN2 were set to 26626369
Phenotypes for gene: TXN2 were set to ?Combined oxidative phosphorylation deficiency 29, 616811; infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy
Genetic epilepsy syndromes v1.370 MT-CO3 Rebecca Foulger gene: MT-CO3 was added
gene: MT-CO3 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene gene: MT-CO3 was set to MITOCHONDRIAL
Publications for gene: MT-CO3 were set to 8739943; 12915481
Phenotypes for gene: MT-CO3 were set to seizures
Genetic epilepsy syndromes v1.370 EXT2 Rebecca Foulger gene: EXT2 was added
gene: EXT2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: EXT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXT2 were set to 26246518; 30997052; 30288735; 30075207
Phenotypes for gene: EXT2 were set to Seizures, scoliosis, and macrocephaly syndrome, 616682
Genetic epilepsy syndromes v1.370 CLPB Rebecca Foulger gene: CLPB was added
gene: CLPB was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: CLPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Phenotypes for gene: CLPB were set to Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271
Genetic epilepsy syndromes v1.369 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995; 22040219; 24561070
Genetic epilepsy syndromes v1.368 GPHN Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from BIALLELIC to BOTH monoallelic and biallelic. Although OMIM records AR inheritance, a review by Tracy Lester notes PMIDs:24561070, 23393157 who report the association of hemizygous GPHN microdeletions with an epilepsy phenotype. The biallelic and monoallelic MOI matches the MOI of GPHN on the metabolism panels.
Genetic epilepsy syndromes v1.368 GPHN Rebecca Foulger Mode of inheritance for gene: GPHN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.367 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995
Genetic epilepsy syndromes v1.366 ABAT Rebecca Foulger Publications for gene: ABAT were set to 20052547; 27376954
Genetic epilepsy syndromes v1.365 ADAR Rebecca Foulger Publications for gene: ADAR were set to
Genetic epilepsy syndromes v1.364 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plu review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plus review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger reviewed Region: ISCA-37433-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger reviewed Region: ISCA-37446-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Genetic epilepsy syndromes v1.364 ISCA-37433-Loss Rebecca Foulger Region: ISCA-37433-Loss was added
Region: ISCA-37433-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Loss were set to 15545748; 15889418; 20301696
Phenotypes for Region: ISCA-37433-Loss were set to Learning difficulties; immune deficiency; renal anomalies; cleft palate, polydactyly; 22q11.2 deletion syndrome; diaphragmatic hernia; 192430; polyhydramnios; DiGeorge syndrome; Velocardiofacial syndrome; 188400; facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; congenital heart disease
Genetic epilepsy syndromes v1.364 ISCA-37446-Loss Rebecca Foulger Region: ISCA-37446-Loss was added
Region: ISCA-37446-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37446-Loss were set to micrognathia; neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; clefting; DiGeorge syndrome; Velocardiofacial syndrome; 188400; cardiac malformations; Hearing deficits
Genetic epilepsy syndromes v1.363 NDUFAF4 Rebecca Foulger commented on gene: NDUFAF4: Amber ratings from Tracy Lester and Zornitza Stark support the current Amber rating of NDUFAF4.
Genetic epilepsy syndromes v1.363 NDUFAF4 Rebecca Foulger Publications for gene: NDUFAF4 were set to
Genetic epilepsy syndromes v1.362 NDUFAF4 Rebecca Foulger Phenotypes for gene: NDUFAF4 were changed from to Mitochondrial complex I deficiency, nuclear type 15, 618237
Genetic epilepsy syndromes v1.361 NDUFAF4 Rebecca Foulger Mode of inheritance for gene: NDUFAF4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Marked gene: CCND2 as ready
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Classified gene: CCND2 as Red List (low evidence)
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Added comment: Comment on list classification: Demoted CCND2 from Amber to Red following Red reviews by Zornitza Stark and Tracy Lester- as noted previously by Sarah Leigh: epilepsy is not a reported feature of the disorder.
Genetic epilepsy syndromes v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.359 CCND2 Rebecca Foulger Mode of inheritance for gene: CCND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.358 CCND2 Rebecca Foulger Publications for gene: CCND2 were set to
Genetic epilepsy syndromes v1.357 CCND2 Rebecca Foulger Phenotypes for gene: CCND2 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, 615938
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger Marked gene: ARID1B as ready
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger Gene: arid1b has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger commented on gene: ARID1B: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ARID1B.
Genetic epilepsy syndromes v1.356 ARID1B Rebecca Foulger Publications for gene: ARID1B were set to
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger Marked gene: ASAH1 as ready
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger Gene: asah1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger commented on gene: ASAH1: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ASAH1.
Genetic epilepsy syndromes v1.355 ASAH1 Rebecca Foulger Phenotypes for gene: ASAH1 were changed from Spinal muscular atrophy with progressive myoclonic epilepsy, 159950 to Spinal muscular atrophy with progressive myoclonic epilepsy, 159950; SMA with myoclonic epilepsy
Genetic epilepsy syndromes v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 8955159; 22703880; 29169047; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Genetic epilepsy syndromes v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 29169047; 22703880; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Genetic epilepsy syndromes v1.353 ISCA-37429-Loss Rebecca Foulger changed review comment from: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.; to: The Green rating by Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Genetic epilepsy syndromes v1.353 CREBBP Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'imprinted status unknown' to 'NOT imprinted' to match reviews from GLH experts Tracy Lester and Alisdair McNeill.
Genetic epilepsy syndromes v1.353 CREBBP Rebecca Foulger Mode of inheritance for gene: CREBBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 CREBBP Rebecca Foulger commented on gene: CREBBP: The Green rating by Dr Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of CREBBP.
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss Rebecca Foulger Marked Region: ISCA-37429-Loss as ready
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss Rebecca Foulger Region: isca-37429-loss has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss Rebecca Foulger commented on Region: ISCA-37429-Loss: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Genetic epilepsy syndromes v1.352 ISCA-37429-Loss alisdair mcneill reviewed Region: ISCA-37429-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 FLNA alisdair mcneill reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 CREBBP alisdair mcneill reviewed gene: CREBBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29460469; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 ASAH1 alisdair mcneill reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: SMA with myoclonic epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.352 ARID1B alisdair mcneill reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.352 KCNA1 Rebecca Foulger Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771
Genetic epilepsy syndromes v1.351 KCNA1 Rebecca Foulger edited their review of gene: KCNA1: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Genetic epilepsy syndromes v1.351 SCN9A Rebecca Foulger edited their review of gene: SCN9A: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Genetic epilepsy syndromes v1.351 FLNA Rebecca Foulger edited their review of gene: FLNA: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Genetic epilepsy syndromes v1.351 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
------------

[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature
Genetic epilepsy syndromes v1.351 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to AMBER
Added comment: This gene was reviewed for the ID panel (details below).

It could be also be considered for inclusion in the epilepsy panel as amber/green.

[Seizures in 8/14 individuals (generalized tonic-clonic/myoclonic, onset 3m - 6yrs) although some individuals were too young when last examined (eg. 8m) and sibs in one family (F7) were discordant for this feature at the ages of 4y7m (+) and 6y (-). Lissencephaly is often associated with seizures which have occasionally been observed in Apc2-deficient mice (PMID cited: 22573669)].

-----

Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
Sources: Literature
Genetic epilepsy syndromes v1.351 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Genetic epilepsy syndromes v1.350 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Genetic epilepsy syndromes v1.349 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome
Genetic epilepsy syndromes v1.348 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from 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 to Epileptic encephalopathy, early infantile, 80, 618580; 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
Genetic epilepsy syndromes v1.347 ACTL6B Rebecca Foulger commented on gene: ACTL6B: ACTL6B now has a 'confirmed' rating for 'EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE' in the DD panel of Gene2Phenotype (DDG2P update, 18/09/2019), supporting the Green rating of ACTL6B on this panel.
Genetic epilepsy syndromes v1.347 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.347 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted ALKBH8 from Green to Amber following review from Helen Lord on behalf of West Midlands, Oxford and Wessex GLH, and agreement from Richard Scott (Genomics England clinical team).
Genetic epilepsy syndromes v1.347 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.346 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Genetic epilepsy syndromes v1.345 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Genetic epilepsy syndromes v1.344 POLG2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept rating as Amber to match Helen Lord's review, but changed MOI from biallelic to 'BOTH biallelic and monoallelic' since (as Helen Lord notes) Young et al 2011 (PMID:21555342) report 4/11 patients with seizures as part of their phenotype and heterozygous variants in POLG2.
Genetic epilepsy syndromes v1.344 POLG2 Rebecca Foulger Mode of inheritance for gene: POLG2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Tag watchlist tag was added to gene: PIGP.
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Classified gene: PIGP as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Added comment: Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and GLH-review by Helen Lord. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Genetic epilepsy syndromes v1.343 PIGP Rebecca Foulger Gene: pigp has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.342 KATNB1 Rebecca Foulger Tag watchlist tag was added to gene: KATNB1.
Genetic epilepsy syndromes v1.342 PMPCB Konstantinos Varvagiannis changed review comment from: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature; to: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature
Genetic epilepsy syndromes v1.342 POLG2 Rebecca Foulger Publications for gene: POLG2 were set to 31286721; 27592148; 30157269
Genetic epilepsy syndromes v1.341 SPATA5 Rebecca Foulger Classified gene: SPATA5 as Green List (high evidence)
Genetic epilepsy syndromes v1.341 SPATA5 Rebecca Foulger Added comment: Comment on list classification: The Green review by Helen Lord (September 23rd 2019) supports the existing Green rating of SPATA5.
Genetic epilepsy syndromes v1.341 SPATA5 Rebecca Foulger Gene: spata5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.340 KATNB1 Rebecca Foulger Classified gene: KATNB1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.340 KATNB1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber, and added watchlist tag: KATNB1 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype. Linked to lissencephaly with microcephaly in OMIM. There are sufficient cases from from the literature to support inclusion on the epilepsy panel (PMIDs:25521378, 25521379, 26640080) but epilepsy is not a feature in all cases and a Red recent review was left by Helen Lord. Therefore rated Amber as other panels may be more appropriate.
Genetic epilepsy syndromes v1.340 KATNB1 Rebecca Foulger Gene: katnb1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.339 GABRA5 Rebecca Foulger Classified gene: GABRA5 as Green List (high evidence)
Genetic epilepsy syndromes v1.339 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA5 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-70 in OMIM, and there are three cases from 2 publications (PMIDs 29961870 and 31056671) of GABRA5 variants associated with early infantile epileptic encephalopathy for a diagnostic rating. A Green rating is supported by a recent review by Helen Lord.
Genetic epilepsy syndromes v1.339 GABRA5 Rebecca Foulger Gene: gabra5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.338 GABRA2 Rebecca Foulger Classified gene: GABRA2 as Green List (high evidence)
Genetic epilepsy syndromes v1.338 GABRA2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA2 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-78 in OMIM, and there are sufficient cases from from the literature (PMIDs:29422393, 29961870, 31032849, https://doi.org/10.1101/678219) of GABRA2 variants associated with early infantile epileptic encephalopathy for a diagnostic rating. A Green rating is supported by a recent review by Helen Lord.
Genetic epilepsy syndromes v1.338 GABRA2 Rebecca Foulger Gene: gabra2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Marked gene: PAK1 as ready
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Classified gene: PAK1 as Green List (high evidence)
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Added comment: Comment on list classification: Updated PAK1 from Amber to Green: Subsequent to the 8th August Webex, Konstantinos Varvagiannis left a Green review of PAK1 on the Epilepsy panel based on an additional 2019 paper (Horn et al, PMID:31504246). Green rating is supported by a new review by Helen Lord.
Genetic epilepsy syndromes v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.336 GABRA2 Rebecca Foulger changed review comment from: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girls with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.; to: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girl with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.
Genetic epilepsy syndromes v1.336 KATNB1 Rebecca Foulger changed review comment from: KATNB1 was added to the panel and rated Grey by Konstantinos Varvagiannis. Summary of evidence is as follows (see Konstantinos Varvagiannis' review for details): 3 publications reporting patients with biallelic KATNB1 variants. The phenotype includes seizures in some, but not all cases:

PMID:25521378. Mishra-Gorur et al. 2014 report 5 families with malformations of cortical development and homozygous KATNB1 variants. In many families homozygous variants in additional genes were also reported. Epilepsy was reported in 3/7 individuals (from 2 families): Supplementary Table S1).

PMID:25521379. Hu et al., 2014 report 3 Middle Eastern families with microcephaly, Global DD and seizures, and 3 different homozygous variants in KATNB1.

PMID:26640080. Yigit el al. 2016 report a homozygous acceptor splice-site intronic KATNB1 variant in a 5 year old Turkish girl born to consanguineous cousins, who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, dental abnormalities and developmental delay. She developed seizures age 6 months.; to: KATNB1 was added to the panel and rated Green by Konstantinos Varvagiannis. Summary of evidence is as follows (see Konstantinos Varvagiannis' review for details): 3 publications reporting patients with biallelic KATNB1 variants. The phenotype includes seizures in some, but not all cases:

PMID:25521378. Mishra-Gorur et al. 2014 report 5 families with malformations of cortical development and homozygous KATNB1 variants. In many families homozygous variants in additional genes were also reported. Epilepsy was reported in 3/7 individuals (from 2 families): Supplementary Table S1).

PMID:25521379. Hu et al., 2014 report 3 Middle Eastern families with microcephaly, Global DD and seizures, and 3 different homozygous variants in KATNB1.

PMID:26640080. Yigit el al. 2016 report a homozygous acceptor splice-site intronic KATNB1 variant in a 5 year old Turkish girl born to consanguineous cousins, who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, dental abnormalities and developmental delay. She developed seizures age 6 months.
Genetic epilepsy syndromes v1.336 PMPCB Konstantinos Varvagiannis gene: PMPCB was added
gene: PMPCB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMPCB were set to 29576218
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954
Penetrance for gene: PMPCB were set to Complete
Review for gene: PMPCB was set to GREEN
Added comment: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature
Genetic epilepsy syndromes v1.336 PAK1 Helen Lord edited their review of gene: PAK1: Added comment: Horn et al paper 2019 (31504246). 4 unrelated patients with intellectual disability, macrocephaly and seizures had de novo het missense variants in the PAK1 gene using trio exome sequencing. 3/4 of the patients reported as having seizures/focal epilepsy. 1/4 had one typical febrile seizure (age not known). All 4 variants located in important domains and are likely to lead to a gain of function.; Changed rating: GREEN; Changed publications: 31504246
Genetic epilepsy syndromes v1.336 POLG2 Helen Lord reviewed gene: POLG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21555342, 27592148, 30157269, 31286721; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.336 SPATA5 Helen Lord reviewed gene: SPATA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 26299366, 29343804; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.336 GOT2 Helen Lord reviewed gene: GOT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.336 GABRA2 Helen Lord reviewed gene: GABRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29422393, 31032849; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.336 GABRA5 Helen Lord reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671, 30033060; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.336 HNRNPR Helen Lord reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 26795593, 31079900; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.336 KATNB1 Helen Lord reviewed gene: KATNB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.336 PIGP Helen Lord reviewed gene: PIGP: Rating: AMBER; Mode of pathogenicity: None; Publications: 28334793, 31139695; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.336 TIMM50 Konstantinos Varvagiannis reviewed gene: TIMM50: Rating: GREEN; Mode of pathogenicity: None; Publications: 27573165, 30190335, 31058414, Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T); Phenotypes: 3-methylglutaconic aciduria, type IX (MIM 617698); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.336 SLC25A12 Rebecca Foulger Publications for gene: SLC25A12 were set to 24515575; 19641205; 27290639; 26633542
Genetic epilepsy syndromes v1.335 GABRA5 Rebecca Foulger commented on gene: GABRA5: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): 3 literature cases from 2 papers of patients with epileptic encephalopathy and GABRA5 missense variants:

PMID:29961870, Butler et al. 2018 report a 2 year old boy with EIEE (seizure onset age 4 months) and a p.V294L variant in GABRA5. Cognitive and motor development slowed at the time of seizure onset. A de novo variant in MIA2 was also detected but was considered unlikely to contribute to the patients phenotypes due to allele frequencies in the gnomAD database.

PMID:31056671, Hernandez et al. 2019 screened a cohort of patients with epilepsy and ID and report 2 individuals with EIEE and GABRA5 missense variants (V294F and S413F). Seizures included focal, febrile, focal and tonic, epileptic spasms and status epilepticus. Both had severe ID and delayed motor development.
Genetic epilepsy syndromes v1.335 GABRA1 Rebecca Foulger Publications for gene: GABRA1 were set to 24623842; 11992121; 21714819; 16718694
Genetic epilepsy syndromes v1.334 GABRA2 Rebecca Foulger commented on gene: GABRA2: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girls with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.
Genetic epilepsy syndromes v1.334 GABRA2 Rebecca Foulger Phenotypes for gene: GABRA2 were changed from Epileptic encephalopathy, early infantile, 78 (MIM 618557) to Epileptic encephalopathy, early infantile, 78, 618557
Genetic epilepsy syndromes v1.333 KATNB1 Rebecca Foulger Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly, 616212 to Lissencephaly 6, with microcephaly, 616212; seizures
Genetic epilepsy syndromes v1.332 KATNB1 Rebecca Foulger commented on gene: KATNB1
Genetic epilepsy syndromes v1.332 KATNB1 Rebecca Foulger Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly (MIM 616212) to Lissencephaly 6, with microcephaly, 616212
Genetic epilepsy syndromes v1.331 GRIA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIA2.
Genetic epilepsy syndromes v1.331 KMT5B Rebecca Foulger Source Wessex and West Midlands GLH was added to KMT5B.
Genetic epilepsy syndromes v1.331 KCNH5 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNH5.
Genetic epilepsy syndromes v1.331 KCND2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCND2.
Genetic epilepsy syndromes v1.331 CSNK2A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to CSNK2A1.
Genetic epilepsy syndromes v1.331 BCORL1 Rebecca Foulger Source Wessex and West Midlands GLH was added to BCORL1.
Genetic epilepsy syndromes v1.331 ZNF142 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZNF142.
Genetic epilepsy syndromes v1.331 ZMIZ1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZMIZ1.
Genetic epilepsy syndromes v1.331 USP7 Rebecca Foulger Source Wessex and West Midlands GLH was added to USP7.
Genetic epilepsy syndromes v1.331 TRRAP Rebecca Foulger Source Wessex and West Midlands GLH was added to TRRAP.
Genetic epilepsy syndromes v1.331 TRPM3 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRPM3.
Genetic epilepsy syndromes v1.331 SLC35A3 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC35A3.
Genetic epilepsy syndromes v1.331 RNF13 Rebecca Foulger Source Wessex and West Midlands GLH was added to RNF13.
Genetic epilepsy syndromes v1.331 PAK1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PAK1.
Genetic epilepsy syndromes v1.331 NUS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NUS1.
Genetic epilepsy syndromes v1.331 LSS Rebecca Foulger Source Wessex and West Midlands GLH was added to LSS.
Genetic epilepsy syndromes v1.331 FUK Rebecca Foulger Source Wessex and West Midlands GLH was added to FUK.
Genetic epilepsy syndromes v1.331 CLCN6 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLCN6.
Genetic epilepsy syndromes v1.331 AIMP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AIMP2.
Genetic epilepsy syndromes v1.331 AFF3 Rebecca Foulger Source Wessex and West Midlands GLH was added to AFF3.
Genetic epilepsy syndromes v1.331 ZDHHC9 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZDHHC9.
Genetic epilepsy syndromes v1.331 WARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to WARS2.
Genetic epilepsy syndromes v1.331 VPS11 Rebecca Foulger Source Wessex and West Midlands GLH was added to VPS11.
Genetic epilepsy syndromes v1.331 VAMP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to VAMP2.
Genetic epilepsy syndromes v1.331 SNAP25 Rebecca Foulger Source Wessex and West Midlands GLH was added to SNAP25.
Genetic epilepsy syndromes v1.331 SMARCC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SMARCC2.
Genetic epilepsy syndromes v1.331 PPP2CA Rebecca Foulger Source Wessex and West Midlands GLH was added to PPP2CA.
Genetic epilepsy syndromes v1.331 PIGB Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGB.
Genetic epilepsy syndromes v1.331 PARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PARS2.
Genetic epilepsy syndromes v1.331 P4HTM Rebecca Foulger Source Wessex and West Midlands GLH was added to P4HTM.
Genetic epilepsy syndromes v1.331 NBEA Rebecca Foulger Source Wessex and West Midlands GLH was added to NBEA.
Genetic epilepsy syndromes v1.331 KMT2E Rebecca Foulger Source Wessex and West Midlands GLH was added to KMT2E.
Genetic epilepsy syndromes v1.331 KCNT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNT2.
Genetic epilepsy syndromes v1.331 DHPS Rebecca Foulger Source Wessex and West Midlands GLH was added to DHPS.
Genetic epilepsy syndromes v1.331 DEGS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DEGS1.
Genetic epilepsy syndromes v1.331 CTNNA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CTNNA2.
Genetic epilepsy syndromes v1.331 CACNA1B Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1B.
Genetic epilepsy syndromes v1.331 ATN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATN1.
Genetic epilepsy syndromes v1.331 AP2M1 Rebecca Foulger Source Wessex and West Midlands GLH was added to AP2M1.
Genetic epilepsy syndromes v1.331 ALKBH8 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALKBH8.
Genetic epilepsy syndromes v1.331 ACTL6B Rebecca Foulger Source Wessex and West Midlands GLH was added to ACTL6B.
Genetic epilepsy syndromes v1.330 GRIA2 Rebecca Foulger Source NHS GMS was added to GRIA2.
Genetic epilepsy syndromes v1.330 KMT5B Rebecca Foulger Source NHS GMS was added to KMT5B.
Genetic epilepsy syndromes v1.330 KCNH5 Rebecca Foulger Source NHS GMS was added to KCNH5.
Genetic epilepsy syndromes v1.330 KCND2 Rebecca Foulger Source NHS GMS was added to KCND2.
Genetic epilepsy syndromes v1.330 CSNK2A1 Rebecca Foulger Source NHS GMS was added to CSNK2A1.
Genetic epilepsy syndromes v1.330 BCORL1 Rebecca Foulger Source NHS GMS was added to BCORL1.
Genetic epilepsy syndromes v1.330 ZNF142 Rebecca Foulger Source NHS GMS was added to ZNF142.
Genetic epilepsy syndromes v1.330 ZMIZ1 Rebecca Foulger Source NHS GMS was added to ZMIZ1.
Genetic epilepsy syndromes v1.330 USP7 Rebecca Foulger Source NHS GMS was added to USP7.
Genetic epilepsy syndromes v1.330 TRRAP Rebecca Foulger Source NHS GMS was added to TRRAP.
Genetic epilepsy syndromes v1.330 TRPM3 Rebecca Foulger Source NHS GMS was added to TRPM3.
Genetic epilepsy syndromes v1.330 SLC35A3 Rebecca Foulger Source NHS GMS was added to SLC35A3.
Genetic epilepsy syndromes v1.330 RNF13 Rebecca Foulger Source NHS GMS was added to RNF13.
Genetic epilepsy syndromes v1.330 PAK1 Rebecca Foulger Source NHS GMS was added to PAK1.
Genetic epilepsy syndromes v1.330 NUS1 Rebecca Foulger Source NHS GMS was added to NUS1.
Genetic epilepsy syndromes v1.330 LSS Rebecca Foulger Source NHS GMS was added to LSS.
Genetic epilepsy syndromes v1.330 FUK Rebecca Foulger Source NHS GMS was added to FUK.
Genetic epilepsy syndromes v1.330 CLCN6 Rebecca Foulger Source NHS GMS was added to CLCN6.
Genetic epilepsy syndromes v1.330 AIMP2 Rebecca Foulger Source NHS GMS was added to AIMP2.
Genetic epilepsy syndromes v1.330 AFF3 Rebecca Foulger Source NHS GMS was added to AFF3.
Genetic epilepsy syndromes v1.330 ZDHHC9 Rebecca Foulger Source NHS GMS was added to ZDHHC9.
Genetic epilepsy syndromes v1.330 WARS2 Rebecca Foulger Source NHS GMS was added to WARS2.
Genetic epilepsy syndromes v1.330 VPS11 Rebecca Foulger Source NHS GMS was added to VPS11.
Genetic epilepsy syndromes v1.330 VAMP2 Rebecca Foulger Source NHS GMS was added to VAMP2.
Genetic epilepsy syndromes v1.330 SNAP25 Rebecca Foulger Source NHS GMS was added to SNAP25.
Genetic epilepsy syndromes v1.330 SMARCC2 Rebecca Foulger Source NHS GMS was added to SMARCC2.
Genetic epilepsy syndromes v1.330 PPP2CA Rebecca Foulger Source NHS GMS was added to PPP2CA.
Genetic epilepsy syndromes v1.330 PIGB Rebecca Foulger Source NHS GMS was added to PIGB.
Genetic epilepsy syndromes v1.330 PARS2 Rebecca Foulger Source NHS GMS was added to PARS2.
Genetic epilepsy syndromes v1.330 P4HTM Rebecca Foulger Source NHS GMS was added to P4HTM.
Genetic epilepsy syndromes v1.330 NBEA Rebecca Foulger Source NHS GMS was added to NBEA.
Genetic epilepsy syndromes v1.330 KMT2E Rebecca Foulger Source NHS GMS was added to KMT2E.
Genetic epilepsy syndromes v1.330 KCNT2 Rebecca Foulger Source NHS GMS was added to KCNT2.
Genetic epilepsy syndromes v1.330 DHPS Rebecca Foulger Source NHS GMS was added to DHPS.
Genetic epilepsy syndromes v1.330 DEGS1 Rebecca Foulger Source NHS GMS was added to DEGS1.
Genetic epilepsy syndromes v1.330 CTNNA2 Rebecca Foulger Source NHS GMS was added to CTNNA2.
Genetic epilepsy syndromes v1.330 CACNA1B Rebecca Foulger Source NHS GMS was added to CACNA1B.
Genetic epilepsy syndromes v1.330 ATN1 Rebecca Foulger Source NHS GMS was added to ATN1.
Genetic epilepsy syndromes v1.330 AP2M1 Rebecca Foulger Source NHS GMS was added to AP2M1.
Genetic epilepsy syndromes v1.330 ALKBH8 Rebecca Foulger Source NHS GMS was added to ALKBH8.
Genetic epilepsy syndromes v1.330 ACTL6B Rebecca Foulger Source NHS GMS was added to ACTL6B.
Genetic epilepsy syndromes v1.329 CACNA2D2 Konstantinos Varvagiannis reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Phenotypes: Cerebellar atrophy with seizures and variable developmental delay (MIM 618501); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic epilepsy syndromes v1.329 PIGP Rebecca Foulger changed review comment from: 2 independent cases reported in OMIM: 2 compound heterozygous siblings with early infantile epileptic encephalopathy-55 reported by Johnstone et al., 2017 (PMID:28334793). Plus a 2-year-old girl, with a homozygous 1bp deletion, born of unrelated parents, with EIEE55 reported by Krenn et al.,2019 (PMID:31139695).; to: Summary of cases (see Konstantinos Varvagiannis' review for details). 2 independent cases reported in OMIM: 2 compound heterozygous siblings with early infantile epileptic encephalopathy-55 reported by Johnstone et al., 2017 (PMID:28334793). Plus a 2-year-old girl, with a homozygous 1bp deletion, born of unrelated parents, with EIEE55 reported by Krenn et al.,2019 (PMID:31139695). The third case reported by Konstantinos comes from LOVD.
Genetic epilepsy syndromes v1.329 PIGP Rebecca Foulger commented on gene: PIGP
Genetic epilepsy syndromes v1.329 PIGP Rebecca Foulger Phenotypes for gene: PIGP were changed from Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to ?Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Genetic epilepsy syndromes v1.328 GABRA5 Rebecca Foulger changed review comment from: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date for Epileptic Encephalopathy.; to: Added missense tag because, as Konstantinos Varvagiannis notes, only missense GABRA5 variants reported to date for Epileptic Encephalopathy.
Genetic epilepsy syndromes v1.328 GABRA5 Rebecca Foulger changed review comment from: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date.; to: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date for Epileptic Encephalopathy.
Genetic epilepsy syndromes v1.328 GABRA5 Rebecca Foulger commented on gene: GABRA5
Genetic epilepsy syndromes v1.328 GABRA5 Rebecca Foulger Phenotypes for gene: GABRA5 were changed from Epileptic encephalopathy, early infantile, 79 (MIM 618559) to Epileptic encephalopathy, early infantile, 79, 618559
Genetic epilepsy syndromes v1.327 GABRA5 Rebecca Foulger Publications for gene: GABRA5 were set to 29961870
Genetic epilepsy syndromes v1.326 GABRA5 Rebecca Foulger Tag missense tag was added to gene: GABRA5.
Genetic epilepsy syndromes v1.326 GABRA2 Rebecca Foulger Deleted their comment
Genetic epilepsy syndromes v1.326 GABRA2 Rebecca Foulger commented on gene: GABRA2: Added 'missense' tag based on Konstantinos Varvagiannis' comment that all variants to-date are missense variants.
Genetic epilepsy syndromes v1.326 GABRA2 Rebecca Foulger Tag missense tag was added to gene: GABRA2.
Genetic epilepsy syndromes v1.326 GABRA2 Rebecca Foulger commented on gene: GABRA2
Genetic epilepsy syndromes v1.326 HNRNPR Catherine Snow Tag watchlist tag was added to gene: HNRNPR.
Genetic epilepsy syndromes v1.326 HNRNPR Catherine Snow Classified gene: HNRNPR as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.326 HNRNPR Catherine Snow Gene: hnrnpr has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.325 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.325 GABRA2 Konstantinos Varvagiannis changed review comment from: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].; to: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized, Maljevic - Table 1 (7 patients) and/or in the suppl. table 1 by Sanchis-Juan et al. (8 patients) (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Genetic epilepsy syndromes v1.325 TRAPPC6B Rebecca Foulger Publications for gene: TRAPPC6B were set to 28626029; 28397838
Genetic epilepsy syndromes v1.324 TRAPPC6B Rebecca Foulger commented on gene: TRAPPC6B: The Amber review by Konstantinos Varvagiannis (25 Aug 2019) agrees with the current Amber rating of TRAPPC6B: therefore no further curation required.
Genetic epilepsy syndromes v1.324 GRIA2 Rebecca Foulger Classified gene: GRIA2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.324 GRIA2 Rebecca Foulger Added comment: Comment on list classification: Changed rating of GRIA2 from Grey to Amber based on Amber post-Webex review from Helen Lord. Currently insufficient evidence for a diagnostic rating.
Genetic epilepsy syndromes v1.324 GRIA2 Rebecca Foulger Gene: gria2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.323 NUS1 Rebecca Foulger Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.322 NUS1 Rebecca Foulger Classified gene: NUS1 as Green List (high evidence)
Genetic epilepsy syndromes v1.322 NUS1 Rebecca Foulger Gene: nus1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.321 NUS1 Rebecca Foulger commented on gene: NUS1: Updated rating from Amber to Green based on Green post-Webex review from Helen Lord. Also updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic' based on Helen's review.
Genetic epilepsy syndromes v1.321 ZMIZ1 Rebecca Foulger commented on gene: ZMIZ1: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.321 ZDHHC9 Rebecca Foulger commented on gene: ZDHHC9: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.321 WARS2 Rebecca Foulger commented on gene: WARS2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.321 VPS11 Rebecca Foulger commented on gene: VPS11: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.321 VAMP2 Rebecca Foulger commented on gene: VAMP2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.321 SNAP25 Rebecca Foulger commented on gene: SNAP25: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.321 SMARCC2 Rebecca Foulger commented on gene: SMARCC2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.321 SMARCC2 Rebecca Foulger Phenotypes for gene: SMARCC2 were changed from Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features to Coffin-Siris syndrome 8, 618362; Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
Genetic epilepsy syndromes v1.320 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.320 RNF13 Rebecca Foulger commented on gene: RNF13: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.320 PPP2CA Rebecca Foulger commented on gene: PPP2CA: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.320 POLG Rebecca Foulger commented on gene: POLG: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.320 POLG Rebecca Foulger changed review comment from: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; to: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.320 PIGB Rebecca Foulger commented on gene: PIGB: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.320 PARS2 Rebecca Foulger commented on gene: PARS2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.320 PAK1 Rebecca Foulger Publications for gene: PAK1 were set to 30290153
Genetic epilepsy syndromes v1.319 P4HTM Rebecca Foulger Phenotypes for gene: P4HTM were changed from Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities, 618493; Abnormality of the eye; Seizures; Dysautonomia; Central hypotonia; Muscular hypotonia; Hypoventilation; Intellectual disability; Sleep apnea; Global developmental delay to Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities, 618493; Seizures; Intellectual disability; Global developmental delay
Genetic epilepsy syndromes v1.318 P4HTM Rebecca Foulger Phenotypes for gene: P4HTM were changed from Abnormality of the eye; Seizures; Dysautonomia; Central hypotonia; Muscular hypotonia; Hypoventilation; Intellectual disability; Sleep apnea; Global developmental delay to Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities, 618493; Abnormality of the eye; Seizures; Dysautonomia; Central hypotonia; Muscular hypotonia; Hypoventilation; Intellectual disability; Sleep apnea; Global developmental delay
Genetic epilepsy syndromes v1.317 NUS1 Rebecca Foulger Phenotypes for gene: NUS1 were changed from #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function to ?Congenital disorder of glycosylation, type 1aa, 617082; Mental retardation, autosomal dominant 55, with seizures, 617831; Abnormality of extrapyramidal motor function
Genetic epilepsy syndromes v1.316 NBEA Rebecca Foulger commented on gene: NBEA: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.316 LSS Rebecca Foulger commented on gene: LSS: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.316 KMT5B Rebecca Foulger commented on gene: KMT5B: Kept rating as Red based on Red post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.316 KMT5B Rebecca Foulger Publications for gene: KMT5B were set to 29276005
Genetic epilepsy syndromes v1.315 KMT2E Rebecca Foulger commented on gene: KMT2E: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.315 KCNT2 Rebecca Foulger commented on gene: KCNT2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.315 KCNH5 Rebecca Foulger commented on gene: KCNH5: Kept rating as Red based on Red post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.315 KCNH5 Rebecca Foulger Publications for gene: KCNH5 were set to 23647072
Genetic epilepsy syndromes v1.314 FUK Rebecca Foulger commented on gene: FUK: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.314 DHPS Rebecca Foulger commented on gene: DHPS: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.314 DEGS1 Rebecca Foulger commented on gene: DEGS1: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.314 CTNNA2 Rebecca Foulger commented on gene: CTNNA2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.314 CACNA1B Rebecca Foulger commented on gene: CACNA1B: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.314 BCORL1 Rebecca Foulger commented on gene: BCORL1: Kept rating as Red based on Red post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.314 BCORL1 Rebecca Foulger Phenotypes for gene: BCORL1 were changed from Intellectual disability and seizures to Intellectual disability and seizures; Shukla-Vernon syndrome, 301029
Genetic epilepsy syndromes v1.313 BCORL1 Rebecca Foulger Publications for gene: BCORL1 were set to 30941876
Genetic epilepsy syndromes v1.312 ATN1 Rebecca Foulger commented on gene: ATN1: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.312 ATN1 Rebecca Foulger Phenotypes for gene: ATN1 were changed from Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures; Generalized hypotonia
Genetic epilepsy syndromes v1.311 ATN1 Rebecca Foulger Phenotypes for gene: ATN1 were changed from Abnormality of the kidney; Seizures; Hypotonia; Cleft palate; Developmental Delay; Abnormality of the cardiovascular system; Epilepsy; Generalized hypotonia; Feeding difficulties; Intellectual disability; Global developmental delay; Digit Abnormalities to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures
Genetic epilepsy syndromes v1.310 AP2M1 Rebecca Foulger commented on gene: AP2M1: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.310 AP2M1 Rebecca Foulger Mode of pathogenicity for gene: AP2M1 was changed from Other to Other
Genetic epilepsy syndromes v1.309 ALKBH8 Rebecca Foulger Phenotypes for gene: ALKBH8 were changed from Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, 618504; Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability
Genetic epilepsy syndromes v1.308 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Kept rating as Green based on Green post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.308 ACTL6B Rebecca Foulger Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy to Epileptic encephalopathy, early infantile, 76, 618468; Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy
Genetic epilepsy syndromes v1.307 USP7 Rebecca Foulger Marked gene: USP7 as ready
Genetic epilepsy syndromes v1.307 USP7 Rebecca Foulger Gene: usp7 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.307 USP7 Rebecca Foulger commented on gene: USP7: Kept rating as Amber based on two post-Webex Amber reviews from Helen Lord and Alison Callaway.
Genetic epilepsy syndromes v1.307 TRPM3 Rebecca Foulger Marked gene: TRPM3 as ready
Genetic epilepsy syndromes v1.307 TRPM3 Rebecca Foulger Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.307 TRPM3 Rebecca Foulger Publications for gene: TRPM3 were set to 31278393
Genetic epilepsy syndromes v1.306 TRPM3 Rebecca Foulger commented on gene: TRPM3: Kept rating as Amber based on two post-Webex Amber reviews from Helen Lord and Alison Callaway.
Genetic epilepsy syndromes v1.306 KCND2 Rebecca Foulger commented on gene: KCND2: Kept rating as Red based on two post-Webex Red reviews from Helen Lord and Alison Callaway.
Genetic epilepsy syndromes v1.306 KCND2 Rebecca Foulger Publications for gene: KCND2 were set to 24501278; 16934482
Genetic epilepsy syndromes v1.305 KCND2 Rebecca Foulger Publications for gene: KCND2 were set to 24501278
Genetic epilepsy syndromes v1.304 CSNK2A1 Rebecca Foulger commented on gene: CSNK2A1: Kept rating as Red based on post-Webex reviews from Helen Lord and Alison Callaway: Although there is an argument to upgrade to Amber, epilepsy is not a major part of the overall phenotype so on balance kept rating as Red.
Genetic epilepsy syndromes v1.304 CSNK2A1 Rebecca Foulger Phenotypes for gene: CSNK2A1 were changed from seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome to Neurodevelopmental abnormalities and dysmorphic features; seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome
Genetic epilepsy syndromes v1.303 CSNK2A1 Rebecca Foulger Publications for gene: CSNK2A1 were set to 30655572
Genetic epilepsy syndromes v1.302 CLCN6 Rebecca Foulger Classified gene: CLCN6 as Red List (low evidence)
Genetic epilepsy syndromes v1.302 CLCN6 Rebecca Foulger Added comment: Comment on list classification: Changed rating from Amber to Red based on post-Webex reviews from Helen Lord and Alison Callaway: the current published association between CLCN6 and seizures is weak.
Genetic epilepsy syndromes v1.302 CLCN6 Rebecca Foulger Gene: clcn6 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.301 AIMP2 Rebecca Foulger commented on gene: AIMP2: Kept rating as Amber based on post-Webex reviews from Helen Lord and Alison Callaway. Added 'watchlist' tag based on PMID:26795593 who report an additional case but there is uncertainty over the clinical significance of the reported variant.
Genetic epilepsy syndromes v1.301 AIMP2 Rebecca Foulger Tag watchlist tag was added to gene: AIMP2.
Genetic epilepsy syndromes v1.301 AIMP2 Rebecca Foulger Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Epileptic Encephalopathy; Infantile Spasms; Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Genetic epilepsy syndromes v1.300 AIMP2 Rebecca Foulger Publications for gene: AIMP2 were set to 29215095
Genetic epilepsy syndromes v1.299 GABRA2 Konstantinos Varvagiannis reviewed gene: GABRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29422393, 29961870, 31032849, 31032848, doi.org/10.1101/678219; Phenotypes: Epileptic encephalopathy, early infantile, 78 (MIM 618557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.299 GABRA2 Konstantinos Varvagiannis Deleted their review
Genetic epilepsy syndromes v1.299 GABRA2 Konstantinos Varvagiannis gene: GABRA2 was added
gene: GABRA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GABRA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GABRA2 were set to 29422393; 29961870; 31032849; 31032848; doi.org/10.1101/678219
Phenotypes for gene: GABRA2 were set to Epileptic encephalopathy, early infantile, 78 (MIM 618557)
Penetrance for gene: GABRA2 were set to unknown
Review for gene: GABRA2 was set to GREEN
Added comment: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In almost all affected individuals, the variants were missense and had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx?download=true). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementionned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various reported mutations to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Sources: Literature
Genetic epilepsy syndromes v1.299 GABRA5 Konstantinos Varvagiannis reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671; Phenotypes: Epileptic encephalopathy, early infantile, 79 (MIM 618559); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.299 GABRA5 Konstantinos Varvagiannis Deleted their review
Genetic epilepsy syndromes v1.299 GABRA5 Konstantinos Varvagiannis gene: GABRA5 was added
gene: GABRA5 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GABRA5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GABRA5 were set to 29961870
Phenotypes for gene: GABRA5 were set to Epileptic encephalopathy, early infantile, 79 (MIM 618559)
Penetrance for gene: GABRA5 were set to unknown
Review for gene: GABRA5 was set to GREEN
Added comment: Heterozygous pathogenic GABRA5 variants cause Epileptic encephalopathy, early infantile, 79 (MIM 618559) [entry recently updated in OMIM].

At least 3 relevant individuals with this diagnosis have been reported to date:

- Butler et al. (2018 - PMID: 29961870) described a 2 y.o. boy with early infantile epileptic encephalopathy (seizure onset at the age of 4m). The boy was found to harbor a de novo missense variant (NM_000810.3:c.880G>C - p.Val294Leu) identified following trio-WGS and confirmed by Sanger sequencing. Studies in HEK293 cells demonstrated expression at the surface and incorporation of the mutant subunit in the channel. The α5(V294L)β2γ2s receptors were 10 times more sensitive to GABA compared to wt, but were more likely to desensitize leading to reduced maximum GABA-evoked currents.

- Hernandez et al. (2019 - PMID: 31056671) reported on 2 unrelated individuals with early-onset epileptic encephalopathy due to de novo GABRA5 variants identified by targeted NGS sequencing (480 epilepsy-related genes):

A 3y 10m male with seizure onset at the age of 4m, severe motor delay and ID, frontotemporal atrophy and thin CC upon MRI imaging was found to harbor a de novo missense variant (NM_000810.3:c.880G>T / p.Val294Phe).

A further unrelated subject (a 7 y.o. male) with seizure onset at the age of 3 months, severe DD and ID and cortical atrophy / thin CC upon MRI imaging was heterozygous for another missense variant which had occurred as a de novo event (NM_000810.3:c.1238C>T - p.Ser413Phe).

Functional studies: Expression of HA-tagged α5(V294F) subunits at dendritic GABAergic synapses of rat hippocampal neurons was decreased compared to wt, in contrast with the expression of α5(S413F) subunits which was similar to wt. As the α5(V294F) appeared accumulated in the soma of the neurons, the authors performed additional studies – using HEK293T cells – to show that while the α5(S413F) spread outside the ER, α5(V294F) subunits localized to the ER. This was suggestive of a trafficking defect/ER retention. Co-expression of wt or mutant HA-tagged subunits, with β3 and γ2 subunits in HEK293T cells was carried out to assess assembly and trafficking to cell membranes. Reduced surface levels as well as total (whole cell lysate) levels were shown for α5(V294F). Surface levels and total levels of the α5(S413F) were not changed compared to wt. Surface levels of the β3 subunit were however lower in the case of α5(S413F), a finding which could be suggestive of a dominant negative effect. Both GABRA5 mutations resulted in decreased GABA-evoked current amplitudes in both neuronal and non-neuronal (HEK293T) cells.
-------
The corresponding phenotype in OMIM is Epileptic encephalopathy, early infantile, 79 (618559).
GABRA5 is not associated with any phenotype in G2P.

This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
-------
As a result, GABRA5 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, 3 unrelated individuals, 3 variants, supporting functional studies for all variants) or amber.
Sources: Literature
Genetic epilepsy syndromes v1.299 SLC35A2 Rebecca Foulger Marked gene: SLC35A2 as ready
Genetic epilepsy syndromes v1.299 SLC35A2 Rebecca Foulger Gene: slc35a2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.299 SLC35A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as XLD based on post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.299 SLC35A2 Rebecca Foulger Mode of inheritance for gene: SLC35A2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.298 SLC35A2 Rebecca Foulger Publications for gene: SLC35A2 were set to 24115232; 27743886; 30746764; 30584598; 29679388
Genetic epilepsy syndromes v1.297 SLC1A2 Rebecca Foulger Marked gene: SLC1A2 as ready
Genetic epilepsy syndromes v1.297 SLC1A2 Rebecca Foulger Gene: slc1a2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.297 SLC1A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.297 SLC1A2 Rebecca Foulger Mode of inheritance for gene: SLC1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.296 SLC16A2 Rebecca Foulger Marked gene: SLC16A2 as ready
Genetic epilepsy syndromes v1.296 SLC16A2 Rebecca Foulger Gene: slc16a2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.296 SLC16A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.296 SLC16A2 Rebecca Foulger Mode of inheritance for gene: SLC16A2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.295 SLC16A2 Rebecca Foulger Phenotypes for gene: SLC16A2 were changed from Allan-Herndon-Dudley syndrome, 300523 to Allan-Herndon-Dudley syndrome, 300523; AHDS
Genetic epilepsy syndromes v1.294 SLC16A2 Rebecca Foulger Publications for gene: SLC16A2 were set to 27212794; 15980113
Genetic epilepsy syndromes v1.293 SLC16A2 Rebecca Foulger Phenotypes for gene: SLC16A2 were changed from Allan-Herndon-Dudley syndrome to Allan-Herndon-Dudley syndrome, 300523
Genetic epilepsy syndromes v1.292 SLC16A2 Rebecca Foulger Publications for gene: SLC16A2 were set to Maranduba et al (2006) J Med Genet 43: 457_460
Genetic epilepsy syndromes v1.291 SLC12A5 Rebecca Foulger Marked gene: SLC12A5 as ready
Genetic epilepsy syndromes v1.291 SLC12A5 Rebecca Foulger Gene: slc12a5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.291 SLC12A5 Rebecca Foulger Phenotypes for gene: SLC12A5 were changed from epilepsy of infancy with migrating focal seizures (EIMFS) to epilepsy of infancy with migrating focal seizures (EIMFS); Epileptic encephalopathy, early infantile, 34, 616645; {Epilepsy, idiopathic generalized, susceptibility to, 14}, 616685
Genetic epilepsy syndromes v1.290 SLC12A5 Rebecca Foulger Publications for gene: SLC12A5 were set to PMID: 26333769; 24668262
Genetic epilepsy syndromes v1.289 SLC12A5 Rebecca Foulger Mode of inheritance for gene: SLC12A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.288 SLC12A5 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of Inheritance from 'BOTH monoallelic and bialleic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' based on post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.288 SLC12A5 Rebecca Foulger Mode of inheritance for gene: SLC12A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.287 PIGA Rebecca Foulger Marked gene: PIGA as ready
Genetic epilepsy syndromes v1.287 PIGA Rebecca Foulger Gene: piga has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.287 PIGA Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as XLR based on post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.287 PIGA Rebecca Foulger Mode of inheritance for gene: PIGA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.286 PIGA Rebecca Foulger Phenotypes for gene: PIGA were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 2 to Multiple congenital anomalies-hypotonia-seizures syndrome 2, 300868
Genetic epilepsy syndromes v1.285 PIGA Rebecca Foulger Publications for gene: PIGA were set to Johnston et al (2012) Am J Hum Genet 90, 295 300
Genetic epilepsy syndromes v1.284 NRXN1 Rebecca Foulger Marked gene: NRXN1 as ready
Genetic epilepsy syndromes v1.284 NRXN1 Rebecca Foulger Gene: nrxn1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.284 NRXN1 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on Post-Webex review by Helen Lord.; to: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.284 NRXN1 Rebecca Foulger Publications for gene: NRXN1 were set to 21964664; 19896112; 30031152; 23533028
Genetic epilepsy syndromes v1.283 NRXN1 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on Post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.283 NRXN1 Rebecca Foulger Mode of inheritance for gene: NRXN1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.282 MED12 Rebecca Foulger Marked gene: MED12 as ready
Genetic epilepsy syndromes v1.282 MED12 Rebecca Foulger Gene: med12 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.282 MED12 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on Post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.282 MED12 Rebecca Foulger Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.281 MAGI2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic' to 'BIALLELIC' based on Post-Webex review by Helen Lord (AD inheritance was based on deletions including the MAGI2 gene).
Genetic epilepsy syndromes v1.281 MAGI2 Rebecca Foulger Mode of inheritance for gene: MAGI2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.280 MAGI2 Rebecca Foulger changed review comment from: Comment on mode of inheritance: OMIM lists AR inheritance for 'Nephrotic syndrome, type 15' (MIM:617609). Gene2Phenotype lists 'monoallelic' inheritance for EARLY ONSET EPILEPTIC ENCEPHALOPATHY.; to: Comment on mode of inheritance: OMIM lists AR inheritance for 'Nephrotic syndrome, type 15' (MIM:617609). Gene2Phenotype lists 'monoallelic' inheritance for EARLY ONSET EPILEPTIC ENCEPHALOPATHY based on PMID:18565486 which examines deletions spanning MAGI2.
Genetic epilepsy syndromes v1.280 IKBKG Rebecca Foulger Marked gene: IKBKG as ready
Genetic epilepsy syndromes v1.280 IKBKG Rebecca Foulger Gene: ikbkg has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.280 IKBKG Rebecca Foulger Publications for gene: IKBKG were set to 30151858; 28794079; 24339369
Genetic epilepsy syndromes v1.279 IKBKG Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as XLD based on Post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.279 IKBKG Rebecca Foulger Mode of inheritance for gene: IKBKG was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.278 IDH2 Rebecca Foulger Marked gene: IDH2 as ready
Genetic epilepsy syndromes v1.278 IDH2 Rebecca Foulger Gene: idh2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.278 IDH2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as MONOALLELIC based on post-Webex review from Helen Lord. Note that the rating of IDH2 was not discussed on the group Webex (2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy) because IDH2 has a Green rating on the 'Inborn errors of metabolism' panel, and therefore will be Green on the Epilepsy super panel for R59.
Genetic epilepsy syndromes v1.278 IDH2 Rebecca Foulger Mode of inheritance for gene: IDH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.277 HEPACAM Rebecca Foulger Marked gene: HEPACAM as ready
Genetic epilepsy syndromes v1.277 HEPACAM Rebecca Foulger Gene: hepacam has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.277 HEPACAM Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as BIALLELIC based on post-Webex review from Helen Lord, and original comment from Zornitza Stark that AD form is not associated with seizures.
Genetic epilepsy syndromes v1.277 HEPACAM Rebecca Foulger Mode of inheritance for gene: HEPACAM was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.276 DEAF1 Rebecca Foulger Marked gene: DEAF1 as ready
Genetic epilepsy syndromes v1.276 DEAF1 Rebecca Foulger Gene: deaf1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.276 DEAF1 Rebecca Foulger Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder 617171 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171
Genetic epilepsy syndromes v1.275 DEAF1 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of Inheritance from 'BOTH monoallelic and biallelic' to 'BIALLELIC' based on post-Webex reviews from Helen Lord. The original comment from West Midlands, Oxford and Wessex GLH (uploaded for Tracy Lester) also supports biallelic inheritance.
Genetic epilepsy syndromes v1.275 DEAF1 Rebecca Foulger Mode of inheritance for gene: DEAF1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v1.274 CACNA1D Rebecca Foulger Marked gene: CACNA1D as ready
Genetic epilepsy syndromes v1.274 CACNA1D Rebecca Foulger Gene: cacna1d has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.274 CACNA1D Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review from Helen Lord.
Genetic epilepsy syndromes v1.274 CACNA1D Rebecca Foulger Mode of inheritance for gene: CACNA1D was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.273 ATRX Rebecca Foulger Marked gene: ATRX as ready
Genetic epilepsy syndromes v1.273 ATRX Rebecca Foulger Gene: atrx has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.273 ATRX Rebecca Foulger Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome; Mental retardation-hypotonic facies syndrome, X-linked to Alpha-thalassemia/mental retardation syndrome, 301040; Mental retardation-hypotonic facies syndrome, X-linked, 309580
Genetic epilepsy syndromes 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
Genetic epilepsy syndromes v1.272 ATRX Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on Post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.272 ATRX Rebecca Foulger Mode of inheritance for gene: ATRX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.271 ATRX Rebecca Foulger Publications for gene: ATRX were set to 25606380; 11449489; 7697714; 11050622
Genetic epilepsy syndromes v1.270 ARHGEF9 Rebecca Foulger Marked gene: ARHGEF9 as ready
Genetic epilepsy syndromes v1.270 ARHGEF9 Rebecca Foulger Gene: arhgef9 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.270 ARHGEF9 Rebecca Foulger Publications for gene: ARHGEF9 were set to 21633362; 15215304
Genetic epilepsy syndromes v1.269 ARHGEF9 Rebecca Foulger Publications for gene: ARHGEF9 were set to
Genetic epilepsy syndromes v1.268 ARHGEF9 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on Post-Webex review by Helen Lord.
Genetic epilepsy syndromes v1.268 ARHGEF9 Rebecca Foulger Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.267 TUBB2A Rebecca Foulger Marked gene: TUBB2A as ready
Genetic epilepsy syndromes v1.267 TUBB2A Rebecca Foulger Gene: tubb2a has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.267 TUBB2A Rebecca Foulger commented on gene: TUBB2A: Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway (West Midlands, Oxford and Wessex GLH).
Genetic epilepsy syndromes v1.267 SLC25A12 Rebecca Foulger Marked gene: SLC25A12 as ready
Genetic epilepsy syndromes v1.267 SLC25A12 Rebecca Foulger Gene: slc25a12 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.267 SLC25A12 Rebecca Foulger commented on gene: SLC25A12: Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway.
Genetic epilepsy syndromes v1.267 SLC25A12 Rebecca Foulger Publications for gene: SLC25A12 were set to 24515575; 19641205; 27290639
Genetic epilepsy syndromes v1.266 KCNMA1 Rebecca Foulger Marked gene: KCNMA1 as ready
Genetic epilepsy syndromes v1.266 KCNMA1 Rebecca Foulger Gene: kcnma1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.266 KCNMA1 Rebecca Foulger Classified gene: KCNMA1 as Green List (high evidence)
Genetic epilepsy syndromes v1.266 KCNMA1 Rebecca Foulger Added comment: Comment on list classification: Updated rating of KCNMA1 from Amber to Green based on post-Webex reviews from Helen Lord, Allison Callaway and Konstantinos Varvagiannis.
Genetic epilepsy syndromes v1.266 KCNMA1 Rebecca Foulger Gene: kcnma1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.265 KCNMA1 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex reviews from Helen Lord and Konstantinos Varvagiannis.
Genetic epilepsy syndromes v1.265 KCNMA1 Rebecca Foulger Mode of inheritance for gene: KCNMA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.264 ALPL Rebecca Foulger commented on gene: ALPL: Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway.
Genetic epilepsy syndromes v1.264 ALPL Rebecca Foulger changed review comment from: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic to 'BIALLELIC' based on Post-Webex review by Helen Lord: AR but not AD Hypophosphatasia associated with seizures.; to: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic' to 'BIALLELIC' based on Post-Webex review by Helen Lord: AR but not AD Hypophosphatasia is associated with seizures.
Genetic epilepsy syndromes v1.264 ALPL Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic to 'BIALLELIC' based on Post-Webex review by Helen Lord: AR but not AD Hypophosphatasia associated with seizures.
Genetic epilepsy syndromes v1.264 ALPL Rebecca Foulger Mode of inheritance for gene: ALPL was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.263 H3F3B Louise Daugherty Tag new-gene-name tag was added to gene: H3F3B.
Genetic epilepsy syndromes v1.263 H3F3B Louise Daugherty commented on gene: H3F3B
Genetic epilepsy syndromes v1.263 H3F3A Louise Daugherty Tag new-gene-name tag was added to gene: H3F3A.
Genetic epilepsy syndromes v1.263 H3F3A Louise Daugherty commented on gene: H3F3A
Genetic epilepsy syndromes v1.263 KIF1BP Louise Daugherty Tag new-gene-name tag was added to gene: KIF1BP.
Genetic epilepsy syndromes v1.263 KIF1BP Louise Daugherty commented on gene: KIF1BP: Added new-gene-name tag, new approved HGNC gene symbol for KIF1BP is KIFBP
Genetic epilepsy syndromes v1.263 VARS Louise Daugherty Tag new-gene-name tag was added to gene: VARS.
Genetic epilepsy syndromes v1.263 VARS Louise Daugherty commented on gene: VARS
Genetic epilepsy syndromes v1.263 QARS Louise Daugherty Tag new-gene-name tag was added to gene: QARS.
Genetic epilepsy syndromes v1.263 QARS Louise Daugherty commented on gene: QARS
Genetic epilepsy syndromes v1.263 KARS Louise Daugherty Tag new-gene-name tag was added to gene: KARS.
Genetic epilepsy syndromes v1.263 KARS Louise Daugherty commented on gene: KARS
Genetic epilepsy syndromes v1.263 AARS Louise Daugherty Tag new-gene-name tag was added to gene: AARS.
Genetic epilepsy syndromes v1.263 AARS Louise Daugherty commented on gene: AARS
Genetic epilepsy syndromes v1.263 KCNA1 Rebecca Foulger Source North West GLH was added to KCNA1.
Genetic epilepsy syndromes v1.263 SCN9A Rebecca Foulger Source North West GLH was added to SCN9A.
Genetic epilepsy syndromes v1.263 FLNA Rebecca Foulger Source North West GLH was added to FLNA.
Genetic epilepsy syndromes v1.262 KCNA1 Rebecca Foulger commented on gene: KCNA1: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Genetic epilepsy syndromes v1.262 SCN9A Rebecca Foulger commented on gene: SCN9A: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Genetic epilepsy syndromes v1.262 FLNA Rebecca Foulger commented on gene: FLNA: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Genetic epilepsy syndromes v1.262 ARHGEF9 Rebecca Foulger commented on gene: ARHGEF9: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 SLC16A2 Rebecca Foulger commented on gene: SLC16A2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 PIGA Rebecca Foulger commented on gene: PIGA: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 MED12 Rebecca Foulger commented on gene: MED12: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 MAGI2 Rebecca Foulger commented on gene: MAGI2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 IDH2 Rebecca Foulger commented on gene: IDH2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded an Amber rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 CACNA1D Rebecca Foulger commented on gene: CACNA1D: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 NRXN1 Rebecca Foulger commented on gene: NRXN1: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 SLC35A2 Rebecca Foulger commented on gene: SLC35A2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 SLC1A2 Rebecca Foulger commented on gene: SLC1A2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 SLC12A5 Rebecca Foulger commented on gene: SLC12A5: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 IKBKG Rebecca Foulger commented on gene: IKBKG: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 HEPACAM Rebecca Foulger commented on gene: HEPACAM: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 DEAF1 Rebecca Foulger commented on gene: DEAF1: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 ATRX Rebecca Foulger commented on gene: ATRX: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Genetic epilepsy syndromes v1.262 GRIA2 Rebecca Foulger edited their review of gene: GRIA2: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 KMT5B Rebecca Foulger reviewed gene: KMT5B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 KCNH5 Rebecca Foulger reviewed gene: KCNH5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 KCND2 Rebecca Foulger reviewed gene: KCND2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 CSNK2A1 Rebecca Foulger commented on gene: CSNK2A1: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 BCORL1 Rebecca Foulger edited their review of gene: BCORL1: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 ZNF142 Rebecca Foulger reviewed gene: ZNF142: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 ZMIZ1 Rebecca Foulger reviewed gene: ZMIZ1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 USP7 Rebecca Foulger edited their review of gene: USP7: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 TRRAP Rebecca Foulger edited their review of gene: TRRAP: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 TRPM3 Rebecca Foulger edited their review of gene: TRPM3: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 SLC35A3 Rebecca Foulger edited their review of gene: SLC35A3: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 RNF13 Rebecca Foulger reviewed gene: RNF13: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 PAK1 Rebecca Foulger reviewed gene: PAK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 NUS1 Rebecca Foulger reviewed gene: NUS1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 LSS Rebecca Foulger reviewed gene: LSS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 FUK Rebecca Foulger reviewed gene: FUK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 CLCN6 Rebecca Foulger reviewed gene: CLCN6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 AIMP2 Rebecca Foulger reviewed gene: AIMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 AFF3 Rebecca Foulger edited their review of gene: AFF3: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 POLG Rebecca Foulger commented on gene: POLG: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 ZDHHC9 Rebecca Foulger reviewed gene: ZDHHC9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 WARS2 Rebecca Foulger reviewed gene: WARS2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 VPS11 Rebecca Foulger reviewed gene: VPS11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 VAMP2 Rebecca Foulger reviewed gene: VAMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 SNAP25 Rebecca Foulger reviewed gene: SNAP25: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 SMARCC2 Rebecca Foulger edited their review of gene: SMARCC2: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 PPP2CA Rebecca Foulger reviewed gene: PPP2CA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 PIGB Rebecca Foulger reviewed gene: PIGB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 PARS2 Rebecca Foulger reviewed gene: PARS2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 P4HTM Rebecca Foulger reviewed gene: P4HTM: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 NBEA Rebecca Foulger reviewed gene: NBEA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 KMT2E Rebecca Foulger reviewed gene: KMT2E: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 KCNT2 Rebecca Foulger reviewed gene: KCNT2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 DHPS Rebecca Foulger reviewed gene: DHPS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 DEGS1 Rebecca Foulger edited their review of gene: DEGS1: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 CTNNA2 Rebecca Foulger reviewed gene: CTNNA2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 CACNA1B Rebecca Foulger reviewed gene: CACNA1B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 ATN1 Rebecca Foulger reviewed gene: ATN1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 AP2M1 Rebecca Foulger reviewed gene: AP2M1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 ALKBH8 Rebecca Foulger reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Genetic epilepsy syndromes v1.262 ACTL6B Rebecca Foulger edited their review of gene: ACTL6B: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Genetic epilepsy syndromes v1.262 ALPL Rebecca Foulger commented on gene: ALPL: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 EMX2 Rebecca Foulger commented on gene: EMX2: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 NPRL2 Rebecca Foulger commented on gene: NPRL2: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 KCNMA1 Rebecca Foulger commented on gene: KCNMA1: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 TUBB2A Rebecca Foulger commented on gene: TUBB2A: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 SLC25A12 Rebecca Foulger commented on gene: SLC25A12: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.262 HCN2 Rebecca Foulger commented on gene: HCN2: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Genetic epilepsy syndromes v1.261 ARHGEF9 Helen Lord reviewed gene: ARHGEF9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.261 SLC16A2 Helen Lord reviewed gene: SLC16A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.261 PIGA Helen Lord reviewed gene: PIGA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.261 MED12 Helen Lord reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.261 MAGI2 Helen Lord reviewed gene: MAGI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 IDH2 Helen Lord reviewed gene: IDH2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 CACNA1D Helen Lord reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 NRXN1 Helen Lord reviewed gene: NRXN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 SLC35A2 Helen Lord reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.261 SLC1A2 Helen Lord reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 SLC12A5 Helen Lord reviewed gene: SLC12A5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 IKBKG Helen Lord reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.261 HEPACAM Helen Lord reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 DEAF1 Helen Lord reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 ATRX Helen Lord reviewed gene: ATRX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.261 GRIA2 Helen Lord reviewed gene: GRIA2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 KMT5B Helen Lord reviewed gene: KMT5B: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 KCNH5 Helen Lord reviewed gene: KCNH5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 KCND2 Helen Lord reviewed gene: KCND2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 CSNK2A1 Helen Lord reviewed gene: CSNK2A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 BCORL1 Helen Lord reviewed gene: BCORL1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.261 ZNF142 Helen Lord reviewed gene: ZNF142: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 ZMIZ1 Helen Lord reviewed gene: ZMIZ1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 USP7 Helen Lord reviewed gene: USP7: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 TRRAP Helen Lord reviewed gene: TRRAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 TRPM3 Helen Lord reviewed gene: TRPM3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 SLC35A3 Helen Lord reviewed gene: SLC35A3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 RNF13 Helen Lord reviewed gene: RNF13: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 PAK1 Helen Lord reviewed gene: PAK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 NUS1 Helen Lord reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 LSS Helen Lord reviewed gene: LSS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 FUK Helen Lord reviewed gene: FUK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 CLCN6 Helen Lord reviewed gene: CLCN6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 AIMP2 Helen Lord reviewed gene: AIMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 AFF3 Helen Lord reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 POLG Helen Lord reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 ZDHHC9 Helen Lord reviewed gene: ZDHHC9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.261 WARS2 Helen Lord reviewed gene: WARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 VPS11 Helen Lord reviewed gene: VPS11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 VAMP2 Helen Lord reviewed gene: VAMP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 SNAP25 Helen Lord reviewed gene: SNAP25: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 SMARCC2 Helen Lord reviewed gene: SMARCC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 PPP2CA Helen Lord reviewed gene: PPP2CA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 PIGB Helen Lord reviewed gene: PIGB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 PARS2 Helen Lord reviewed gene: PARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 P4HTM Helen Lord reviewed gene: P4HTM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 NBEA Helen Lord reviewed gene: NBEA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 KMT2E Helen Lord reviewed gene: KMT2E: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 KCNT2 Helen Lord reviewed gene: KCNT2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 DHPS Helen Lord reviewed gene: DHPS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 DEGS1 Helen Lord reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 CTNNA2 Helen Lord reviewed gene: CTNNA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 CACNA1B Helen Lord reviewed gene: CACNA1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 ATN1 Helen Lord reviewed gene: ATN1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 AP2M1 Helen Lord reviewed gene: AP2M1: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 ALKBH8 Helen Lord reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 ACTL6B Helen Lord reviewed gene: ACTL6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 ALPL Helen Lord reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 EMX2 Helen Lord reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 NPRL2 Helen Lord reviewed gene: NPRL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.261 KCNMA1 Helen Lord reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 TUBB2A Helen Lord reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.261 SLC25A12 Helen Lord reviewed gene: SLC25A12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.261 HCN2 Helen Lord reviewed gene: HCN2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.260 KATNB1 Konstantinos Varvagiannis gene: KATNB1 was added
gene: KATNB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KATNB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KATNB1 were set to 25521378; 25521379; 26640080
Phenotypes for gene: KATNB1 were set to Lissencephaly 6, with microcephaly (MIM 616212)
Review for gene: KATNB1 was set to GREEN
Added comment: Biallelic pathogenic KATNB1 variants cause Lissencephaly 6, with microcephaly (MIM 616212). At least 13 affected individuals from 9 (mostly consanguineous) families have probably been reported in the following articles:

- Mishra-Gorur et al. (2014 - PMID: 25521378) [7 individuals from 5 unrelated families]
- Hu et al. (2014 - PMID: 25521379) [5 individuals from 3 families]
- Yigit el al. (2016 - PMID: 26640080) [1 subject born to consanguineous parents]

Seizures can be part of the phenotype (although not universal / reported in all 3 studies in several families). Several different variants have been reported to date. Extensive studies as for the impact of mutations at the cellular level as well as animal models (zebrafish, mouse, drosophila) support involvement of KATNB1. These arguments, provided mainly by the first two studies, are summarized in the respective OMIM entry for the disorder : https://omim.org/entry/616212 (variants and their effect are discussed in the entry for KATNB1 - https://omim.org/entry/602703).

The individual reported by Yigit el al. was a 5 year-old girl with - among others - severely delayed psychomotor development and seizures. The child was found to harbor a homozygous splice site variant (removing the acceptor AG signature). Confirmation of the variant and segregation studies were performed with Sanger sequencing. cDNA studies were carried out and demonstrated aberrant splicing.

KATNB1 is not associated with any disorder in G2P.
The gene is included in panels for ID offered by several diagnostic laboratories (incl. Radboudumc).

As a result, this gene can be considered for inclusion in the current panel probably as green (or amber).
Sources: Literature
Genetic epilepsy syndromes v1.260 PAK1 Konstantinos Varvagiannis edited their review of gene: PAK1: Added comment: Based on a further recent study, PAK1 can probably be upgraded to green in both ID and epilepsy gene panels:

Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al).

PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function.

CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures).

Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel).

4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events:
c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576].

The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67.

The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable).

PAK1 is included in the gene panel for ID offered by Radboudumc.

(Previous review below); Changed rating: GREEN; Changed publications: 30290153, doi.org/10.1093/brain/awz264
Genetic epilepsy syndromes v1.260 GABBR2 Rebecca Foulger Phenotypes for gene: GABBR2 were changed from EPILEPTIC ENCEPHALOPATHY; Rett syndrome to EPILEPTIC ENCEPHALOPATHY; Rett syndrome; Epileptic encephalopathy, early infantile, 59, 617904
Genetic epilepsy syndromes v1.259 GOT2 Catherine Snow Tag treatable tag was added to gene: GOT2.
Tag watchlist tag was added to gene: GOT2.
Genetic epilepsy syndromes v1.259 GOT2 Catherine Snow Classified gene: GOT2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.259 GOT2 Catherine Snow Gene: got2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.258 GOT2 Catherine Snow reviewed gene: GOT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.258 ALPL Rebecca Foulger changed review comment from: PMID:30979546: Whyte et al., 2019 report Vitamin B6-dependent seizures in 10/38 (26%) of patients: 7 patients had documented seizures and 3 patients had a family hisotry of seizures based upon medical records.; to: PMID:30979546: Whyte et al., 2019 report Vitamin B6-dependent seizures in 10/38 (26%) of patients: 7 patients had documented seizures and 3 patients had a family history of seizures based upon medical records.
Genetic epilepsy syndromes v1.258 TRRAP Rebecca Foulger Publications for gene: TRRAP were set to 30827496
Genetic epilepsy syndromes v1.257 TRRAP Rebecca Foulger Added comment: Comment on phenotypes: MIM:603015 is the gene identifier. Therefore updated OMIM phenotype to the disorder identifier (618454) as per Alison Callaway's review.
Genetic epilepsy syndromes v1.257 TRRAP Rebecca Foulger Phenotypes for gene: TRRAP were changed from Microcephaly; Seizures; Abnormal heart morphology; Autism; Developmental delay with or without dysmorphic facies and autism, 603015; Intellectual disability; Abnormality of the urinary system; Global developmental delay to Microcephaly; Seizures; Abnormal heart morphology; Autism; Developmental delay with or without dysmorphic facies and autism, 618454; Intellectual disability; Abnormality of the urinary system; Global developmental delay
Genetic epilepsy syndromes v1.256 KCNMA1 Konstantinos Varvagiannis changed review comment from: In a recent extensive review of the literature, Bailey et al. (2019 - PMID: 31427379) summarize the phenotype of KCNMA1-related channelopathy. Overall the features of 37 subjects with 16 KCNMA1 pathogenic variants are discussed in detail. [An also relevant report by Liang et al. published in 6/2019 - PMID: 31152168 - was also considered for this review].

KCNMA1 encodes the pore-forming α subunit of large-conductance voltage- and Ca(2+)-activated K+ channel (also called BK channel). BK channels have highest expression levels in brain (acting as regulators of neuronal exciatbility) and muscle.

Variants in the review are distinguished in GoF, LoF and VUS (the latter used for variants of unknown/uncharacterized effect on BK channel activity) [NM_002247.3 mentioned as RefSeq]:
- GoF variants included D434G (a variant reported in 13 individuals) and N995S (also reported as N999S or N1053S).
- LoF variants included S351Y, G356R, G375R, N449fs*, I663V, C413Y, P805L, D984N, G354S.
- Uncharacterized variants included R458Ter, Y676Lfs*7 (both presumed to result to LoF), K518N, E656A, N1195S, E884K.

The disorder exhibited in most cases aut. dominant inheritance (either as de novo occurrence of a variant or identification in successive generations), with autosomal recessive inheritance reported in one pedigree (sibs with Y676Lfs*fs) (Tabarki et al. 2016 - PMID: 27567911).

As the authors comment, the hallmark of KCNMA1-related channelopathy is neurological dysfunction incl. seizures, movement disorders, DD and ID.

Epilepsy was a feature in approx. half individuals (18/37) irrespective of mutation type (eg. 9/20 in the case of GoF, 6/13 in LoF variants). Seizure characteristics were highly variable as for the onset, type, EEG pattern, frequency/duration and response to medication. Overlapping types were noted for GoF and LoF mutations incl. myoclonic, GTCS, absence seizures with few being more frequent or specific in certain mutation types.

Individuals with the same variant may present or not certain features eg. 6/13 members of a large family with D434G or 3/7 (all unrelated) individuals with N1053S developed epilepsy.

Animal studies support a role for both LoF and GoF alterations in BK channel activity as for the seizures, with more solid evidence/correlation with GoF mutations. (Other phenotypes eg. movement disorders are also supported by animal models).

Similarly developmental delay has been reported in 21/37 individuals and intellectual disability in 12/37 (both GoF and LoF) with severe presentation in certain cases (eg. in 3 individuals with G375R) while on several occasions severity (or presence of this feature(?)) has probably not been commented on.

The KCNMA1-related disorders in OMIM are the following:
?Cerebellar atrophy, developmental delay, and seizures, 617643 (AR)
Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 (AD)

KCNMA1 is part of the DD panel of G2P associated with Generalized epilepsy and paroxysmal dyskinesia (monoallelic, activating mutations / disease confidence : possible).

KCNMA1 is included in several gene panels for epilepsy incl. those of Radboudumc and Victorian Clinical Genetics and several other panels summarized in the supplement of the review. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

As a result upgrade to green rating can be considered for the epilepsy panel. The gene could possibly be upgraded to amber (or green) in the ID panel, too.; to: In a recent extensive review of the literature, Bailey et al. (2019 - PMID: 31427379) summarize the phenotype of KCNMA1-related channelopathy. Overall the features of 37 subjects with 16 KCNMA1 pathogenic variants are discussed in detail. [An also relevant report by Liang et al. published in 6/2019 - PMID: 31152168 - was also considered for this review].

KCNMA1 encodes the pore-forming α subunit of large-conductance voltage- and Ca(2+)-activated K+ channel (also called BK channel). BK channels have highest expression levels in brain (acting as regulators of neuronal exciatbility) and muscle.

Variants in the review are distinguished in GoF, LoF and VUS (the latter used for variants of unknown/uncharacterized effect on BK channel activity) [NM_002247.3 mentioned as RefSeq]:
- GoF variants included D434G (a variant reported in 13 individuals) and N995S (also reported as N999S or N1053S).
- LoF variants included S351Y, G356R, G375R, N449fs*, I663V, C413Y, P805L, D984N, G354S.
- Uncharacterized variants included R458Ter, Y676Lfs*7 (both presumed to result to LoF), K518N, E656A, N1195S, E884K.

The disorder exhibited in most cases aut. dominant inheritance (either as de novo occurrence of a variant or identification in successive generations), with autosomal recessive inheritance reported in one pedigree (sibs with Y676Lfs*fs) (Tabarki et al. 2016 - PMID: 27567911).

As the authors comment, the hallmark of KCNMA1-related channelopathy is neurological dysfunction incl. seizures, movement disorders, DD and ID.

Epilepsy was a feature in approx. half individuals (18/37) irrespective of mutation type (eg. 9/20 in the case of GoF, 6/13 in LoF variants). Seizure characteristics were highly variable as for the onset, type, EEG pattern, frequency/duration and response to medication. Overlapping types were noted for GoF and LoF mutations incl. myoclonic, GTCS, absence seizures with few being more frequent or specific in certain mutation types.

Individuals with the same variant may present or not certain features eg. 6/13 members of a large family with D434G or 3/7 (all unrelated) individuals with N1053S developed epilepsy.

Animal studies support a role for both LoF and GoF alterations in BK channel activity as for the seizures, with more solid evidence/correlation with GoF mutations. (Other phenotypes eg. movement disorders are also supported by animal models).

Similarly developmental delay has been reported in 21/37 individuals and intellectual disability in 12/37 (both GoF and LoF) with severe presentation in certain cases (eg. in 3 individuals with G375R) while on several occasions severity (or presence of this feature(?)) has probably not been commented on.

The KCNMA1-related disorders in OMIM are the following :
?Cerebellar atrophy, developmental delay, and seizures, 617643 (AR)
Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 (AD)

KCNMA1 is part of the DD panel of G2P associated with Generalized epilepsy and paroxysmal dyskinesia (monoallelic, activating mutations / disease confidence : possible).

KCNMA1 is included in several gene panels for epilepsy incl. those of Radboudumc and Victorian Clinical Genetics and several other panels summarized in the supplement of the review. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

As a result upgrade to green rating can be considered for the epilepsy panel. The gene could possibly be upgraded to amber (or green) in the ID panel, too.
Genetic epilepsy syndromes v1.256 HNRNPR Konstantinos Varvagiannis gene: HNRNPR was added
gene: HNRNPR was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPR were set to 31079900; 26795593
Phenotypes for gene: HNRNPR were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit
Penetrance for gene: HNRNPR were set to unknown
Review for gene: HNRNPR was set to AMBER
Added comment: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures (4/5), brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (seizures in 4/5) or green.
Sources: Literature
Genetic epilepsy syndromes v1.256 GOT2 Konstantinos Varvagiannis gene: GOT2 was added
gene: GOT2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GOT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOT2 were set to 31422819
Phenotypes for gene: GOT2 were set to Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology
Penetrance for gene: GOT2 were set to Complete
Review for gene: GOT2 was set to GREEN
Added comment: van Karnebeek et al. (2019 - PMID: 31422819) report on 4 individuals from 3 families, with biallelic GOT2 pathogenic variants (3 missense SNVs and 1 in-frame deletion).

The phenotype corresponded to a metabolic encephalopathy with onset of epilepsy in the first year of life (4/4) with DD and ID (4/4). Additional features included postnatal microcephaly, failure to thrive/feeding difficulties and cerebral anomalies (atrophy and white matter). All subjects had high blood lactate and hyperammonemia. Plasma serine was low in one case (alternative causes were ruled out).

Administration of serine and pyridoxine led to clinical improvement (cessation / better control of seizures) in 2 subjects suggesting that GOT2 deficiency may be amenable to therapeutic intervention. [Treatment could not be started in the 2 further affected individuals].

GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase, a component of the malate-aspartate shuttle (MAS). The latter is important for intracellular NAD(H) redox homeostasis.

The authors provide several lines of evidence that GOT2 deficiency explains the patients' phenotype and metabolic defects incl. :
- Reduced GOT2 protein levels (due to lower expression/impaired stability) and diminished activity in patient fibroblasts (lower activity was also shown for carriers). Rescue of the GOT enzymatic activity was observed upon transduction of patient fibroblasts using lentiviral particles with wt GOT2.
- Impairment of de novo serine biosynthesis in patient (and to a lesser extent in carrier) fibroblasts compared to controls. This was similar in GOT2-knockout HEK293 cells. Serine biosynthesis in these cells was restored by pyruvate supplementation.
- CRISPR/Cas9 Got2-knockout mice resulted in early lethality (during pregnancy). Heterozygous mice were viable and healthy.
- Morpholino knockdown of got2a in zebrafish was shown to perturb embryonic development (smaller head, slow circulation, bend body, brain developmental defects, etc). Pyridoxine and serine in embryo water resulted in milder phenotypes/improved morphant survival. Zebrafish got2a morphants had seizure-like spikes upon EEG that were rescued by treatment with pyridoxine.

GOT2 is not associated with any phenotype in OMIM/G2P.

As a result, this gene can be considered for inclusion in both epilepsy and ID gene panels probably as green (3 families, relevant phenotypes and severity, evidence from cell and animal studies) or amber.

[Please consider inclusion in other relevant panels eg. mitochondrial disorders, metabolic disorders and/or addition of the 'treatable' tag].
Sources: Literature
Genetic epilepsy syndromes v1.256 TRAPPC6B Konstantinos Varvagiannis reviewed gene: TRAPPC6B: Rating: AMBER; Mode of pathogenicity: None; Publications: 28626029, 28397838, DOI 10.1055/s-0039-1693664; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.256 KCNMA1 Konstantinos Varvagiannis reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31427379, 31152168, 27567911; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic epilepsy syndromes v1.256 KCND2 Alison Callaway reviewed gene: KCND2: Rating: RED; Mode of pathogenicity: None; Publications: 16934482; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 CSNK2A1 Alison Callaway reviewed gene: CSNK2A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27048600; Phenotypes: Neurodevelopmental abnormalities and dysmorphic features; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 ZNF142 Alison Callaway reviewed gene: ZNF142: Rating: AMBER; Mode of pathogenicity: None; Publications: 31036918; Phenotypes: NEURODEVELOPMENTAL DISORDER WITH IMPAIRED SPEECH AND HYPERKINETIC MOVEMENTS; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 USP7 Alison Callaway reviewed gene: USP7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 TRRAP Alison Callaway reviewed gene: TRRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 28628100, 30827496; Phenotypes: DEVELOPMENTAL DELAY WITH OR WITHOUT DYSMORPHIC FACIES AND AUTISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.256 TRPM3 Alison Callaway reviewed gene: TRPM3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29156220; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 CLCN6 Alison Callaway reviewed gene: CLCN6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 AIMP2 Alison Callaway reviewed gene: AIMP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26795593; Phenotypes: Epileptic Encephalopathy, Infantile Spasms; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.256 AFF3 Alison Callaway reviewed gene: AFF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 ALPL Alison Callaway changed review comment from: Epilepsy can be associated with hypophosphasia; no further literature identified. From reviews below, appears to have sufficient evidence for a green gene.; to: Epilepsy can be associated with hypophosphatasia; no further literature identified. From reviews below, appears to have sufficient evidence for a green gene.
Genetic epilepsy syndromes v1.256 ALPL Alison Callaway reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 EMX2 Alison Callaway reviewed gene: EMX2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 NPRL2 Alison Callaway reviewed gene: NPRL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 KCNMA1 Alison Callaway reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29933521; Phenotypes: Generalised epilepsy and paroxysmal dyskinesia; Mode of inheritance: None
Genetic epilepsy syndromes v1.256 TUBB2A Alison Callaway reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24702957; Phenotypes: CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.256 SLC25A12 Alison Callaway reviewed gene: SLC25A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 19641205, 24515575, 27290639, 26633542; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.256 HCN2 Alison Callaway reviewed gene: HCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29064616, 22131395; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.256 HCN2 Alison Callaway Deleted their review
Genetic epilepsy syndromes v1.256 HCN2 Alison Callaway reviewed gene: HCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29064616, 22131395; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v1.256 SPATA5 Sarah Leigh Publications for gene: SPATA5 were set to PMID: 27246907; 29343804; 26299366
Genetic epilepsy syndromes v1.255 SPATA5 Sarah Leigh Classified gene: SPATA5 as Green List (high evidence)
Genetic epilepsy syndromes v1.255 SPATA5 Sarah Leigh Added comment: Comment on list classification: Based on review from Rachel Jones (GSTT): Tanaka et al PMID: 26299366 identified "14 individuals [from 10 families] with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants" in SPATA5 Puussep et al PMID: 29343804 describes 5 further patients "with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene" Szczaluba et al PMID: 28293831 describes a family where a sibling has isolated sensorineural hearing loss and the same two pathogenic SPATA5 variants as her more typically affected sister. In addition, typically affected individuals may present as congenital SNHL on newborn hearing screen prior to onset of seizures, microcephaly and intellectual disability.
Genetic epilepsy syndromes v1.255 SPATA5 Sarah Leigh Gene: spata5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.254 SPATA5 Rachel Jones gene: SPATA5 was added
gene: SPATA5 was added to Genetic epilepsy syndromes. Sources: Other
Mode of inheritance for gene: SPATA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5 were set to PMID: 27246907; 29343804; 26299366
Phenotypes for gene: SPATA5 were set to Epilepsy, hearing loss, and mental retardation syndrome 616577
Penetrance for gene: SPATA5 were set to Incomplete
Review for gene: SPATA5 was set to GREEN
Added comment: Greater than 15 families have been identified in multiple publications showing that patients with SPATA5 biallelic variants present with intellectual disability, epilepsy, microcephaly and hearing loss. May present as epileptic encephalopathy/epilepsy in the first year of life prior to onset of obvious developmental delay.
Sources: Other
Genetic epilepsy syndromes v1.254 SLC2A1 Ellen McDonagh edited their review of gene: SLC2A1: Added comment: Added the tag 'treatable' as a ketogenic diet can help ameloriate symptoms (PMID: 29303961).; Changed publications: 29303961
Genetic epilepsy syndromes v1.254 SLC2A1 Ellen McDonagh Tag treatable tag was added to gene: SLC2A1.
Genetic epilepsy syndromes v1.254 KMT2E Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Genetic epilepsy syndromes v1.254 KMT2E Louise Daugherty Phenotypes for gene: KMT2E were changed from Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size to O'Donnell-Luria-Rodan syndrome, 618512; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size
Genetic epilepsy syndromes v1.253 CACNA1B Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Genetic epilepsy syndromes v1.253 CACNA1B Louise Daugherty Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia to Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, 618497; Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia
Genetic epilepsy syndromes v1.252 ISCA-46290-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-46290-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-46290-Gain.
Genetic epilepsy syndromes v1.251 ISCA-37493-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37493-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37493-Loss.
Genetic epilepsy syndromes v1.250 ISCA-37478-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37478-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37478-Loss.
Genetic epilepsy syndromes v1.249 ISCA-37478-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-37478-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-37478-Gain.
Genetic epilepsy syndromes v1.248 ISCA-37434-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37434-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37434-Loss.
Genetic epilepsy syndromes v1.247 ISCA-37432-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-37432-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-37432-Gain.
Genetic epilepsy syndromes v1.246 ISCA-37430-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37430-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37430-Loss.
Genetic epilepsy syndromes v1.245 ISCA-37429-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37429-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37429-Loss.
Genetic epilepsy syndromes v1.244 ISCA-37423-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-37423-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-37423-Gain.
Genetic epilepsy syndromes v1.243 ISCA-37415-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37415-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37415-Loss.
Genetic epilepsy syndromes v1.242 ISCA-37411-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37411-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37411-Loss.
Genetic epilepsy syndromes v1.241 ISCA-37404-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37404-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37404-Loss.
Genetic epilepsy syndromes v1.240 ISCA-46295-Loss Rebecca Foulger Triplosensitivity Score for ISCA-46295-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-46295-Loss.
Genetic epilepsy syndromes v1.239 ISCA-46295-Loss Rebecca Foulger commented on Region: ISCA-46295-Loss
Genetic epilepsy syndromes v1.239 ISCA-46290-Gain Rebecca Foulger commented on Region: ISCA-46290-Gain
Genetic epilepsy syndromes v1.239 ISCA-37493-Loss Rebecca Foulger reviewed Region: ISCA-37493-Loss: Rating: ; Mode of pathogenicity: None; Publications: 28283832; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.239 ISCA-37478-Loss Rebecca Foulger commented on Region: ISCA-37478-Loss
Genetic epilepsy syndromes v1.239 ISCA-37478-Gain Rebecca Foulger commented on Region: ISCA-37478-Gain
Genetic epilepsy syndromes v1.239 ISCA-37434-Loss Rebecca Foulger commented on Region: ISCA-37434-Loss
Genetic epilepsy syndromes v1.239 ISCA-37432-Gain Rebecca Foulger commented on Region: ISCA-37432-Gain
Genetic epilepsy syndromes v1.239 ISCA-37430-Loss Rebecca Foulger commented on Region: ISCA-37430-Loss
Genetic epilepsy syndromes v1.239 ISCA-37429-Loss Rebecca Foulger commented on Region: ISCA-37429-Loss
Genetic epilepsy syndromes v1.239 ISCA-37415-Loss Rebecca Foulger reviewed Region: ISCA-37415-Loss: Rating: ; Mode of pathogenicity: None; Publications: 10573006; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.239 ISCA-37423-Gain Rebecca Foulger reviewed Region: ISCA-37423-Gain: Rating: ; Mode of pathogenicity: None; Publications: 28533195; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.239 ISCA-37411-Loss Rebecca Foulger reviewed Region: ISCA-37411-Loss: Rating: ; Mode of pathogenicity: None; Publications: 19289393; Phenotypes: ; Mode of inheritance: None
Genetic epilepsy syndromes v1.239 ISCA-37404-Loss Rebecca Foulger commented on Region: ISCA-37404-Loss
Genetic epilepsy syndromes v1.239 GATM Rebecca Foulger Phenotypes for gene: GATM were changed from to Cerebral creatine deficiency syndrome 3, 612718
Genetic epilepsy syndromes v1.238 GATM Rebecca Foulger Mode of inheritance for gene: GATM was changed from to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.237 GATM Rebecca Foulger Publications for gene: GATM were set to
Genetic epilepsy syndromes v1.236 SETD5 Rebecca Foulger changed review comment from: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although four reviewers agreed it should be on EE panel, there is limited evidence of a seizure phenotype. PMID:26482601: (Kobayashi et al., 2016) examined 11 patients with early-onset epileptic encephalopathy, and SETD5 variants were amongst the findings. Therefore awaited clinical input on whether SETD5 should be demoted on this panel.; to: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: although four reviewers agreed it should be on EE panel, there is limited evidence of a seizure phenotype. PMID:26482601: (Kobayashi et al., 2016) examined 11 patients with early-onset epileptic encephalopathy, and SETD5 variants were amongst the findings. Therefore consider demoting SETD5.
Genetic epilepsy syndromes v1.236 LYST Rebecca Foulger changed review comment from: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the mouse model displays seizures (PMID:16518687), there is limited evidence of patients with seizures (no mention of seizures in PMID:9215679, and one 1990 report of Chédiak-Higashi syndrome with seizures from PMID:10450360). Therefore awaiting clinical opinion on whether LYST should be demoted on this panel.; to: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: although the mouse model displays seizures (PMID:16518687), there is limited evidence of patients with seizures (no mention of seizures in PMID:9215679, and one 1990 report of Chédiak-Higashi syndrome with seizures from PMID:10450360). Therefore consider demoting LYST.
Genetic epilepsy syndromes v1.236 KIF1BP Rebecca Foulger changed review comment from: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the association with GOLDBERG-SHPRINTZEN MEGACOLON SYNDROME is strong, there is little direct evidence for seizures (PMID:28277559 identifies one case). Therefore awaiting clinical opinion on whether KIF1BP should be demoted.; to: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: although the association with GOLDBERG-SHPRINTZEN MEGACOLON SYNDROME is strong, there is little direct evidence for seizures (PMID:28277559 identifies one case). Therefore consider demoting KIF1BP.
Genetic epilepsy syndromes v1.236 AKT1 Rebecca Foulger Marked gene: AKT1 as ready
Genetic epilepsy syndromes v1.236 AKT1 Rebecca Foulger Gene: akt1 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.236 PTEN Rebecca Foulger Marked gene: PTEN as ready
Genetic epilepsy syndromes v1.236 PTEN Rebecca Foulger Gene: pten has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.236 PIK3CA Rebecca Foulger Marked gene: PIK3CA as ready
Genetic epilepsy syndromes v1.236 PIK3CA Rebecca Foulger Gene: pik3ca has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.236 PIK3CA Rebecca Foulger Classified gene: PIK3CA as Red List (low evidence)
Genetic epilepsy syndromes v1.236 PIK3CA Rebecca Foulger Gene: pik3ca has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.235 PIK3CA Rebecca Foulger commented on gene: PIK3CA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote PIK3CA from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Genetic epilepsy syndromes v1.235 PTEN Rebecca Foulger commented on gene: PTEN: Added tags: 'mosaicism' and 'somatic'.
Genetic epilepsy syndromes v1.235 PTEN Rebecca Foulger Classified gene: PTEN as Red List (low evidence)
Genetic epilepsy syndromes v1.235 PTEN Rebecca Foulger Gene: pten has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.234 PTEN Rebecca Foulger commented on gene: PTEN: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote AKT1 from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Genetic epilepsy syndromes v1.234 PTEN Rebecca Foulger Tag mosaicism tag was added to gene: PTEN.
Tag somatic tag was added to gene: PTEN.
Genetic epilepsy syndromes v1.234 AKT1 Rebecca Foulger Classified gene: AKT1 as Red List (low evidence)
Genetic epilepsy syndromes v1.234 AKT1 Rebecca Foulger Gene: akt1 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v1.233 AKT1 Rebecca Foulger commented on gene: AKT1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote AKT1 from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Genetic epilepsy syndromes v1.233 WDR37 Rebecca Foulger Marked gene: WDR37 as ready
Genetic epilepsy syndromes v1.233 WDR37 Rebecca Foulger Gene: wdr37 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.233 PEX5 Rebecca Foulger Marked gene: PEX5 as ready
Genetic epilepsy syndromes v1.233 PEX5 Rebecca Foulger Gene: pex5 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.233 KIAA1109 Rebecca Foulger Marked gene: KIAA1109 as ready
Genetic epilepsy syndromes v1.233 KIAA1109 Rebecca Foulger Gene: kiaa1109 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.233 GTPBP3 Rebecca Foulger Marked gene: GTPBP3 as ready
Genetic epilepsy syndromes v1.233 GTPBP3 Rebecca Foulger Gene: gtpbp3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.233 EIF2B3 Rebecca Foulger Marked gene: EIF2B3 as ready
Genetic epilepsy syndromes v1.233 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.233 EIF2B1 Rebecca Foulger Marked gene: EIF2B1 as ready
Genetic epilepsy syndromes v1.233 EIF2B1 Rebecca Foulger Gene: eif2b1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.233 EFHC1 Rebecca Foulger Marked gene: EFHC1 as ready
Genetic epilepsy syndromes v1.233 EFHC1 Rebecca Foulger Gene: efhc1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.233 DPM2 Rebecca Foulger Marked gene: DPM2 as ready
Genetic epilepsy syndromes v1.233 DPM2 Rebecca Foulger Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.233 CUL4B Rebecca Foulger Marked gene: CUL4B as ready
Genetic epilepsy syndromes v1.233 CUL4B Rebecca Foulger Gene: cul4b has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.233 CNPY3 Rebecca Foulger Marked gene: CNPY3 as ready
Genetic epilepsy syndromes v1.233 CNPY3 Rebecca Foulger Gene: cnpy3 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.233 PTS Rebecca Foulger Marked gene: PTS as ready
Genetic epilepsy syndromes v1.233 PTS Rebecca Foulger Gene: pts has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.233 PTS Rebecca Foulger Classified gene: PTS as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.233 PTS Rebecca Foulger Gene: pts has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.232 PTS Rebecca Foulger commented on gene: PTS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber to match the rating on the 'Inborn errors of metabolism' panel. The prevailing phenotype is a movement disorder. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.232 PTS Rebecca Foulger commented on gene: PTS: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: Severe Hyperphenylalaninemia, BH4-deficient, is accepted to include seizures (PMID:8801112). Because this condition is diagnosed and treated from an early age, seizures may not be reported frequently. PMID:31000854 (Ahmed et al., 2019)assessed hyperphenylalaninemia patients and found 14/18 (78%) had seizures and ID however genetic analysis to see which of these had PTPS/PTS variants was not performed. PMID:9222757 report 1 case of seizures.
Genetic epilepsy syndromes v1.232 KCNA1 Rebecca Foulger Marked gene: KCNA1 as ready
Genetic epilepsy syndromes v1.232 KCNA1 Rebecca Foulger Gene: kcna1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.232 KCNA1 Rebecca Foulger commented on gene: KCNA1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Genetic epilepsy syndromes v1.232 WDR62 Rebecca Foulger Marked gene: WDR62 as ready
Genetic epilepsy syndromes v1.232 WDR62 Rebecca Foulger Gene: wdr62 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.232 WDR62 Rebecca Foulger Classified gene: WDR62 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.232 WDR62 Rebecca Foulger Gene: wdr62 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.231 WDR62 Rebecca Foulger commented on gene: WDR62: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber- the microcephaly panels are more appropriate for testing. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.231 TSEN2 Rebecca Foulger Marked gene: TSEN2 as ready
Genetic epilepsy syndromes v1.231 TSEN2 Rebecca Foulger Gene: tsen2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.231 TSEN2 Rebecca Foulger Classified gene: TSEN2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.231 TSEN2 Rebecca Foulger Gene: tsen2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.230 TSEN2 Rebecca Foulger commented on gene: TSEN2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber because epilepsy is unlikely to be the primary presenting feature. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.230 SCN9A Rebecca Foulger Marked gene: SCN9A as ready
Genetic epilepsy syndromes v1.230 SCN9A Rebecca Foulger Gene: scn9a has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.230 SCN9A Rebecca Foulger commented on gene: SCN9A: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Genetic epilepsy syndromes v1.230 FLNA Rebecca Foulger Marked gene: FLNA as ready
Genetic epilepsy syndromes v1.230 FLNA Rebecca Foulger Gene: flna has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.230 FLNA Rebecca Foulger commented on gene: FLNA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Genetic epilepsy syndromes v1.230 FGFR3 Rebecca Foulger Classified gene: FGFR3 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.230 FGFR3 Rebecca Foulger Gene: fgfr3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.229 FGFR3 Rebecca Foulger Marked gene: FGFR3 as ready
Genetic epilepsy syndromes v1.229 FGFR3 Rebecca Foulger Gene: fgfr3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.229 FGFR3 Rebecca Foulger Classified gene: FGFR3 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.229 FGFR3 Rebecca Foulger Gene: fgfr3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.228 FGFR3 Rebecca Foulger commented on gene: FGFR3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber because the Craniosynostosis panel is more appropriate for testing. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.228 ATP1A2 Rebecca Foulger Marked gene: ATP1A2 as ready
Genetic epilepsy syndromes v1.228 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.228 ATP1A2 Rebecca Foulger commented on gene: ATP1A2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Genetic epilepsy syndromes v1.228 LYST Rebecca Foulger Marked gene: LYST as ready
Genetic epilepsy syndromes v1.228 LYST Rebecca Foulger Gene: lyst has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.228 SETD5 Rebecca Foulger Marked gene: SETD5 as ready
Genetic epilepsy syndromes v1.228 SETD5 Rebecca Foulger Gene: setd5 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.228 WDR45B Rebecca Foulger Marked gene: WDR45B as ready
Genetic epilepsy syndromes v1.228 WDR45B Rebecca Foulger Gene: wdr45b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.228 WDR45B Rebecca Foulger Classified gene: WDR45B as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.228 WDR45B Rebecca Foulger Gene: wdr45b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.227 WDR45B Rebecca Foulger commented on gene: WDR45B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.227 WDR45B Rebecca Foulger commented on gene: WDR45B: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary, the evidence is borderline: PMID:28503735 (Suleiman et al) report 6 individuals from 3 families with homozygous pathogenic variants in WDR45B, and 2 of the families (5 indivs) had seizures- seizures were not reported in the sole individual from family 3.
Genetic epilepsy syndromes v1.227 SETD5 Rebecca Foulger Classified gene: SETD5 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.227 SETD5 Rebecca Foulger Gene: setd5 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.226 SETD5 Rebecca Foulger commented on gene: SETD5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.226 SETD5 Rebecca Foulger commented on gene: SETD5: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although four reviewers agreed it should be on EE panel, there is limited evidence of a seizure phenotype. PMID:26482601: (Kobayashi et al., 2016) examined 11 patients with early-onset epileptic encephalopathy, and SETD5 variants were amongst the findings. Therefore awaited clinical input on whether SETD5 should be demoted on this panel.
Genetic epilepsy syndromes v1.226 LYST Rebecca Foulger Classified gene: LYST as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.226 LYST Rebecca Foulger Gene: lyst has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.225 LYST Rebecca Foulger commented on gene: LYST: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.225 LYST Rebecca Foulger commented on gene: LYST: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the mouse model displays seizures (PMID:16518687), there is limited evidence of patients with seizures (no mention of seizures in PMID:9215679, and one 1990 report of Chédiak-Higashi syndrome with seizures from PMID:10450360). Therefore awaiting clinical opinion on whether LYST should be demoted on this panel.
Genetic epilepsy syndromes v1.225 KIF1BP Rebecca Foulger Marked gene: KIF1BP as ready
Genetic epilepsy syndromes v1.225 KIF1BP Rebecca Foulger Gene: kif1bp has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.225 KIF1BP Rebecca Foulger Classified gene: KIF1BP as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.225 KIF1BP Rebecca Foulger Gene: kif1bp has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.224 KIF1BP Rebecca Foulger commented on gene: KIF1BP: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Genetic epilepsy syndromes v1.224 KIF1BP Rebecca Foulger commented on gene: KIF1BP: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the association with GOLDBERG-SHPRINTZEN MEGACOLON SYNDROME is strong, there is little direct evidence for seizures (PMID:28277559 identifies one case). Therefore awaiting clinical opinion on whether KIF1BP should be demoted.
Genetic epilepsy syndromes v1.224 GRIA2 Rebecca Foulger changed review comment from: PMID:8938126 (animal model): GluR2 heterozygous (+/−) mice showed reduced motor coordination but no sign of seizure activity as measured by observation, EEG, or post-mortem analysis.; to: PMID:8938126- animal model doesn't report seizures: GluR2 heterozygous (+/−) mice showed reduced motor coordination but no sign of seizure activity as measured by observation, EEG, or post-mortem analysis.
Genetic epilepsy syndromes v1.224 WDR37 Rebecca Foulger Classified gene: WDR37 as Green List (high evidence)
Genetic epilepsy syndromes v1.224 WDR37 Rebecca Foulger Gene: wdr37 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.223 WDR37 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Grey to Green.
Genetic epilepsy syndromes v1.223 WDR37 Rebecca Foulger commented on gene: WDR37: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green.
Genetic epilepsy syndromes v1.223 WDR37 Rebecca Foulger commented on gene: WDR37: WDR37 was added to the panel and rated Green by Konstantinos Varvagiannis. Although WDR37 is not yet associated with a disorder in OMIM or Gene2Phenotype, (as Konstantinos notes) there are sufficient unrelated cases from PMID:31327510 and PMID:31327508 with seizures (all 9 patients) for inclusion on the panel.
Genetic epilepsy syndromes v1.223 WDR37 Rebecca Foulger changed review comment from: Added missense tag: only missense variants reported so far (PMID:31327510).; to: Added missense tag: only missense variants reported so far (PMIDs 31327510, 31327508).
Genetic epilepsy syndromes v1.223 WDR37 Rebecca Foulger commented on gene: WDR37
Genetic epilepsy syndromes v1.223 WDR37 Rebecca Foulger Tag missense tag was added to gene: WDR37.
Genetic epilepsy syndromes v1.223 PIGU Rebecca Foulger Marked gene: PIGU as ready
Genetic epilepsy syndromes v1.223 PIGU Rebecca Foulger Gene: pigu has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.223 PIGH Rebecca Foulger Marked gene: PIGH as ready
Genetic epilepsy syndromes v1.223 PIGH Rebecca Foulger Gene: pigh has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.223 PIGC Rebecca Foulger Marked gene: PIGC as ready
Genetic epilepsy syndromes v1.223 PIGC Rebecca Foulger Gene: pigc has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.223 RRM2B Rebecca Foulger Marked gene: RRM2B as ready
Genetic epilepsy syndromes v1.223 RRM2B Rebecca Foulger Gene: rrm2b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.223 TRAF7 Rebecca Foulger Marked gene: TRAF7 as ready
Genetic epilepsy syndromes v1.223 TRAF7 Rebecca Foulger Gene: traf7 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.223 TRAPPC12 Rebecca Foulger Marked gene: TRAPPC12 as ready
Genetic epilepsy syndromes v1.223 TRAPPC12 Rebecca Foulger Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.223 TRAPPC6B Rebecca Foulger Marked gene: TRAPPC6B as ready
Genetic epilepsy syndromes v1.223 TRAPPC6B Rebecca Foulger Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.223 GNB5 Rebecca Foulger Marked gene: GNB5 as ready
Genetic epilepsy syndromes v1.223 GNB5 Rebecca Foulger Gene: gnb5 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.223 GNB5 Rebecca Foulger commented on gene: GNB5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green.
Genetic epilepsy syndromes v1.223 TRAPPC6B Rebecca Foulger commented on gene: TRAPPC6B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber.
Genetic epilepsy syndromes v1.223 TRAPPC12 Rebecca Foulger commented on gene: TRAPPC12: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber:
Genetic epilepsy syndromes v1.223 TRAF7 Rebecca Foulger commented on gene: TRAF7: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: TRAF7 is Green on the Intellectual disability and Paediatric disorders panels, which would be appropriate for the presenting phenotype.
Genetic epilepsy syndromes v1.223 RRM2B Rebecca Foulger commented on gene: RRM2B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: RRM2B is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Genetic epilepsy syndromes v1.223 PIGU Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Grey to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Grey to Green.
Genetic epilepsy syndromes v1.223 PIGH Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.223 PIGC Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.223 PEX5 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: PEX5 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: PEX5 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Genetic epilepsy syndromes v1.223 KIAA1109 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green- although epilepsy may be secondary to the cerebral malformations presentation, include KIAA1109 so that cases recruited through different routes are not missed. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green- although epilepsy may be secondary to the cerebral malformations presentation, include KIAA1109 so that cases recruited through different routes are not missed. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.223 EIF2B3 Rebecca Foulger Classified gene: EIF2B3 as Green List (high evidence)
Genetic epilepsy syndromes v1.223 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.222 EIF2B3 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.222 EIF2B1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.222 EFHC1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene should remain as Amber: EFHC1 may be a susceptibility locus. Currently insufficient evidence to support a monogenic association with epilepsy.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should remain as Amber: EFHC1 may be a susceptibility locus. Currently insufficient evidence to support a monogenic association with epilepsy.
Genetic epilepsy syndromes v1.222 DPM2 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: DPM2 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: DPM2 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Genetic epilepsy syndromes v1.222 CUL4B Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.222 CNPY3 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Helen Lord (Oxford Medical Genetics Laboratories) notes that there are two further 2019 paper supporting inclusion. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Helen Lord (Oxford Medical Genetics Laboratories) notes that there are two further 2019 paper supporting inclusion. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.222 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Genetic epilepsy syndromes v1.221 PIGU Rebecca Foulger Classified gene: PIGU as Green List (high evidence)
Genetic epilepsy syndromes v1.221 PIGU Rebecca Foulger Gene: pigu has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.220 PIGU Rebecca Foulger commented on gene: PIGU: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Grey to Green.
Genetic epilepsy syndromes v1.220 PIGU Rebecca Foulger changed review comment from: PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures (myoclonic and focal myoclonic in all 5 probands), brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).; to: PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures (myoclonic/focal myoclonic in all 5 probands), brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).
Genetic epilepsy syndromes v1.220 PIGU Rebecca Foulger commented on gene: PIGU: PIGU is not yet associated with a disorder in OMIM or Gene2Phenotype.
Genetic epilepsy syndromes v1.220 PIGU Rebecca Foulger commented on gene: PIGU: PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures (myoclonic and focal myoclonic in all 5 probands), brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).
Genetic epilepsy syndromes v1.220 PIGH Rebecca Foulger Classified gene: PIGH as Green List (high evidence)
Genetic epilepsy syndromes v1.220 PIGH Rebecca Foulger Gene: pigh has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.219 PIGH Rebecca Foulger commented on gene: PIGH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.219 PIGC Rebecca Foulger Classified gene: PIGC as Green List (high evidence)
Genetic epilepsy syndromes v1.219 PIGC Rebecca Foulger Gene: pigc has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.218 PIGC Rebecca Foulger commented on gene: PIGC: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.218 PEX5 Rebecca Foulger commented on gene: PEX5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: PEX5 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Genetic epilepsy syndromes v1.218 KIAA1109 Rebecca Foulger Classified gene: KIAA1109 as Green List (high evidence)
Genetic epilepsy syndromes v1.218 KIAA1109 Rebecca Foulger Gene: kiaa1109 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.217 KIAA1109 Rebecca Foulger commented on gene: KIAA1109: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green- although epilepsy may be secondary to the cerebral malformations presentation, include KIAA1109 so that cases recruited through different routes are not missed. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.217 GTPBP3 Rebecca Foulger commented on gene: GTPBP3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: GTPBP3 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Genetic epilepsy syndromes v1.217 EIF2B3 Rebecca Foulger Classified gene: EIF2B3 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.217 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.216 EIF2B3 Rebecca Foulger commented on gene: EIF2B3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.216 EIF2B1 Rebecca Foulger Classified gene: EIF2B1 as Green List (high evidence)
Genetic epilepsy syndromes v1.216 EIF2B1 Rebecca Foulger Gene: eif2b1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.215 EIF2B1 Rebecca Foulger commented on gene: EIF2B1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.215 EFHC1 Rebecca Foulger commented on gene: EFHC1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene should remain as Amber: EFHC1 may be a susceptibility locus. Currently insufficient evidence to support a monogenic association with epilepsy.
Genetic epilepsy syndromes v1.215 DPM2 Rebecca Foulger commented on gene: DPM2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: DPM2 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Genetic epilepsy syndromes v1.215 CUL4B Rebecca Foulger Classified gene: CUL4B as Green List (high evidence)
Genetic epilepsy syndromes v1.215 CUL4B Rebecca Foulger Gene: cul4b has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.214 CUL4B Rebecca Foulger commented on gene: CUL4B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.214 CNPY3 Rebecca Foulger Classified gene: CNPY3 as Green List (high evidence)
Genetic epilepsy syndromes v1.214 CNPY3 Rebecca Foulger Gene: cnpy3 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v1.213 CNPY3 Rebecca Foulger commented on gene: CNPY3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Helen Lord (Oxford Medical Genetics Laboratories) notes that there are two further 2019 paper supporting inclusion. Promoted from Amber to Green.
Genetic epilepsy syndromes v1.213 NPRL2 Rebecca Foulger commented on gene: NPRL2: NPRL2 re-reviewed for curation of GMS epilepsy panel: Sufficient cases for inclusion but variants in unaffected family members (explained by the authors as incomplete penetrance). Other members of the complex, NPRL3 and DEPDC5, are Green on the panel. Since the last curation there has been a Green review by Deb Pal (Kings College London): PMID:30093711 (2019) note 3 further probands with epilepsy (including 1 with infantile spasm and unclear effect on the protein). They also note incomplete penetrance for variants in their cohort of 73 patients (covering DEPDC5 + NPRL2 + NPRL3 genes which all form the GATOR1 complex together). Awaiting clinical review for final gene rating.
Genetic epilepsy syndromes v1.213 IKBKG Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists XLD inheritance for Incontinentia pigmenti (MIM:308300).
Genetic epilepsy syndromes v1.213 IKBKG Rebecca Foulger Mode of inheritance for gene: IKBKG was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.212 ARHGEF9 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists XLR mode of inheritance for 'Epileptic encephalopathy, early infantile, 8' (MIM:300607). Gene2Phenotype lists hemizygous mode of inheritance (XLR) for EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 8.
Genetic epilepsy syndromes v1.212 ARHGEF9 Rebecca Foulger Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.211 NDUFA1 Rebecca Foulger Added comment: Comment on mode of inheritance: There is a case of female with variant and symptoms in PMID:21596602. (Mayr et al., 2011), but she does not have epilepsy but rather a metabolic defect. Therefore XLD is appropriate for metabolism panel but MOI is kept as XLR on this epilepsy panel for now.
Genetic epilepsy syndromes v1.211 NDUFA1 Rebecca Foulger Mode of inheritance for gene: NDUFA1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.210 SLC16A2 Rebecca Foulger Added comment: Comment on mode of inheritance: MOI is recorded as hemizygous in Gene2Phenotype and XL in OMIM. XLR inheritance was confirmed with reviewer, as stated by Ellen McDonagh.
Genetic epilepsy syndromes v1.210 SLC16A2 Rebecca Foulger Mode of inheritance for gene: SLC16A2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.209 PIGA Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM records XLR inheritance for 'Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MIM:300868). Gene2Phenotype reports 'hemizygous' allelic requirement for MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 2. Johnston et al., 2012 (PMID:22305531) report 3 deceased males and 2 carrier females. Both carrier females had 100% skewed X-inactivation and neither presented with a phenotype.
Genetic epilepsy syndromes v1.209 PIGA Rebecca Foulger Mode of inheritance for gene: PIGA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.208 MED12 Rebecca Foulger Added comment: Comment on mode of inheritance: Allelic requirement listed in Gene2Phenotype is 'hemizygous' for both 'OPITZ-KAVEGGIA SYNDROME' and 'LUJAN-FRYNS SYNDROME'.
Genetic epilepsy syndromes v1.208 MED12 Rebecca Foulger Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic epilepsy syndromes v1.207 MAGI2 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists AR inheritance for 'Nephrotic syndrome, type 15' (MIM:617609). Gene2Phenotype lists 'monoallelic' inheritance for EARLY ONSET EPILEPTIC ENCEPHALOPATHY.
Genetic epilepsy syndromes v1.207 MAGI2 Rebecca Foulger Mode of inheritance for gene: MAGI2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.206 IDH2 Rebecca Foulger Added comment: Comment on mode of inheritance: The mode of inheritance for IDH2 is currently MONOALLELIC on the 'Intellectual disability' panel, and the 'Inborn errors of metabolism' panel.
Genetic epilepsy syndromes v1.206 IDH2 Rebecca Foulger Mode of inheritance for gene: IDH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.205 IDH2 Rebecca Foulger Phenotypes for gene: IDH2 were changed from D-2-hydroxyglutaric aciduria 2 to D-2-hydroxyglutaric aciduria 2, 613657
Genetic epilepsy syndromes v1.204 IDH2 Rebecca Foulger Publications for gene: IDH2 were set to
Genetic epilepsy syndromes v1.203 NRXN1 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:30031152 (Al Shehhi et al.) report heterozygous deletions of NRXN1 with phenotypes including seizures. At least PMID:21964664 (Harrison et al.) and PMID:19896112 report a biallelic mode of inheritance.
Genetic epilepsy syndromes v1.203 NRXN1 Rebecca Foulger Mode of inheritance for gene: NRXN1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.202 SLC35A2 Rebecca Foulger Added comment: Comment on mode of inheritance: MOI in OMIM for SLC35A2 is listed as X-linked dominant.
Genetic epilepsy syndromes v1.202 SLC35A2 Rebecca Foulger Mode of inheritance for gene: SLC35A2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v1.201 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plu review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.
Genetic epilepsy syndromes v1.201 KCNJ11 Rebecca Foulger Mode of inheritance for gene: KCNJ11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v1.200 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.
Genetic epilepsy syndromes v1.200 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given.; to: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.
Genetic epilepsy syndromes v1.200 KCNJ11 Rebecca Foulger Publications for gene: KCNJ11 were set to 25678012; 16670688; 16609879; 27681997; 17065345; 28943513
Genetic epilepsy syndromes v1.199 KCNJ11 Rebecca Foulger Added comment: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given.
Genetic epilepsy syndromes v1.199 KCNJ11 Rebecca Foulger Mode of inheritance for gene: KCNJ11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v1.198 TUBB2A Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain: 3 unrelated cases from literature. Although not all with the genotype may develop seizures, there are sufficient cases of the epilepsy phenotype for inclusion on the panel.; to: Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain: 3 unrelated cases from literature (two cases from PMID:24702957 and one from large-scale study PMID:25326637. Although not all with the genotype may develop seizures, there are sufficient cases of the epilepsy phenotype for inclusion on the panel.
Genetic epilepsy syndromes v1.198 HCN2 Rebecca Foulger changed review comment from: Comment on mode of inheritance: PMID:22131395: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.; to: Comment on mode of inheritance: PMID:22131395: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance. Hence MOI listed as BOTH monoallelic and biallelic.
Genetic epilepsy syndromes v1.198 POLG2 Sarah Leigh Classified gene: POLG2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.198 POLG2 Sarah Leigh Added comment: Comment on list classification: Single case of recessive epilepsy.
Genetic epilepsy syndromes v1.198 POLG2 Sarah Leigh Gene: polg2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.197 POLG2 Sarah Leigh gene: POLG2 was added
gene: POLG2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: POLG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLG2 were set to 31286721; 27592148; 30157269
Phenotypes for gene: POLG2 were set to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia
Review for gene: POLG2 was set to AMBER
Added comment: Single case of Autosomal Recessive Epilepsy Family Without Ophthalmoplegia in a 27-year-old Pakistani male, who was homozygous for POLG2 c.694G>A, p.G232S. Both his parents were heterozygous for this variant, and none of them had liver disease, ophthalmoplegia, ptosis, nystagmus, or myopathy, and the parents showed no symptoms of epilepsy or ophthalmoplegia.
Sources: Literature
Genetic epilepsy syndromes v1.196 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
----
As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
----
As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

---------------

Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
Genetic epilepsy syndromes v1.196 AFF3 Rebecca Foulger Tag missense tag was added to gene: AFF3.
Tag watchlist tag was added to gene: AFF3.
Genetic epilepsy syndromes v1.196 AFF3 Rebecca Foulger Classified gene: AFF3 as Amber List (moderate evidence)
Genetic epilepsy syndromes v1.196 AFF3 Rebecca Foulger Gene: aff3 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v1.195 AFF3 Rebecca Foulger commented on gene: AFF3
Genetic epilepsy syndromes v1.195 WWOX Rebecca Foulger commented on gene: WWOX: Usha Kini (Oxford Medical Genetics Laboratories) confirmed that WWOX should be on the epilepsy panel (personal communication via email on August 8th, 2019).
Genetic epilepsy syndromes v1.195 AFF3 Rebecca Foulger Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures; Abnormality of skeletal morphology; Abnormality of the urinary system; Hypertrichosis; Abnormality of the respiratory system to Intellectual disability; Seizures; KINSSHIP syndrome
Genetic epilepsy syndromes v1.194 PIGU Rebecca Foulger commented on gene: PIGU
Genetic epilepsy syndromes v1.194 PIGU Rebecca Foulger Tag missense tag was added to gene: PIGU.
Genetic epilepsy syndromes v1.194 GRIA2 Rebecca Foulger commented on gene: GRIA2: GRIA2 is not yet associated with a disorder in OMIM or Gene2Phenotype.
Genetic epilepsy syndromes v1.194 GRIA2 Rebecca Foulger commented on gene: GRIA2: PMID:8938126 (animal model): GluR2 heterozygous (+/−) mice showed reduced motor coordination but no sign of seizure activity as measured by observation, EEG, or post-mortem analysis.
Genetic epilepsy syndromes v1.194 GRIA2 Rebecca Foulger Phenotypes for gene: GRIA2 were changed from Intellectual disability; Seizures; Autism to Intellectual disability; Seizures; myoclonic seizures; status epilepticus; tonic-clonic seizures; focal seizures
Genetic epilepsy syndromes v1.193 GRIA2 Rebecca Foulger commented on gene: GRIA2
Genetic epilepsy syndromes v1.193 GRIA2 Konstantinos Varvagiannis gene: GRIA2 was added
gene: GRIA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GRIA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GRIA2 were set to 31300657
Phenotypes for gene: GRIA2 were set to Intellectual disability; Seizures; Autism
Penetrance for gene: GRIA2 were set to unknown
Review for gene: GRIA2 was set to AMBER
Added comment: There is a recent publication by Salpietro et al. (2019 - PMID: 31300657) reporting on 28 unrelated individuals. Seizures were observed in 12/28 (~40%), so the gene may also be relevant for the current panel.

The phenotype overall corresponds to a NDD disorder with DD, ID (universal feature in those with appropriate age for evaluation, relevant severity), ASD, Rett-like features and seizures. All types of variants were reported (15 missense, 2 splice-site, 1 in-frame del, 1 stopgain, 2 frameshift ones, 3 CNVs spanning GRIA2 and other genes, the latter more tolerant to LoF). The role of this gene (encoding AMPA receptor GluA2 subunit), functional studies (loss of function demonstrated for the majority of mutations, though by multiple molecular mechanisms), overlapping phenotype with disorders due to other ionotropic glutamate receptor subunit genes (eg. GRIA3/4 - ID with or without seizures), animal models (PMID cited: 8938126) are among the arguments provided.
Sources: Literature
Genetic epilepsy syndromes v1.193 AFF3 Konstantinos Varvagiannis gene: AFF3 was added
gene: AFF3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: AFF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733
Phenotypes for gene: AFF3 were set to Intellectual disability; Seizures; Abnormality of skeletal morphology; Abnormality of the urinary system; Hypertrichosis; Abnormality of the respiratory system
Penetrance for gene: AFF3 were set to unknown
Mode of pathogenicity for gene: AFF3 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: AFF3 was set to GREEN
Added comment: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
----
As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature
Genetic epilepsy syndromes v1.193 PIGU Konstantinos Varvagiannis gene: PIGU was added
gene: PIGU was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PIGU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGU were set to 31353022
Phenotypes for gene: PIGU were set to Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Penetrance for gene: PIGU were set to Complete
Review for gene: PIGU was set to GREEN
Added comment: Knaus et al. (2019 - PMID: 31353022) report on 5 affected individuals (from 3 unrelated families) with biallelic pathogenic PIGU variants.

Common features included tone abnormalities, global DD, ID, seizures, CNS anomalies (cerebral atrophy and/or cerebellar hypoplasia), scoliosis. Affected individuals presented also with facial similarities. DD/ID were universal features and their severity appears to be relevant to the panel. Seizures were also reported in all individuals (myoclonic in 3, for whom this was specified). ALP was normal in all.

Three individuals from 2 non-consanguineous families (one from Norway, the other not specified) were homozygous for a missense variant NM_080476.4:c.1149C>A (or p.Asn383Lys) present with an AF of 7/277197 in Europeans. Two individuals born to consanguineous parents from Turkey were homozygous for another missense variant (c.209T>A or p.Ile70Lys - same RefSeq).

Segregation analyses in parents and unaffected sibs were carried out.

PIGU encodes a subunit of the GPI transaminidase, a heteropentameric complex (other subunits encoded by PIGK, PIGS, PIGT and GPAA1) that mediates attachment in the endoplasmic reticulum of glycosylphosphatidylinositol (GPI) to the C-termini of proteins which are subsequently anchored to the cell surface.

Pathogenic variants in 18 of 29 genes implicated in biosynthesis of the GPI anchor have been identified as a cause of GPI biosynthesis disorders, with ID and seizures as principal features. Mutations in other genes encoding components of the GPI transaminidase complex (GPAA1, PIGT and PIGS) lead to neurodevelopmental disorders.

Functional impairment of PIGU was supported by flow-cytometric analysis showing significant reduction of cell surface expression of GPI anchored proteins (mainly FLAER, CD16 and CD24) on granulocytes from affected individuals. In addition accumulation of free GPI anchors on the cell surface of B cells from affected individuals further suggested deficiency of the GPI transaminidase.

Transient expression of mutant (Asn383Lys) protein failed to rescue expression of GPI-APs to the same extent as wt in a CHO cell line deficient for PIGU.

Feature analysis demonstrated similarities among individuals with mutations in other genes of the GPI transamidase complex (GPAA1 and PIGT) as well as with GPI biosynthesis disorders. Facial analysis was also suggestive of facial similarities between individuals with GPAA1 and PIGU mutations.

PIGU is not associated with any phenotype in OMIM or G2P.

As a result this gene can be considered for inclusion in the ID and epilepsy panels probably as green (3 families, ID of relevant severity and seizures in all affected individuals, known group of disorders and supportive evidence) or amber.
Sources: Literature
Genetic epilepsy syndromes v1.193 WDR37 Konstantinos Varvagiannis gene: WDR37 was added
gene: WDR37 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WDR37 were set to 31327510; 31327508
Phenotypes for gene: WDR37 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Penetrance for gene: WDR37 were set to unknown
Mode of pathogenicity for gene: WDR37 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: WDR37 was set to GREEN
Added comment: Two concurrent publications by Reis et al. and Kanca et al. (2019 - PMIDs: 31327510, 31327508) report on the phenotype of individuals with de novo WDR37 mutations.

The study by Reis et al. provides clinical details on 4 affected individuals, while 5 further are described by Kanca et al.

4 different de novo variants were reported in these individuals who appear to be unrelated in (and between) the 2 studies [NM_014023.3]:
- c.356C>T (p.Ser119Phe) [Reis indiv. 1 - 3y, Kanca proband 3 - 5m2w]
- c.389C>T (p.Thr130Ile) [Reis indiv. 2 - 22m , Kanca proband 5 - 6 w]
- c.374C>T (p.Thr125Ile) [Reis indiv. 3 - 8y , Kanca proband 1 - 7y]
- c.386C>G (p.Ser129Cys) [Reis indiv. 4 - unkn age, Kanca probands 2 and 4, 6.5y and 19y]

Common features included DD/ID (severity relevant for the current panel), seizures (9/9), ocular anomalies (corneal opacity/Peters anomaly, coloboma, microphthalmia etc.) and variable brain, hearing, cardiovascular, skeletal and genitourinary anomalies. Some facial and/or other dysmorphic features (incl. excess nuchal skin / webbed neck) were also frequent among affected individuals. Feeding difficulties and growth deficiency were also among the features observed.

The function of WDR37 is not known. Variants demonstrated comparable protein levels and cellular localization compared to wt.

Reis et al. provide evidence using CRISPR-Cas9 mediated genome editing in zebrafish, to introduce the Ser129Cys variant observed in affected individuals as well as novel missense and frameshift variants. Poor growth (similar to the human phenotype) and larval lethality were noted for missense variants. Head size was proportionately small. Ocular (coloboma/corneal) or craniofacial anomalies were not observed. Zebrafish heterozygous for LoF variants survived to adulthood.

Based on these a dominant-negative mechanism was postulated for missense alleles.

RNA-seq analysis in zebrafish showed upregulation of cholesterol biosynthesis pathways (among the most dysregulated ones).

Previous data in mice, suggest a broad expression pattern for Wdr37 with enrichment in ocular and brain tissues, significant associations in homozygous mutant mice for decreased body weight, grip strength, skeletal anomalies and possible increase (p =< 0.05) in ocular (lens/corneal) and other anomalies [BioGPS and International Mouse Phenotyping Consortium cited].

CG12333 loss (the Drosophila WDR37 ortholog) causes increased bang sensitivity in flies (analogous to the human epilepsy phenotype), defects in copulation and grip strength, phenotypes that were rescued by human reference but not variant cDNAs.

As discussed by Kanca et al. based on data from Drosophila and mice, limited phenotypic similarity of CNVs spanning WDR37 and adjacent genes with the reported individuals and the presence of LoF variants in control populations haploinsufficiency appears unlikely. Gain-of-function is also unlikely, as expression of human variants in flies did not exacerbate the observed phenotypes. A dominant-negative effect is again proposed.

WDR37 is not associated with any phenotype in OMIM/G2P.

As a result WDR37 can be considered for inclusion in the ID and epilepsy panels with green (relevant phenotype, sufficient cases, animal models) or amber rating.
Sources: Literature
Genetic epilepsy syndromes v1.193 ATN1_CAG Rebecca Foulger Source NHS GMS was added to STR: ATN1_CAG.
Genetic epilepsy syndromes v1.192 CSTB_CCCCGCCCCGCG Rebecca Foulger Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Genetic epilepsy syndromes v1.191 CSTB_CCCCGCCCCGCG Rebecca Foulger commented on STR: CSTB_CCCCGCCCCGCG
Genetic epilepsy syndromes v1.191 ATN1_CAG Rebecca Foulger commented on STR: ATN1_CAG
Genetic epilepsy syndromes v1.191 CUL4B Rebecca Foulger Source Wessex and West Midlands GLH was added to CUL4B.
Genetic epilepsy syndromes v1.191 TUBA3E Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBA3E.
Genetic epilepsy syndromes v1.191 SLC6A5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A5.
Genetic epilepsy syndromes v1.191 SHH Rebecca Foulger Source Wessex and West Midlands GLH was added to SHH.
Genetic epilepsy syndromes v1.191 SEC24D Rebecca Foulger Source Wessex and West Midlands GLH was added to SEC24D.
Genetic epilepsy syndromes v1.191 SCN2B Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN2B.
Genetic epilepsy syndromes v1.191 RYR3 Rebecca Foulger Source Wessex and West Midlands GLH was added to RYR3.
Genetic epilepsy syndromes v1.191 RUBCN Rebecca Foulger Source Wessex and West Midlands GLH was added to RUBCN.
Genetic epilepsy syndromes v1.191 PSMB8 Rebecca Foulger Source Wessex and West Midlands GLH was added to PSMB8.
Genetic epilepsy syndromes v1.191 PRICKLE2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRICKLE2.
Genetic epilepsy syndromes v1.191 PCDHB4 Rebecca Foulger Source Wessex and West Midlands GLH was added to PCDHB4.
Genetic epilepsy syndromes v1.191 NRAS Rebecca Foulger Source Wessex and West Midlands GLH was added to NRAS.
Genetic epilepsy syndromes v1.191 NID1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NID1.
Genetic epilepsy syndromes v1.191 NDUFA11 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA11.
Genetic epilepsy syndromes v1.191 MT-TL1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MT-TL1.
Genetic epilepsy syndromes v1.191 MATN4 Rebecca Foulger Source Wessex and West Midlands GLH was added to MATN4.
Genetic epilepsy syndromes v1.191 MAPK10 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAPK10.
Genetic epilepsy syndromes v1.191 KAT5 Rebecca Foulger Source Wessex and West Midlands GLH was added to KAT5.
Genetic epilepsy syndromes v1.191 INO80 Rebecca Foulger Source Wessex and West Midlands GLH was added to INO80.
Genetic epilepsy syndromes v1.191 H3F3B Rebecca Foulger Source Wessex and West Midlands GLH was added to H3F3B.
Genetic epilepsy syndromes v1.191 H3F3A Rebecca Foulger Source Wessex and West Midlands GLH was added to H3F3A.
Genetic epilepsy syndromes v1.191 GLRB Rebecca Foulger Source Wessex and West Midlands GLH was added to GLRB.
Genetic epilepsy syndromes v1.191 GCSH Rebecca Foulger Source Wessex and West Midlands GLH was added to GCSH.
Genetic epilepsy syndromes v1.191 GATM Rebecca Foulger Source Wessex and West Midlands GLH was added to GATM.
Genetic epilepsy syndromes v1.191 GATAD2B Rebecca Foulger Source Wessex and West Midlands GLH was added to GATAD2B.
Genetic epilepsy syndromes v1.191 GAL Rebecca Foulger Source Wessex and West Midlands GLH was added to GAL.
Genetic epilepsy syndromes v1.191 GABRD Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRD.
Genetic epilepsy syndromes v1.191 FTL Rebecca Foulger Source Wessex and West Midlands GLH was added to FTL.
Genetic epilepsy syndromes v1.191 FIG4 Rebecca Foulger Source Wessex and West Midlands GLH was added to FIG4.
Genetic epilepsy syndromes v1.191 DMBX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DMBX1.
Genetic epilepsy syndromes v1.191 CYP27A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to CYP27A1.
Genetic epilepsy syndromes v1.191 CSNK1G1 Rebecca Foulger Source Wessex and West Midlands GLH was added to CSNK1G1.
Genetic epilepsy syndromes v1.191 CRH Rebecca Foulger Source Wessex and West Midlands GLH was added to CRH.
Genetic epilepsy syndromes v1.191 CNTN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNTN2.
Genetic epilepsy syndromes v1.191 CLN6 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN6.
Genetic epilepsy syndromes v1.191 CLN5 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN5.
Genetic epilepsy syndromes v1.191 CLCN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLCN2.
Genetic epilepsy syndromes v1.191 CBL Rebecca Foulger Source Wessex and West Midlands GLH was added to CBL.
Genetic epilepsy syndromes v1.191 CASR Rebecca Foulger Source Wessex and West Midlands GLH was added to CASR.
Genetic epilepsy syndromes v1.191 CAMK2G Rebecca Foulger Source Wessex and West Midlands GLH was added to CAMK2G.
Genetic epilepsy syndromes v1.191 CACNB4 Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNB4.
Genetic epilepsy syndromes v1.191 ASAH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ASAH1.
Genetic epilepsy syndromes v1.191 ALG2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG2.
Genetic epilepsy syndromes v1.191 ALG12 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG12.
Genetic epilepsy syndromes v1.191 ADGRV1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADGRV1.
Genetic epilepsy syndromes v1.191 AARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AARS2.
Genetic epilepsy syndromes v1.191 VLDLR Rebecca Foulger Source Wessex and West Midlands GLH was added to VLDLR.
Genetic epilepsy syndromes v1.191 UFC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to UFC1.
Genetic epilepsy syndromes v1.191 TXNRD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TXNRD1.
Genetic epilepsy syndromes v1.191 TUBB Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB.
Genetic epilepsy syndromes v1.191 TUBA8 Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBA8.
Genetic epilepsy syndromes v1.191 TSFM Rebecca Foulger Source Wessex and West Midlands GLH was added to TSFM.
Genetic epilepsy syndromes v1.191 TSEN34 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN34.
Genetic epilepsy syndromes v1.191 TSEN15 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN15.
Genetic epilepsy syndromes v1.191 TRIP13 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRIP13.
Genetic epilepsy syndromes v1.191 TRAPPC6B Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAPPC6B.
Genetic epilepsy syndromes v1.191 TRAPPC12 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAPPC12.
Genetic epilepsy syndromes v1.191 TRAF7 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAF7.
Genetic epilepsy syndromes v1.191 TNK2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TNK2.
Genetic epilepsy syndromes v1.191 TIMM50 Rebecca Foulger Source Wessex and West Midlands GLH was added to TIMM50.
Genetic epilepsy syndromes v1.191 TFE3 Rebecca Foulger Source Wessex and West Midlands GLH was added to TFE3.
Genetic epilepsy syndromes v1.191 TELO2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TELO2.
Genetic epilepsy syndromes v1.191 TBC1D20 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBC1D20.
Genetic epilepsy syndromes v1.191 SUCLG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SUCLG1.
Genetic epilepsy syndromes v1.191 ST3GAL3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ST3GAL3.
Genetic epilepsy syndromes v1.191 SRPX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SRPX2.
Genetic epilepsy syndromes v1.191 SPR Rebecca Foulger Source Wessex and West Midlands GLH was added to SPR.
Genetic epilepsy syndromes v1.191 SNIP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SNIP1.
Genetic epilepsy syndromes v1.191 SMC1A Rebecca Foulger Source Wessex and West Midlands GLH was added to SMC1A.
Genetic epilepsy syndromes v1.191 SLC45A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC45A1.
Genetic epilepsy syndromes v1.191 SLC35A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC35A1.
Genetic epilepsy syndromes v1.191 SIX3 Rebecca Foulger Source Wessex and West Midlands GLH was added to SIX3.
Genetic epilepsy syndromes v1.191 SETD1B Rebecca Foulger Source Wessex and West Midlands GLH was added to SETD1B.
Genetic epilepsy syndromes v1.191 SDHA Rebecca Foulger Source Wessex and West Midlands GLH was added to SDHA.
Genetic epilepsy syndromes v1.191 RYR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RYR2.
Genetic epilepsy syndromes v1.191 RUSC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RUSC2.
Genetic epilepsy syndromes v1.191 RRM2B Rebecca Foulger Source Wessex and West Midlands GLH was added to RRM2B.
Genetic epilepsy syndromes v1.191 RPIA Rebecca Foulger Source Wessex and West Midlands GLH was added to RPIA.
Genetic epilepsy syndromes v1.191 RNU4ATAC Rebecca Foulger Source Wessex and West Midlands GLH was added to RNU4ATAC.
Genetic epilepsy syndromes v1.191 RAB3GAP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB3GAP2.
Genetic epilepsy syndromes v1.191 RAB3GAP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB3GAP1.
Genetic epilepsy syndromes v1.191 PTF1A Rebecca Foulger Source Wessex and West Midlands GLH was added to PTF1A.
Genetic epilepsy syndromes v1.191 PSPH Rebecca Foulger Source Wessex and West Midlands GLH was added to PSPH.
Genetic epilepsy syndromes v1.191 PSAT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PSAT1.
Genetic epilepsy syndromes v1.191 POMT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to POMT2.
Genetic epilepsy syndromes v1.191 PIGQ Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGQ.
Genetic epilepsy syndromes v1.191 PIGH Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGH.
Genetic epilepsy syndromes v1.191 PIGC Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGC.
Genetic epilepsy syndromes v1.191 PEX5 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX5.
Genetic epilepsy syndromes v1.191 PDSS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PDSS2.
Genetic epilepsy syndromes v1.191 PCLO Rebecca Foulger Source Wessex and West Midlands GLH was added to PCLO.
Genetic epilepsy syndromes v1.191 OTX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to OTX2.
Genetic epilepsy syndromes v1.191 NUBPL Rebecca Foulger Source Wessex and West Midlands GLH was added to NUBPL.
Genetic epilepsy syndromes v1.191 NPRL2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NPRL2.
Genetic epilepsy syndromes v1.191 NEDD4L Rebecca Foulger Source Wessex and West Midlands GLH was added to NEDD4L.
Genetic epilepsy syndromes v1.191 NECAP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NECAP1.
Genetic epilepsy syndromes v1.191 NDUFS7 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS7.
Genetic epilepsy syndromes v1.191 NDUFS6 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS6.
Genetic epilepsy syndromes v1.191 NDUFS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS2.
Genetic epilepsy syndromes v1.191 NDUFS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS1.
Genetic epilepsy syndromes v1.191 NDUFAF4 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF4.
Genetic epilepsy syndromes v1.191 NDUFAF3 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF3.
Genetic epilepsy syndromes v1.191 NDUFA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA2.
Genetic epilepsy syndromes v1.191 NDP Rebecca Foulger Source Wessex and West Midlands GLH was added to NDP.
Genetic epilepsy syndromes v1.191 MED17 Rebecca Foulger Source Wessex and West Midlands GLH was added to MED17.
Genetic epilepsy syndromes v1.191 MAST1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAST1.
Genetic epilepsy syndromes v1.191 MANBA Rebecca Foulger Source Wessex and West Midlands GLH was added to MANBA.
Genetic epilepsy syndromes v1.191 LNPK Rebecca Foulger Source Wessex and West Midlands GLH was added to LNPK.
Genetic epilepsy syndromes v1.191 LIPT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to LIPT2.
Genetic epilepsy syndromes v1.191 LARGE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to LARGE1.
Genetic epilepsy syndromes v1.191 KPTN Rebecca Foulger Source Wessex and West Midlands GLH was added to KPTN.
Genetic epilepsy syndromes v1.191 KIAA1109 Rebecca Foulger Source Wessex and West Midlands GLH was added to KIAA1109.
Genetic epilepsy syndromes v1.191 KCNMA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNMA1.
Genetic epilepsy syndromes v1.191 ISPD Rebecca Foulger Source Wessex and West Midlands GLH was added to ISPD.
Genetic epilepsy syndromes v1.191 HSPD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HSPD1.
Genetic epilepsy syndromes v1.191 HPRT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HPRT1.
Genetic epilepsy syndromes v1.191 HOXA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HOXA1.
Genetic epilepsy syndromes v1.191 HEXB Rebecca Foulger Source Wessex and West Midlands GLH was added to HEXB.
Genetic epilepsy syndromes v1.191 HCCS Rebecca Foulger Source Wessex and West Midlands GLH was added to HCCS.
Genetic epilepsy syndromes v1.191 GTPBP3 Rebecca Foulger Source Wessex and West Midlands GLH was added to GTPBP3.
Genetic epilepsy syndromes v1.191 GLRA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLRA1.
Genetic epilepsy syndromes v1.191 GLI3 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLI3.
Genetic epilepsy syndromes v1.191 FOXRED1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FOXRED1.
Genetic epilepsy syndromes v1.191 FKRP Rebecca Foulger Source Wessex and West Midlands GLH was added to FKRP.
Genetic epilepsy syndromes v1.191 FASTKD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to FASTKD2.
Genetic epilepsy syndromes v1.191 EIF2B3 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B3.
Genetic epilepsy syndromes v1.191 EIF2B1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B1.
Genetic epilepsy syndromes v1.191 EFHC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EFHC1.
Genetic epilepsy syndromes v1.191 DPM2 Rebecca Foulger Source Wessex and West Midlands GLH was added to DPM2.
Genetic epilepsy syndromes v1.191 DOLK Rebecca Foulger Source Wessex and West Midlands GLH was added to DOLK.
Genetic epilepsy syndromes v1.191 DNAJC6 Rebecca Foulger Source Wessex and West Midlands GLH was added to DNAJC6.
Genetic epilepsy syndromes v1.191 DHCR24 Rebecca Foulger Source Wessex and West Midlands GLH was added to DHCR24.
Genetic epilepsy syndromes v1.191 DBT Rebecca Foulger Source Wessex and West Midlands GLH was added to DBT.
Genetic epilepsy syndromes v1.191 CUX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CUX2.
Genetic epilepsy syndromes v1.191 CSNK2B Rebecca Foulger Source Wessex and West Midlands GLH was added to CSNK2B.
Genetic epilepsy syndromes v1.191 COX15 Rebecca Foulger Source Wessex and West Midlands GLH was added to COX15.
Genetic epilepsy syndromes v1.191 COX10 Rebecca Foulger Source Wessex and West Midlands GLH was added to COX10.
Genetic epilepsy syndromes v1.191 COQ6 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ6.
Genetic epilepsy syndromes v1.191 COG8 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG8.
Genetic epilepsy syndromes v1.191 COG6 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG6.
Genetic epilepsy syndromes v1.191 COG4 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG4.
Genetic epilepsy syndromes v1.191 CNPY3 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNPY3.
Genetic epilepsy syndromes v1.191 CCND2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CCND2.
Genetic epilepsy syndromes v1.191 CCDC88C Rebecca Foulger Source Wessex and West Midlands GLH was added to CCDC88C.
Genetic epilepsy syndromes v1.191 CCDC88A Rebecca Foulger Source Wessex and West Midlands GLH was added to CCDC88A.
Genetic epilepsy syndromes v1.191 CACNA2D2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA2D2.
Genetic epilepsy syndromes v1.191 CACNA1H Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1H.
Genetic epilepsy syndromes v1.191 ATP6AP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP6AP2.
Genetic epilepsy syndromes v1.191 ATP5A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP5A1.
Genetic epilepsy syndromes v1.191 ATP1A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP1A2.
Genetic epilepsy syndromes v1.191 ADAT3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADAT3.
Genetic epilepsy syndromes v1.191 ZBTB18 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZBTB18.
Genetic epilepsy syndromes v1.191 YWHAG Rebecca Foulger Source Wessex and West Midlands GLH was added to YWHAG.
Genetic epilepsy syndromes v1.191 WDR73 Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR73.
Genetic epilepsy syndromes v1.191 WDR62 Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR62.
Genetic epilepsy syndromes v1.191 WASF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to WASF1.
Genetic epilepsy syndromes v1.191 VARS Rebecca Foulger Source Wessex and West Midlands GLH was added to VARS.
Genetic epilepsy syndromes v1.191 UNC80 Rebecca Foulger Source Wessex and West Midlands GLH was added to UNC80.
Genetic epilepsy syndromes v1.191 UFM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to UFM1.
Genetic epilepsy syndromes v1.191 UBA5 Rebecca Foulger Source Wessex and West Midlands GLH was added to UBA5.
Genetic epilepsy syndromes v1.191 TUBG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBG1.
Genetic epilepsy syndromes v1.191 TUBB4A Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB4A.
Genetic epilepsy syndromes v1.191 TUBB3 Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB3.
Genetic epilepsy syndromes v1.191 TUBB2B Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB2B.
Genetic epilepsy syndromes v1.191 TUBB2A Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB2A.
Genetic epilepsy syndromes v1.191 TUBA1A Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBA1A.
Genetic epilepsy syndromes v1.191 TSEN54 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN54.
Genetic epilepsy syndromes v1.191 TSEN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN2.
Genetic epilepsy syndromes v1.191 TSC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSC2.
Genetic epilepsy syndromes v1.191 TSC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSC1.
Genetic epilepsy syndromes v1.191 TRIM8 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRIM8.
Genetic epilepsy syndromes v1.191 TREX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TREX1.
Genetic epilepsy syndromes v1.191 TMEM70 Rebecca Foulger Source Wessex and West Midlands GLH was added to TMEM70.
Genetic epilepsy syndromes v1.191 TBL1XR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBL1XR1.
Genetic epilepsy syndromes v1.191 TBCK Rebecca Foulger Source Wessex and West Midlands GLH was added to TBCK.
Genetic epilepsy syndromes v1.191 TBCD Rebecca Foulger Source Wessex and West Midlands GLH was added to TBCD.
Genetic epilepsy syndromes v1.191 TANGO2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TANGO2.
Genetic epilepsy syndromes v1.191 SYN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SYN1.
Genetic epilepsy syndromes v1.191 SURF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SURF1.
Genetic epilepsy syndromes v1.191 SUCLA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SUCLA2.
Genetic epilepsy syndromes v1.191 STAMBP Rebecca Foulger Source Wessex and West Midlands GLH was added to STAMBP.
Genetic epilepsy syndromes v1.191 STAG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to STAG1.
Genetic epilepsy syndromes v1.191 ST3GAL5 Rebecca Foulger Source Wessex and West Midlands GLH was added to ST3GAL5.
Genetic epilepsy syndromes v1.191 SNORD118 Rebecca Foulger Source Wessex and West Midlands GLH was added to SNORD118.
Genetic epilepsy syndromes v1.191 SMS Rebecca Foulger Source Wessex and West Midlands GLH was added to SMS.
Genetic epilepsy syndromes v1.191 SMARCA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SMARCA2.
Genetic epilepsy syndromes v1.191 SLC6A8 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A8.
Genetic epilepsy syndromes v1.191 SLC25A12 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC25A12.
Genetic epilepsy syndromes v1.191 SLC1A4 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC1A4.
Genetic epilepsy syndromes v1.191 SETBP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SETBP1.
Genetic epilepsy syndromes v1.191 SEPSECS Rebecca Foulger Source Wessex and West Midlands GLH was added to SEPSECS.
Genetic epilepsy syndromes v1.191 SCO2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SCO2.
Genetic epilepsy syndromes v1.191 SCO1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SCO1.
Genetic epilepsy syndromes v1.191 SCN3A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN3A.
Genetic epilepsy syndromes v1.191 SAMHD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SAMHD1.
Genetic epilepsy syndromes v1.191 RTTN Rebecca Foulger Source Wessex and West Midlands GLH was added to RTTN.
Genetic epilepsy syndromes v1.191 RTN4IP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RTN4IP1.
Genetic epilepsy syndromes v1.191 RORB Rebecca Foulger Source Wessex and West Midlands GLH was added to RORB.
Genetic epilepsy syndromes v1.191 RORA Rebecca Foulger Source Wessex and West Midlands GLH was added to RORA.
Genetic epilepsy syndromes v1.191 ROGDI Rebecca Foulger Source Wessex and West Midlands GLH was added to ROGDI.
Genetic epilepsy syndromes v1.191 RNASET2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASET2.
Genetic epilepsy syndromes v1.191 RNASEH2C Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASEH2C.
Genetic epilepsy syndromes v1.191 RNASEH2B Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASEH2B.
Genetic epilepsy syndromes v1.191 RNASEH2A Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASEH2A.
Genetic epilepsy syndromes v1.191 RMND1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RMND1.
Genetic epilepsy syndromes v1.191 RHOBTB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RHOBTB2.
Genetic epilepsy syndromes v1.191 RFT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RFT1.
Genetic epilepsy syndromes v1.191 RELN Rebecca Foulger Source Wessex and West Midlands GLH was added to RELN.
Genetic epilepsy syndromes v1.191 RARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RARS2.
Genetic epilepsy syndromes v1.191 RALA Rebecca Foulger Source Wessex and West Midlands GLH was added to RALA.
Genetic epilepsy syndromes v1.191 RAB18 Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB18.
Genetic epilepsy syndromes v1.191 RAB11B Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB11B.
Genetic epilepsy syndromes v1.191 QDPR Rebecca Foulger Source Wessex and West Midlands GLH was added to QDPR.
Genetic epilepsy syndromes v1.191 PTS Rebecca Foulger Source Wessex and West Midlands GLH was added to PTS.
Genetic epilepsy syndromes v1.191 PTPN23 Rebecca Foulger Source Wessex and West Midlands GLH was added to PTPN23.
Genetic epilepsy syndromes v1.191 PTEN Rebecca Foulger Source Wessex and West Midlands GLH was added to PTEN.
Genetic epilepsy syndromes v1.191 PSAP Rebecca Foulger Source Wessex and West Midlands GLH was added to PSAP.
Genetic epilepsy syndromes v1.191 PRMT7 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRMT7.
Genetic epilepsy syndromes v1.191 PRICKLE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRICKLE1.
Genetic epilepsy syndromes v1.191 PPT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PPT1.
Genetic epilepsy syndromes v1.191 PPP3CA Rebecca Foulger Source Wessex and West Midlands GLH was added to PPP3CA.
Genetic epilepsy syndromes v1.191 POMT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to POMT1.
Genetic epilepsy syndromes v1.191 POMGNT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to POMGNT1.
Genetic epilepsy syndromes v1.191 PMM2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PMM2.
Genetic epilepsy syndromes v1.191 PLAA Rebecca Foulger Source Wessex and West Midlands GLH was added to PLAA.
Genetic epilepsy syndromes v1.191 PIK3R2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PIK3R2.
Genetic epilepsy syndromes v1.191 PIK3CA Rebecca Foulger Source Wessex and West Midlands GLH was added to PIK3CA.
Genetic epilepsy syndromes v1.191 PIGW Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGW.
Genetic epilepsy syndromes v1.191 PIGO Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGO.
Genetic epilepsy syndromes v1.191 PIGG Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGG.
Genetic epilepsy syndromes v1.191 PHGDH Rebecca Foulger Source Wessex and West Midlands GLH was added to PHGDH.
Genetic epilepsy syndromes v1.191 PHACTR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PHACTR1.
Genetic epilepsy syndromes v1.191 PEX7 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX7.
Genetic epilepsy syndromes v1.191 PEX6 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX6.
Genetic epilepsy syndromes v1.191 PEX3 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX3.
Genetic epilepsy syndromes v1.191 PEX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX2.
Genetic epilepsy syndromes v1.191 PEX19 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX19.
Genetic epilepsy syndromes v1.191 PEX13 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX13.
Genetic epilepsy syndromes v1.191 PEX12 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX12.
Genetic epilepsy syndromes v1.191 PEX10 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX10.
Genetic epilepsy syndromes v1.191 PEX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX1.
Genetic epilepsy syndromes v1.191 PET100 Rebecca Foulger Source Wessex and West Midlands GLH was added to PET100.
Genetic epilepsy syndromes v1.191 PDHX Rebecca Foulger Source Wessex and West Midlands GLH was added to PDHX.
Genetic epilepsy syndromes v1.191 PDHA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PDHA1.
Genetic epilepsy syndromes v1.191 PCDH12 Rebecca Foulger Source Wessex and West Midlands GLH was added to PCDH12.
Genetic epilepsy syndromes v1.191 PCCB Rebecca Foulger Source Wessex and West Midlands GLH was added to PCCB.
Genetic epilepsy syndromes v1.191 PCCA Rebecca Foulger Source Wessex and West Midlands GLH was added to PCCA.
Genetic epilepsy syndromes v1.191 PAH Rebecca Foulger Source Wessex and West Midlands GLH was added to PAH.
Genetic epilepsy syndromes v1.191 PAFAH1B1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PAFAH1B1.
Genetic epilepsy syndromes v1.191 PACS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PACS2.
Genetic epilepsy syndromes v1.191 PACS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PACS1.
Genetic epilepsy syndromes v1.191 OTUD6B Rebecca Foulger Source Wessex and West Midlands GLH was added to OTUD6B.
Genetic epilepsy syndromes v1.191 OPHN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to OPHN1.
Genetic epilepsy syndromes v1.191 OCLN Rebecca Foulger Source Wessex and West Midlands GLH was added to OCLN.
Genetic epilepsy syndromes v1.191 NTRK2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NTRK2.
Genetic epilepsy syndromes v1.191 NSDHL Rebecca Foulger Source Wessex and West Midlands GLH was added to NSDHL.
Genetic epilepsy syndromes v1.191 NSD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NSD1.
Genetic epilepsy syndromes v1.191 NRXN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NRXN1.
Genetic epilepsy syndromes v1.191 NPRL3 Rebecca Foulger Source Wessex and West Midlands GLH was added to NPRL3.
Genetic epilepsy syndromes v1.191 NHLRC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NHLRC1.
Genetic epilepsy syndromes v1.191 NGLY1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NGLY1.
Genetic epilepsy syndromes v1.191 NDUFV1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFV1.
Genetic epilepsy syndromes v1.191 NDUFS8 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS8.
Genetic epilepsy syndromes v1.191 NDUFS4 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS4.
Genetic epilepsy syndromes v1.191 NDUFAF5 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF5.
Genetic epilepsy syndromes v1.191 NDUFAF2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF2.
Genetic epilepsy syndromes v1.191 NDUFA10 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA10.
Genetic epilepsy syndromes v1.191 NDUFA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA1.
Genetic epilepsy syndromes v1.191 NDE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDE1.
Genetic epilepsy syndromes v1.191 NARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NARS2.
Genetic epilepsy syndromes v1.191 NAGA Rebecca Foulger Source Wessex and West Midlands GLH was added to NAGA.
Genetic epilepsy syndromes v1.191 MTR Rebecca Foulger Source Wessex and West Midlands GLH was added to MTR.
Genetic epilepsy syndromes v1.191 MTHFR Rebecca Foulger Source Wessex and West Midlands GLH was added to MTHFR.
Genetic epilepsy syndromes v1.191 MPDU1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MPDU1.
Genetic epilepsy syndromes v1.191 MOCS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MOCS2.
Genetic epilepsy syndromes v1.191 MOCS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MOCS1.
Genetic epilepsy syndromes v1.191 MMADHC Rebecca Foulger Source Wessex and West Midlands GLH was added to MMADHC.
Genetic epilepsy syndromes v1.191 MMACHC Rebecca Foulger Source Wessex and West Midlands GLH was added to MMACHC.
Genetic epilepsy syndromes v1.191 MLC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MLC1.
Genetic epilepsy syndromes v1.191 MFSD8 Rebecca Foulger Source Wessex and West Midlands GLH was added to MFSD8.
Genetic epilepsy syndromes v1.191 MED12 Rebecca Foulger Source Wessex and West Midlands GLH was added to MED12.
Genetic epilepsy syndromes v1.191 MAP2K2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAP2K2.
Genetic epilepsy syndromes v1.191 MAP2K1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAP2K1.
Genetic epilepsy syndromes v1.191 MAGI2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAGI2.
Genetic epilepsy syndromes v1.191 MAF Rebecca Foulger Source Wessex and West Midlands GLH was added to MAF.
Genetic epilepsy syndromes v1.191 MACF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MACF1.
Genetic epilepsy syndromes v1.191 LYST Rebecca Foulger Source Wessex and West Midlands GLH was added to LYST.
Genetic epilepsy syndromes v1.191 LIAS Rebecca Foulger Source Wessex and West Midlands GLH was added to LIAS.
Genetic epilepsy syndromes v1.191 KRAS Rebecca Foulger Source Wessex and West Midlands GLH was added to KRAS.
Genetic epilepsy syndromes v1.191 KIF5C Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF5C.
Genetic epilepsy syndromes v1.191 KIF2A Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF2A.
Genetic epilepsy syndromes v1.191 KIF1A Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF1A.
Genetic epilepsy syndromes v1.191 KCTD3 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCTD3.
Genetic epilepsy syndromes v1.191 KCNQ5 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNQ5.
Genetic epilepsy syndromes v1.191 KCNK4 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNK4.
Genetic epilepsy syndromes v1.191 KCNJ11 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNJ11.
Genetic epilepsy syndromes v1.191 KCNA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNA1.
Genetic epilepsy syndromes v1.191 KARS Rebecca Foulger Source Wessex and West Midlands GLH was added to KARS.
Genetic epilepsy syndromes v1.191 IRF2BPL Rebecca Foulger Source Wessex and West Midlands GLH was added to IRF2BPL.
Genetic epilepsy syndromes v1.191 IKBKG Rebecca Foulger Source Wessex and West Midlands GLH was added to IKBKG.
Genetic epilepsy syndromes v1.191 IFIH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to IFIH1.
Genetic epilepsy syndromes v1.191 HSD17B4 Rebecca Foulger Source Wessex and West Midlands GLH was added to HSD17B4.
Genetic epilepsy syndromes v1.191 HRAS Rebecca Foulger Source Wessex and West Midlands GLH was added to HRAS.
Genetic epilepsy syndromes v1.191 HLCS Rebecca Foulger Source Wessex and West Midlands GLH was added to HLCS.
Genetic epilepsy syndromes v1.191 HEXA Rebecca Foulger Source Wessex and West Midlands GLH was added to HEXA.
Genetic epilepsy syndromes v1.191 HEPACAM Rebecca Foulger Source Wessex and West Midlands GLH was added to HEPACAM.
Genetic epilepsy syndromes v1.191 HCN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HCN2.
Genetic epilepsy syndromes v1.191 HCFC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HCFC1.
Genetic epilepsy syndromes v1.191 HAX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HAX1.
Genetic epilepsy syndromes v1.191 HACE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HACE1.
Genetic epilepsy syndromes v1.191 GTPBP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GTPBP2.
Genetic epilepsy syndromes v1.191 GRIN2D Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN2D.
Genetic epilepsy syndromes v1.191 GRIA4 Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIA4.
Genetic epilepsy syndromes v1.191 GPHN Rebecca Foulger Source Wessex and West Midlands GLH was added to GPHN.
Genetic epilepsy syndromes v1.191 GOSR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GOSR2.
Genetic epilepsy syndromes v1.191 GNB5 Rebecca Foulger Source Wessex and West Midlands GLH was added to GNB5.
Genetic epilepsy syndromes v1.191 GNB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GNB1.
Genetic epilepsy syndromes v1.191 GNAQ Rebecca Foulger Source Wessex and West Midlands GLH was added to GNAQ.
Genetic epilepsy syndromes v1.191 GM2A Rebecca Foulger Source Wessex and West Midlands GLH was added to GM2A.
Genetic epilepsy syndromes v1.191 GLUL Rebecca Foulger Source Wessex and West Midlands GLH was added to GLUL.
Genetic epilepsy syndromes v1.191 GLUD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLUD1.
Genetic epilepsy syndromes v1.191 GLDC Rebecca Foulger Source Wessex and West Midlands GLH was added to GLDC.
Genetic epilepsy syndromes v1.191 GLB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLB1.
Genetic epilepsy syndromes v1.191 GFM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GFM1.
Genetic epilepsy syndromes v1.191 GFAP Rebecca Foulger Source Wessex and West Midlands GLH was added to GFAP.
Genetic epilepsy syndromes v1.191 GCH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GCH1.
Genetic epilepsy syndromes v1.191 GBA Rebecca Foulger Source Wessex and West Midlands GLH was added to GBA.
Genetic epilepsy syndromes v1.191 GAMT Rebecca Foulger Source Wessex and West Midlands GLH was added to GAMT.
Genetic epilepsy syndromes v1.191 GALC Rebecca Foulger Source Wessex and West Midlands GLH was added to GALC.
Genetic epilepsy syndromes v1.191 GABRB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRB2.
Genetic epilepsy syndromes v1.191 FUT8 Rebecca Foulger Source Wessex and West Midlands GLH was added to FUT8.
Genetic epilepsy syndromes v1.191 FUCA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FUCA1.
Genetic epilepsy syndromes v1.191 FRRS1L Rebecca Foulger Source Wessex and West Midlands GLH was added to FRRS1L.
Genetic epilepsy syndromes v1.191 FOLR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FOLR1.
Genetic epilepsy syndromes v1.191 FLNA Rebecca Foulger Source Wessex and West Midlands GLH was added to FLNA.
Genetic epilepsy syndromes v1.191 FKTN Rebecca Foulger Source Wessex and West Midlands GLH was added to FKTN.
Genetic epilepsy syndromes v1.191 FH Rebecca Foulger Source Wessex and West Midlands GLH was added to FH.
Genetic epilepsy syndromes v1.191 FGFR3 Rebecca Foulger Source Wessex and West Midlands GLH was added to FGFR3.
Genetic epilepsy syndromes v1.191 FGF12 Rebecca Foulger Source Wessex and West Midlands GLH was added to FGF12.
Genetic epilepsy syndromes v1.191 FBXO11 Rebecca Foulger Source Wessex and West Midlands GLH was added to FBXO11.
Genetic epilepsy syndromes v1.191 FBXL4 Rebecca Foulger Source Wessex and West Midlands GLH was added to FBXL4.
Genetic epilepsy syndromes v1.191 FARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to FARS2.
Genetic epilepsy syndromes v1.191 FAR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FAR1.
Genetic epilepsy syndromes v1.191 EXOSC3 Rebecca Foulger Source Wessex and West Midlands GLH was added to EXOSC3.
Genetic epilepsy syndromes v1.191 ETHE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ETHE1.
Genetic epilepsy syndromes v1.191 EMX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EMX2.
Genetic epilepsy syndromes v1.191 EIF3F Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF3F.
Genetic epilepsy syndromes v1.191 EIF2S3 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2S3.
Genetic epilepsy syndromes v1.191 EIF2B5 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B5.
Genetic epilepsy syndromes v1.191 EIF2B4 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B4.
Genetic epilepsy syndromes v1.191 EIF2B2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B2.
Genetic epilepsy syndromes v1.191 EFTUD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EFTUD2.
Genetic epilepsy syndromes v1.191 EEF1A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EEF1A2.
Genetic epilepsy syndromes v1.191 EARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EARS2.
Genetic epilepsy syndromes v1.191 DYNC1H1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DYNC1H1.
Genetic epilepsy syndromes v1.191 DPM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DPM1.
Genetic epilepsy syndromes v1.191 DPAGT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DPAGT1.
Genetic epilepsy syndromes v1.191 DNM1L Rebecca Foulger Source Wessex and West Midlands GLH was added to DNM1L.
Genetic epilepsy syndromes v1.191 DHX30 Rebecca Foulger Source Wessex and West Midlands GLH was added to DHX30.
Genetic epilepsy syndromes v1.191 DHDDS Rebecca Foulger Source Wessex and West Midlands GLH was added to DHDDS.
Genetic epilepsy syndromes v1.191 DHCR7 Rebecca Foulger Source Wessex and West Midlands GLH was added to DHCR7.
Genetic epilepsy syndromes v1.191 DENND5A Rebecca Foulger Source Wessex and West Midlands GLH was added to DENND5A.
Genetic epilepsy syndromes v1.191 DEAF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DEAF1.
Genetic epilepsy syndromes v1.191 DDX3X Rebecca Foulger Source Wessex and West Midlands GLH was added to DDX3X.
Genetic epilepsy syndromes v1.191 DCX Rebecca Foulger Source Wessex and West Midlands GLH was added to DCX.
Genetic epilepsy syndromes v1.191 D2HGDH Rebecca Foulger Source Wessex and West Midlands GLH was added to D2HGDH.
Genetic epilepsy syndromes v1.191 CTSD Rebecca Foulger Source Wessex and West Midlands GLH was added to CTSD.
Genetic epilepsy syndromes v1.191 CSTB Rebecca Foulger Source Wessex and West Midlands GLH was added to CSTB.
Genetic epilepsy syndromes v1.191 CREBBP Rebecca Foulger Source Wessex and West Midlands GLH was added to CREBBP.
Genetic epilepsy syndromes v1.191 COQ9 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ9.
Genetic epilepsy syndromes v1.191 COQ4 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ4.
Genetic epilepsy syndromes v1.191 COQ2 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ2.
Genetic epilepsy syndromes v1.191 COL4A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to COL4A2.
Genetic epilepsy syndromes v1.191 COL4A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to COL4A1.
Genetic epilepsy syndromes v1.191 COL18A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to COL18A1.
Genetic epilepsy syndromes v1.191 COG7 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG7.
Genetic epilepsy syndromes v1.191 CNNM2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNNM2.
Genetic epilepsy syndromes v1.191 CLN3 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN3.
Genetic epilepsy syndromes v1.191 CLCN4 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLCN4.
Genetic epilepsy syndromes v1.191 CC2D2A Rebecca Foulger Source Wessex and West Midlands GLH was added to CC2D2A.
Genetic epilepsy syndromes v1.191 CASK Rebecca Foulger Source Wessex and West Midlands GLH was added to CASK.
Genetic epilepsy syndromes v1.191 CAD Rebecca Foulger Source Wessex and West Midlands GLH was added to CAD.
Genetic epilepsy syndromes v1.191 CACNA1G Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1G.
Genetic epilepsy syndromes v1.191 CACNA1E Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1E.
Genetic epilepsy syndromes v1.191 CACNA1A Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1A.
Genetic epilepsy syndromes v1.191 C12orf57 Rebecca Foulger Source Wessex and West Midlands GLH was added to C12orf57.
Genetic epilepsy syndromes v1.191 BTD Rebecca Foulger Source Wessex and West Midlands GLH was added to BTD.
Genetic epilepsy syndromes v1.191 BRAF Rebecca Foulger Source Wessex and West Midlands GLH was added to BRAF.
Genetic epilepsy syndromes v1.191 BOLA3 Rebecca Foulger Source Wessex and West Midlands GLH was added to BOLA3.
Genetic epilepsy syndromes v1.191 BCS1L Rebecca Foulger Source Wessex and West Midlands GLH was added to BCS1L.
Genetic epilepsy syndromes v1.191 BCKDHB Rebecca Foulger Source Wessex and West Midlands GLH was added to BCKDHB.
Genetic epilepsy syndromes v1.191 BCKDHA Rebecca Foulger Source Wessex and West Midlands GLH was added to BCKDHA.
Genetic epilepsy syndromes v1.191 ATP7A Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP7A.
Genetic epilepsy syndromes v1.191 ATP6V1A Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP6V1A.
Genetic epilepsy syndromes v1.191 ATP1A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP1A1.
Genetic epilepsy syndromes v1.191 ASPA Rebecca Foulger Source Wessex and West Midlands GLH was added to ASPA.
Genetic epilepsy syndromes v1.191 ARV1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARV1.
Genetic epilepsy syndromes v1.191 ARID1B Rebecca Foulger Source Wessex and West Midlands GLH was added to ARID1B.
Genetic epilepsy syndromes v1.191 ARG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARG1.
Genetic epilepsy syndromes v1.191 ARFGEF2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARFGEF2.
Genetic epilepsy syndromes v1.191 AP3B2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AP3B2.
Genetic epilepsy syndromes v1.191 AMT Rebecca Foulger Source Wessex and West Midlands GLH was added to AMT.
Genetic epilepsy syndromes v1.191 AMPD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AMPD2.
Genetic epilepsy syndromes v1.191 ALPL Rebecca Foulger Source Wessex and West Midlands GLH was added to ALPL.
Genetic epilepsy syndromes v1.191 ALG9 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG9.
Genetic epilepsy syndromes v1.191 ALG8 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG8.
Genetic epilepsy syndromes v1.191 ALG6 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG6.
Genetic epilepsy syndromes v1.191 ALG3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG3.
Genetic epilepsy syndromes v1.191 ALG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG1.
Genetic epilepsy syndromes v1.191 ALDH5A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALDH5A1.
Genetic epilepsy syndromes v1.191 AKT3 Rebecca Foulger Source Wessex and West Midlands GLH was added to AKT3.
Genetic epilepsy syndromes v1.191 AKT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to AKT1.
Genetic epilepsy syndromes v1.191 AIMP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to AIMP1.
Genetic epilepsy syndromes v1.191 ADPRHL2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADPRHL2.
Genetic epilepsy syndromes v1.191 ADGRG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADGRG1.
Genetic epilepsy syndromes v1.191 ADAR Rebecca Foulger Source Wessex and West Midlands GLH was added to ADAR.
Genetic epilepsy syndromes v1.191 ACOX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ACOX1.
Genetic epilepsy syndromes v1.191 ABAT Rebecca Foulger Source Wessex and West Midlands GLH was added to ABAT.
Genetic epilepsy syndromes v1.191 ZEB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZEB2.
Genetic epilepsy syndromes v1.191 WWOX Rebecca Foulger Source Wessex and West Midlands GLH was added to WWOX.
Genetic epilepsy syndromes v1.191 WDR45B Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR45B.
Genetic epilepsy syndromes v1.191 WDR45 Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR45.
Genetic epilepsy syndromes v1.191 UBE3A Rebecca Foulger Source Wessex and West Midlands GLH was added to UBE3A.
Genetic epilepsy syndromes v1.191 UBE2A Rebecca Foulger Source Wessex and West Midlands GLH was added to UBE2A.
Genetic epilepsy syndromes v1.191 TRPM6 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRPM6.
Genetic epilepsy syndromes v1.191 TRAK1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAK1.
Genetic epilepsy syndromes v1.191 TPP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TPP1.
Genetic epilepsy syndromes v1.191 TCF4 Rebecca Foulger Source Wessex and West Midlands GLH was added to TCF4.
Genetic epilepsy syndromes v1.191 TBC1D24 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBC1D24.
Genetic epilepsy syndromes v1.191 SZT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SZT2.
Genetic epilepsy syndromes v1.191 SYNJ1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SYNJ1.
Genetic epilepsy syndromes v1.191 SYNGAP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SYNGAP1.
Genetic epilepsy syndromes v1.191 SUOX Rebecca Foulger Source Wessex and West Midlands GLH was added to SUOX.
Genetic epilepsy syndromes v1.191 STXBP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to STXBP1.
Genetic epilepsy syndromes v1.191 STX1B Rebecca Foulger Source Wessex and West Midlands GLH was added to STX1B.
Genetic epilepsy syndromes v1.191 STRADA Rebecca Foulger Source Wessex and West Midlands GLH was added to STRADA.
Genetic epilepsy syndromes v1.191 SPTAN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SPTAN1.
Genetic epilepsy syndromes v1.191 SLC9A6 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC9A6.
Genetic epilepsy syndromes v1.191 SLC6A19 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A19.
Genetic epilepsy syndromes v1.191 SLC6A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A1.
Genetic epilepsy syndromes v1.191 SLC35A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC35A2.
Genetic epilepsy syndromes v1.191 SLC2A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC2A1.
Genetic epilepsy syndromes v1.191 SLC25A22 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC25A22.
Genetic epilepsy syndromes v1.191 SLC25A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC25A1.
Genetic epilepsy syndromes v1.191 SLC1A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC1A2.
Genetic epilepsy syndromes v1.191 SLC16A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC16A2.
Genetic epilepsy syndromes v1.191 SLC13A5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC13A5.
Genetic epilepsy syndromes v1.191 SLC12A5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC12A5.
Genetic epilepsy syndromes v1.191 SIK1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SIK1.
Genetic epilepsy syndromes v1.191 SETD5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SETD5.
Genetic epilepsy syndromes v1.191 SCN9A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN9A.
Genetic epilepsy syndromes v1.191 SCN8A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN8A.
Genetic epilepsy syndromes v1.191 SCN2A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN2A.
Genetic epilepsy syndromes v1.191 SCN1B Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN1B.
Genetic epilepsy syndromes v1.191 SCN1A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN1A.
Genetic epilepsy syndromes v1.191 SCARB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SCARB2.
Genetic epilepsy syndromes v1.191 RANBP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RANBP2.
Genetic epilepsy syndromes v1.191 QARS Rebecca Foulger Source Wessex and West Midlands GLH was added to QARS.
Genetic epilepsy syndromes v1.191 PURA Rebecca Foulger Source Wessex and West Midlands GLH was added to PURA.
Genetic epilepsy syndromes v1.191 PRRT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRRT2.
Genetic epilepsy syndromes v1.191 PRODH Rebecca Foulger Source Wessex and West Midlands GLH was added to PRODH.
Genetic epilepsy syndromes v1.191 POLG Rebecca Foulger Source Wessex and West Midlands GLH was added to POLG.
Genetic epilepsy syndromes v1.191 PNPO Rebecca Foulger Source Wessex and West Midlands GLH was added to PNPO.
Genetic epilepsy syndromes v1.191 PNKP Rebecca Foulger Source Wessex and West Midlands GLH was added to PNKP.
Genetic epilepsy syndromes v1.191 PLPBP Rebecca Foulger Source Wessex and West Midlands GLH was added to PLPBP.
Genetic epilepsy syndromes v1.191 PLCB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PLCB1.
Genetic epilepsy syndromes v1.191 PIGT Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGT.
Genetic epilepsy syndromes v1.191 PIGN Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGN.
Genetic epilepsy syndromes v1.191 PIGA Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGA.
Genetic epilepsy syndromes v1.191 PCDH19 Rebecca Foulger Source Wessex and West Midlands GLH was added to PCDH19.
Genetic epilepsy syndromes v1.191 NEXMIF Rebecca Foulger Source Wessex and West Midlands GLH was added to NEXMIF.
Genetic epilepsy syndromes v1.191 NACC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NACC1.
Genetic epilepsy syndromes v1.191 MTOR Rebecca Foulger Source Wessex and West Midlands GLH was added to MTOR.
Genetic epilepsy syndromes v1.191 MOGS Rebecca Foulger Source Wessex and West Midlands GLH was added to MOGS.
Genetic epilepsy syndromes v1.191 MFF Rebecca Foulger Source Wessex and West Midlands GLH was added to MFF.
Genetic epilepsy syndromes v1.191 MEF2C Rebecca Foulger Source Wessex and West Midlands GLH was added to MEF2C.
Genetic epilepsy syndromes v1.191 MECP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MECP2.
Genetic epilepsy syndromes v1.191 MDH2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MDH2.
Genetic epilepsy syndromes v1.191 MBOAT7 Rebecca Foulger Source Wessex and West Midlands GLH was added to MBOAT7.
Genetic epilepsy syndromes v1.191 MBD5 Rebecca Foulger Source Wessex and West Midlands GLH was added to MBD5.
Genetic epilepsy syndromes v1.191 LGI1 Rebecca Foulger Source Wessex and West Midlands GLH was added to LGI1.
Genetic epilepsy syndromes v1.191 KIF1BP Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF1BP.
Genetic epilepsy syndromes v1.191 KCTD7 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCTD7.
Genetic epilepsy syndromes v1.191 KCNT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNT1.
Genetic epilepsy syndromes v1.191 KCNQ3 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNQ3.
Genetic epilepsy syndromes v1.191 KCNQ2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNQ2.
Genetic epilepsy syndromes v1.191 KCNJ10 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNJ10.
Genetic epilepsy syndromes v1.191 KCNC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNC1.
Genetic epilepsy syndromes v1.191 KCNB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNB1.
Genetic epilepsy syndromes v1.191 KCNA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNA2.
Genetic epilepsy syndromes v1.191 ITPA Rebecca Foulger Source Wessex and West Midlands GLH was added to ITPA.
Genetic epilepsy syndromes v1.191 IQSEC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to IQSEC2.
Genetic epilepsy syndromes v1.191 IER3IP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to IER3IP1.
Genetic epilepsy syndromes v1.191 IDH2 Rebecca Foulger Source Wessex and West Midlands GLH was added to IDH2.
Genetic epilepsy syndromes v1.191 HTRA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HTRA2.
Genetic epilepsy syndromes v1.191 HNRNPU Rebecca Foulger Source Wessex and West Midlands GLH was added to HNRNPU.
Genetic epilepsy syndromes v1.191 HNRNPH2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HNRNPH2.
Genetic epilepsy syndromes v1.191 HMGCL Rebecca Foulger Source Wessex and West Midlands GLH was added to HMGCL.
Genetic epilepsy syndromes v1.191 HECW2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HECW2.
Genetic epilepsy syndromes v1.191 HCN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HCN1.
Genetic epilepsy syndromes v1.191 GSS Rebecca Foulger Source Wessex and West Midlands GLH was added to GSS.
Genetic epilepsy syndromes v1.191 GRIN2B Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN2B.
Genetic epilepsy syndromes v1.191 GRIN2A Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN2A.
Genetic epilepsy syndromes v1.191 GRIN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN1.
Genetic epilepsy syndromes v1.191 GPAA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GPAA1.
Genetic epilepsy syndromes v1.191 GNAO1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GNAO1.
Genetic epilepsy syndromes v1.191 GLYCTK Rebecca Foulger Source Wessex and West Midlands GLH was added to GLYCTK.
Genetic epilepsy syndromes v1.191 GABRG2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRG2.
Genetic epilepsy syndromes v1.191 GABRB3 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRB3.
Genetic epilepsy syndromes v1.191 GABRA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRA1.
Genetic epilepsy syndromes v1.191 GABBR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABBR2.
Genetic epilepsy syndromes v1.191 FOXG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FOXG1.
Genetic epilepsy syndromes v1.191 EPM2A Rebecca Foulger Source Wessex and West Midlands GLH was added to EPM2A.
Genetic epilepsy syndromes v1.191 EPG5 Rebecca Foulger Source Wessex and West Midlands GLH was added to EPG5.
Genetic epilepsy syndromes v1.191 EML1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EML1.
Genetic epilepsy syndromes v1.191 EHMT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EHMT1.
Genetic epilepsy syndromes v1.191 DYRK1A Rebecca Foulger Source Wessex and West Midlands GLH was added to DYRK1A.
Genetic epilepsy syndromes v1.191 DPYD Rebecca Foulger Source Wessex and West Midlands GLH was added to DPYD.
Genetic epilepsy syndromes v1.191 DOCK7 Rebecca Foulger Source Wessex and West Midlands GLH was added to DOCK7.
Genetic epilepsy syndromes v1.191 DNM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DNM1.
Genetic epilepsy syndromes v1.191 DIAPH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DIAPH1.
Genetic epilepsy syndromes v1.191 DEPDC5 Rebecca Foulger Source Wessex and West Midlands GLH was added to DEPDC5.
Genetic epilepsy syndromes v1.191 CYFIP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CYFIP2.
Genetic epilepsy syndromes v1.191 CPA6 Rebecca Foulger Source Wessex and West Midlands GLH was added to CPA6.
Genetic epilepsy syndromes v1.191 CNTNAP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNTNAP2.
Genetic epilepsy syndromes v1.191 CNKSR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNKSR2.
Genetic epilepsy syndromes v1.191 CLTC Rebecca Foulger Source Wessex and West Midlands GLH was added to CLTC.
Genetic epilepsy syndromes v1.191 CLN8 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN8.
Genetic epilepsy syndromes v1.191 CIC Rebecca Foulger Source Wessex and West Midlands GLH was added to CIC.
Genetic epilepsy syndromes v1.191 CHRNB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHRNB2.
Genetic epilepsy syndromes v1.191 CHRNA4 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHRNA4.
Genetic epilepsy syndromes v1.191 CHRNA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHRNA2.
Genetic epilepsy syndromes v1.191 CHD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHD2.
Genetic epilepsy syndromes v1.191 CDKL5 Rebecca Foulger Source Wessex and West Midlands GLH was added to CDKL5.
Genetic epilepsy syndromes v1.191 CACNA1D Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1D.
Genetic epilepsy syndromes v1.191 BSCL2 Rebecca Foulger Source Wessex and West Midlands GLH was added to BSCL2.
Genetic epilepsy syndromes v1.191 BRAT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to BRAT1.
Genetic epilepsy syndromes v1.191 ATRX Rebecca Foulger Source Wessex and West Midlands GLH was added to ATRX.
Genetic epilepsy syndromes v1.191 ATP6V0A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP6V0A2.
Genetic epilepsy syndromes v1.191 ATP1A3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP1A3.
Genetic epilepsy syndromes v1.191 ARX Rebecca Foulger Source Wessex and West Midlands GLH was added to ARX.
Genetic epilepsy syndromes v1.191 ARHGEF9 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARHGEF9.
Genetic epilepsy syndromes v1.191 ALG13 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG13.
Genetic epilepsy syndromes v1.191 ALG11 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG11.
Genetic epilepsy syndromes v1.191 ALDH7A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALDH7A1.
Genetic epilepsy syndromes v1.191 ADSL Rebecca Foulger Source Wessex and West Midlands GLH was added to ADSL.
Genetic epilepsy syndromes v1.191 AARS Rebecca Foulger Source Wessex and West Midlands GLH was added to AARS.
Genetic epilepsy syndromes v1.190 TUBA3E Rebecca Foulger Source NHS GMS was added to TUBA3E.
Genetic epilepsy syndromes v1.190 SLC6A5 Rebecca Foulger Source NHS GMS was added to SLC6A5.
Genetic epilepsy syndromes v1.190 SHH Rebecca Foulger Source NHS GMS was added to SHH.
Genetic epilepsy syndromes v1.190 SEC24D Rebecca Foulger Source NHS GMS was added to SEC24D.
Genetic epilepsy syndromes v1.190 SCN2B Rebecca Foulger Source NHS GMS was added to SCN2B.
Genetic epilepsy syndromes v1.190 RYR3 Rebecca Foulger Source NHS GMS was added to RYR3.
Genetic epilepsy syndromes v1.190 RUBCN Rebecca Foulger Source NHS GMS was added to RUBCN.
Genetic epilepsy syndromes v1.190 PSMB8 Rebecca Foulger Source NHS GMS was added to PSMB8.
Genetic epilepsy syndromes v1.190 PRICKLE2 Rebecca Foulger Source NHS GMS was added to PRICKLE2.
Genetic epilepsy syndromes v1.190 PCDHB4 Rebecca Foulger Source NHS GMS was added to PCDHB4.
Genetic epilepsy syndromes v1.190 NRAS Rebecca Foulger Source NHS GMS was added to NRAS.
Genetic epilepsy syndromes v1.190 NID1 Rebecca Foulger Source NHS GMS was added to NID1.
Genetic epilepsy syndromes v1.190 NDUFA11 Rebecca Foulger Source NHS GMS was added to NDUFA11.
Genetic epilepsy syndromes v1.190 MT-TL1 Rebecca Foulger Source NHS GMS was added to MT-TL1.
Genetic epilepsy syndromes v1.190 MATN4 Rebecca Foulger Source NHS GMS was added to MATN4.
Genetic epilepsy syndromes v1.190 MAPK10 Rebecca Foulger Source NHS GMS was added to MAPK10.
Genetic epilepsy syndromes v1.190 KAT5 Rebecca Foulger Source NHS GMS was added to KAT5.
Genetic epilepsy syndromes v1.190 INO80 Rebecca Foulger Source NHS GMS was added to INO80.
Genetic epilepsy syndromes v1.190 H3F3B Rebecca Foulger Source NHS GMS was added to H3F3B.
Genetic epilepsy syndromes v1.190 H3F3A Rebecca Foulger Source NHS GMS was added to H3F3A.
Genetic epilepsy syndromes v1.190 GLRB Rebecca Foulger Source NHS GMS was added to GLRB.
Genetic epilepsy syndromes v1.190 GCSH Rebecca Foulger Source NHS GMS was added to GCSH.
Genetic epilepsy syndromes v1.190 GATM Rebecca Foulger Source NHS GMS was added to GATM.
Genetic epilepsy syndromes v1.190 GATAD2B Rebecca Foulger Source NHS GMS was added to GATAD2B.
Genetic epilepsy syndromes v1.190 GAL Rebecca Foulger Source NHS GMS was added to GAL.
Genetic epilepsy syndromes v1.190 GABRD Rebecca Foulger Source NHS GMS was added to GABRD.
Genetic epilepsy syndromes v1.190 FTL Rebecca Foulger Source NHS GMS was added to FTL.
Genetic epilepsy syndromes v1.190 FIG4 Rebecca Foulger Source NHS GMS was added to FIG4.
Genetic epilepsy syndromes v1.190 DMBX1 Rebecca Foulger Source NHS GMS was added to DMBX1.
Genetic epilepsy syndromes v1.190 CYP27A1 Rebecca Foulger Source NHS GMS was added to CYP27A1.
Genetic epilepsy syndromes v1.190 CSNK1G1 Rebecca Foulger Source NHS GMS was added to CSNK1G1.
Genetic epilepsy syndromes v1.190 CRH Rebecca Foulger Source NHS GMS was added to CRH.
Genetic epilepsy syndromes v1.190 CNTN2 Rebecca Foulger Source NHS GMS was added to CNTN2.
Genetic epilepsy syndromes v1.190 CLN6 Rebecca Foulger Source NHS GMS was added to CLN6.
Genetic epilepsy syndromes v1.190 CLN5 Rebecca Foulger Source NHS GMS was added to CLN5.
Genetic epilepsy syndromes v1.190 CLCN2 Rebecca Foulger Source NHS GMS was added to CLCN2.
Genetic epilepsy syndromes v1.190 CBL Rebecca Foulger Source NHS GMS was added to CBL.
Genetic epilepsy syndromes v1.190 CASR Rebecca Foulger Source NHS GMS was added to CASR.
Genetic epilepsy syndromes v1.190 CAMK2G Rebecca Foulger Source NHS GMS was added to CAMK2G.
Genetic epilepsy syndromes v1.190 CACNB4 Rebecca Foulger Source NHS GMS was added to CACNB4.
Genetic epilepsy syndromes v1.190 ASAH1 Rebecca Foulger Source NHS GMS was added to ASAH1.
Genetic epilepsy syndromes v1.190 ALG2 Rebecca Foulger Source NHS GMS was added to ALG2.
Genetic epilepsy syndromes v1.190 ALG12 Rebecca Foulger Source NHS GMS was added to ALG12.
Genetic epilepsy syndromes v1.190 ADGRV1 Rebecca Foulger Source NHS GMS was added to ADGRV1.
Genetic epilepsy syndromes v1.190 AARS2 Rebecca Foulger Source NHS GMS was added to AARS2.
Genetic epilepsy syndromes v1.190 VLDLR Rebecca Foulger Source NHS GMS was added to VLDLR.
Genetic epilepsy syndromes v1.190 UFC1 Rebecca Foulger Source NHS GMS was added to UFC1.
Genetic epilepsy syndromes v1.190 TXNRD1 Rebecca Foulger Source NHS GMS was added to TXNRD1.
Genetic epilepsy syndromes v1.190 TUBB Rebecca Foulger Source NHS GMS was added to TUBB.
Genetic epilepsy syndromes v1.190 TUBA8 Rebecca Foulger Source NHS GMS was added to TUBA8.
Genetic epilepsy syndromes v1.190 TSFM Rebecca Foulger Source NHS GMS was added to TSFM.
Genetic epilepsy syndromes v1.190 TSEN34 Rebecca Foulger Source NHS GMS was added to TSEN34.
Genetic epilepsy syndromes v1.190 TSEN15 Rebecca Foulger Source NHS GMS was added to TSEN15.
Genetic epilepsy syndromes v1.190 TRIP13 Rebecca Foulger Source NHS GMS was added to TRIP13.
Genetic epilepsy syndromes v1.190 TRAPPC6B Rebecca Foulger Source NHS GMS was added to TRAPPC6B.
Genetic epilepsy syndromes v1.190 TRAPPC12 Rebecca Foulger Source NHS GMS was added to TRAPPC12.
Genetic epilepsy syndromes v1.190 TRAF7 Rebecca Foulger Source NHS GMS was added to TRAF7.
Genetic epilepsy syndromes v1.190 TNK2 Rebecca Foulger Source NHS GMS was added to TNK2.
Genetic epilepsy syndromes v1.190 TIMM50 Rebecca Foulger Source NHS GMS was added to TIMM50.
Genetic epilepsy syndromes v1.190 TFE3 Rebecca Foulger Source NHS GMS was added to TFE3.
Genetic epilepsy syndromes v1.190 TELO2 Rebecca Foulger Source NHS GMS was added to TELO2.
Genetic epilepsy syndromes v1.190 TBC1D20 Rebecca Foulger Source NHS GMS was added to TBC1D20.
Genetic epilepsy syndromes v1.190 SUCLG1 Rebecca Foulger Source NHS GMS was added to SUCLG1.
Genetic epilepsy syndromes v1.190 ST3GAL3 Rebecca Foulger Source NHS GMS was added to ST3GAL3.
Genetic epilepsy syndromes v1.190 SRPX2 Rebecca Foulger Source NHS GMS was added to SRPX2.
Genetic epilepsy syndromes v1.190 SPR Rebecca Foulger Source NHS GMS was added to SPR.
Genetic epilepsy syndromes v1.190 SNIP1 Rebecca Foulger Source NHS GMS was added to SNIP1.
Genetic epilepsy syndromes v1.190 SMC1A Rebecca Foulger Source NHS GMS was added to SMC1A.
Genetic epilepsy syndromes v1.190 SLC45A1 Rebecca Foulger Source NHS GMS was added to SLC45A1.
Genetic epilepsy syndromes v1.190 SLC35A1 Rebecca Foulger Source NHS GMS was added to SLC35A1.
Genetic epilepsy syndromes v1.190 SIX3 Rebecca Foulger Source NHS GMS was added to SIX3.
Genetic epilepsy syndromes v1.190 SETD1B Rebecca Foulger Source NHS GMS was added to SETD1B.
Genetic epilepsy syndromes v1.190 SDHA Rebecca Foulger Source NHS GMS was added to SDHA.
Genetic epilepsy syndromes v1.190 RYR2 Rebecca Foulger Source NHS GMS was added to RYR2.
Genetic epilepsy syndromes v1.190 RUSC2 Rebecca Foulger Source NHS GMS was added to RUSC2.
Genetic epilepsy syndromes v1.190 RRM2B Rebecca Foulger Source NHS GMS was added to RRM2B.
Genetic epilepsy syndromes v1.190 RPIA Rebecca Foulger Source NHS GMS was added to RPIA.
Genetic epilepsy syndromes v1.190 RNU4ATAC Rebecca Foulger Source NHS GMS was added to RNU4ATAC.
Genetic epilepsy syndromes v1.190 RAB3GAP2 Rebecca Foulger Source NHS GMS was added to RAB3GAP2.
Genetic epilepsy syndromes v1.190 RAB3GAP1 Rebecca Foulger Source NHS GMS was added to RAB3GAP1.
Genetic epilepsy syndromes v1.190 PTF1A Rebecca Foulger Source NHS GMS was added to PTF1A.
Genetic epilepsy syndromes v1.190 PSPH Rebecca Foulger Source NHS GMS was added to PSPH.
Genetic epilepsy syndromes v1.190 PSAT1 Rebecca Foulger Source NHS GMS was added to PSAT1.
Genetic epilepsy syndromes v1.190 POMT2 Rebecca Foulger Source NHS GMS was added to POMT2.
Genetic epilepsy syndromes v1.190 PIGQ Rebecca Foulger Source NHS GMS was added to PIGQ.
Genetic epilepsy syndromes v1.190 PIGH Rebecca Foulger Source NHS GMS was added to PIGH.
Genetic epilepsy syndromes v1.190 PIGC Rebecca Foulger Source NHS GMS was added to PIGC.
Genetic epilepsy syndromes v1.190 PEX5 Rebecca Foulger Source NHS GMS was added to PEX5.
Genetic epilepsy syndromes v1.190 PDSS2 Rebecca Foulger Source NHS GMS was added to PDSS2.
Genetic epilepsy syndromes v1.190 PCLO Rebecca Foulger Source NHS GMS was added to PCLO.
Genetic epilepsy syndromes v1.190 OTX2 Rebecca Foulger Source NHS GMS was added to OTX2.
Genetic epilepsy syndromes v1.190 NUBPL Rebecca Foulger Source NHS GMS was added to NUBPL.
Genetic epilepsy syndromes v1.190 NPRL2 Rebecca Foulger Source NHS GMS was added to NPRL2.
Genetic epilepsy syndromes v1.190 NEDD4L Rebecca Foulger Source NHS GMS was added to NEDD4L.
Genetic epilepsy syndromes v1.190 NECAP1 Rebecca Foulger Source NHS GMS was added to NECAP1.
Genetic epilepsy syndromes v1.190 NDUFS7 Rebecca Foulger Source NHS GMS was added to NDUFS7.
Genetic epilepsy syndromes v1.190 NDUFS6 Rebecca Foulger Source NHS GMS was added to NDUFS6.
Genetic epilepsy syndromes v1.190 NDUFS2 Rebecca Foulger Source NHS GMS was added to NDUFS2.
Genetic epilepsy syndromes v1.190 NDUFS1 Rebecca Foulger Source NHS GMS was added to NDUFS1.
Genetic epilepsy syndromes v1.190 NDUFAF4 Rebecca Foulger Source NHS GMS was added to NDUFAF4.
Genetic epilepsy syndromes v1.190 NDUFAF3 Rebecca Foulger Source NHS GMS was added to NDUFAF3.
Genetic epilepsy syndromes v1.190 NDUFA2 Rebecca Foulger Source NHS GMS was added to NDUFA2.
Genetic epilepsy syndromes v1.190 NDP Rebecca Foulger Source NHS GMS was added to NDP.
Genetic epilepsy syndromes v1.190 MED17 Rebecca Foulger Source NHS GMS was added to MED17.
Genetic epilepsy syndromes v1.190 MAST1 Rebecca Foulger Source NHS GMS was added to MAST1.
Genetic epilepsy syndromes v1.190 MANBA Rebecca Foulger Source NHS GMS was added to MANBA.
Genetic epilepsy syndromes v1.190 LNPK Rebecca Foulger Source NHS GMS was added to LNPK.
Genetic epilepsy syndromes v1.190 LIPT2 Rebecca Foulger Source NHS GMS was added to LIPT2.
Genetic epilepsy syndromes v1.190 LARGE1 Rebecca Foulger Source NHS GMS was added to LARGE1.
Genetic epilepsy syndromes v1.190 KPTN Rebecca Foulger Source NHS GMS was added to KPTN.
Genetic epilepsy syndromes v1.190 KIAA1109 Rebecca Foulger Source NHS GMS was added to KIAA1109.
Genetic epilepsy syndromes v1.190 KCNMA1 Rebecca Foulger Source NHS GMS was added to KCNMA1.
Genetic epilepsy syndromes v1.190 ISPD Rebecca Foulger Source NHS GMS was added to ISPD.
Genetic epilepsy syndromes v1.190 HSPD1 Rebecca Foulger Source NHS GMS was added to HSPD1.
Genetic epilepsy syndromes v1.190 HPRT1 Rebecca Foulger Source NHS GMS was added to HPRT1.
Genetic epilepsy syndromes v1.190 HOXA1 Rebecca Foulger Source NHS GMS was added to HOXA1.
Genetic epilepsy syndromes v1.190 HEXB Rebecca Foulger Source NHS GMS was added to HEXB.
Genetic epilepsy syndromes v1.190 HCCS Rebecca Foulger Source NHS GMS was added to HCCS.
Genetic epilepsy syndromes v1.190 GTPBP3 Rebecca Foulger Source NHS GMS was added to GTPBP3.
Genetic epilepsy syndromes v1.190 GLRA1 Rebecca Foulger Source NHS GMS was added to GLRA1.
Genetic epilepsy syndromes v1.190 GLI3 Rebecca Foulger Source NHS GMS was added to GLI3.
Genetic epilepsy syndromes v1.190 FOXRED1 Rebecca Foulger Source NHS GMS was added to FOXRED1.
Genetic epilepsy syndromes v1.190 FKRP Rebecca Foulger Source NHS GMS was added to FKRP.
Genetic epilepsy syndromes v1.190 FASTKD2 Rebecca Foulger Source NHS GMS was added to FASTKD2.
Genetic epilepsy syndromes v1.190 EIF2B3 Rebecca Foulger Source NHS GMS was added to EIF2B3.
Genetic epilepsy syndromes v1.190 EIF2B1 Rebecca Foulger Source NHS GMS was added to EIF2B1.
Genetic epilepsy syndromes v1.190 EFHC1 Rebecca Foulger Source NHS GMS was added to EFHC1.
Genetic epilepsy syndromes v1.190 DPM2 Rebecca Foulger Source NHS GMS was added to DPM2.
Genetic epilepsy syndromes v1.190 DOLK Rebecca Foulger Source NHS GMS was added to DOLK.
Genetic epilepsy syndromes v1.190 DNAJC6 Rebecca Foulger Source NHS GMS was added to DNAJC6.
Genetic epilepsy syndromes v1.190 DHCR24 Rebecca Foulger Source NHS GMS was added to DHCR24.
Genetic epilepsy syndromes v1.190 DBT Rebecca Foulger Source NHS GMS was added to DBT.
Genetic epilepsy syndromes v1.190 CUX2 Rebecca Foulger Source NHS GMS was added to CUX2.
Genetic epilepsy syndromes v1.190 CSNK2B Rebecca Foulger Source NHS GMS was added to CSNK2B.
Genetic epilepsy syndromes v1.190 COX15 Rebecca Foulger Source NHS GMS was added to COX15.
Genetic epilepsy syndromes v1.190 COX10 Rebecca Foulger Source NHS GMS was added to COX10.
Genetic epilepsy syndromes v1.190 COQ6 Rebecca Foulger Source NHS GMS was added to COQ6.
Genetic epilepsy syndromes v1.190 COG8 Rebecca Foulger Source NHS GMS was added to COG8.
Genetic epilepsy syndromes v1.190 COG6 Rebecca Foulger Source NHS GMS was added to COG6.
Genetic epilepsy syndromes v1.190 COG4 Rebecca Foulger Source NHS GMS was added to COG4.
Genetic epilepsy syndromes v1.190 CNPY3 Rebecca Foulger Source NHS GMS was added to CNPY3.
Genetic epilepsy syndromes v1.190 CCND2 Rebecca Foulger Source NHS GMS was added to CCND2.
Genetic epilepsy syndromes v1.190 CCDC88C Rebecca Foulger Source NHS GMS was added to CCDC88C.
Genetic epilepsy syndromes v1.190 CCDC88A Rebecca Foulger Source NHS GMS was added to CCDC88A.
Genetic epilepsy syndromes v1.190 CACNA2D2 Rebecca Foulger Source NHS GMS was added to CACNA2D2.
Genetic epilepsy syndromes v1.190 CACNA1H Rebecca Foulger Source NHS GMS was added to CACNA1H.
Genetic epilepsy syndromes v1.190 ATP6AP2 Rebecca Foulger Source NHS GMS was added to ATP6AP2.
Genetic epilepsy syndromes v1.190 ATP5A1 Rebecca Foulger Source NHS GMS was added to ATP5A1.
Genetic epilepsy syndromes v1.190 ATP1A2 Rebecca Foulger Source NHS GMS was added to ATP1A2.
Genetic epilepsy syndromes v1.190 ADAT3 Rebecca Foulger Source NHS GMS was added to ADAT3.
Genetic epilepsy syndromes v1.190 ZBTB18 Rebecca Foulger Source NHS GMS was added to ZBTB18.
Genetic epilepsy syndromes v1.190 YWHAG Rebecca Foulger Source NHS GMS was added to YWHAG.
Genetic epilepsy syndromes v1.190 WDR73 Rebecca Foulger Source NHS GMS was added to WDR73.
Genetic epilepsy syndromes v1.190 WDR62 Rebecca Foulger Source NHS GMS was added to WDR62.
Genetic epilepsy syndromes v1.190 WASF1 Rebecca Foulger Source NHS GMS was added to WASF1.
Genetic epilepsy syndromes v1.190 VARS Rebecca Foulger Source NHS GMS was added to VARS.
Genetic epilepsy syndromes v1.190 UNC80 Rebecca Foulger Source NHS GMS was added to UNC80.
Genetic epilepsy syndromes v1.190 UFM1 Rebecca Foulger Source NHS GMS was added to UFM1.
Genetic epilepsy syndromes v1.190 UBA5 Rebecca Foulger Source NHS GMS was added to UBA5.
Genetic epilepsy syndromes v1.190 TUBG1 Rebecca Foulger Source NHS GMS was added to TUBG1.
Genetic epilepsy syndromes v1.190 TUBB4A Rebecca Foulger Source NHS GMS was added to TUBB4A.
Genetic epilepsy syndromes v1.190 TUBB3 Rebecca Foulger Source NHS GMS was added to TUBB3.
Genetic epilepsy syndromes v1.190 TUBB2B Rebecca Foulger Source NHS GMS was added to TUBB2B.
Genetic epilepsy syndromes v1.190 TUBB2A Rebecca Foulger Source NHS GMS was added to TUBB2A.
Genetic epilepsy syndromes v1.190 TUBA1A Rebecca Foulger Source NHS GMS was added to TUBA1A.
Genetic epilepsy syndromes v1.190 TSEN54 Rebecca Foulger Source NHS GMS was added to TSEN54.
Genetic epilepsy syndromes v1.190 TSEN2 Rebecca Foulger Source NHS GMS was added to TSEN2.
Genetic epilepsy syndromes v1.190 TSC2 Rebecca Foulger Source NHS GMS was added to TSC2.
Genetic epilepsy syndromes v1.190 TSC1 Rebecca Foulger Source NHS GMS was added to TSC1.
Genetic epilepsy syndromes v1.190 TRIM8 Rebecca Foulger Source NHS GMS was added to TRIM8.
Genetic epilepsy syndromes v1.190 TREX1 Rebecca Foulger Source NHS GMS was added to TREX1.
Genetic epilepsy syndromes v1.190 TMEM70 Rebecca Foulger Source NHS GMS was added to TMEM70.
Genetic epilepsy syndromes v1.190 TBL1XR1 Rebecca Foulger Source NHS GMS was added to TBL1XR1.
Genetic epilepsy syndromes v1.190 TBCK Rebecca Foulger Source NHS GMS was added to TBCK.
Genetic epilepsy syndromes v1.190 TBCD Rebecca Foulger Source NHS GMS was added to TBCD.
Genetic epilepsy syndromes v1.190 TANGO2 Rebecca Foulger Source NHS GMS was added to TANGO2.
Genetic epilepsy syndromes v1.190 SYN1 Rebecca Foulger Source NHS GMS was added to SYN1.
Genetic epilepsy syndromes v1.190 SURF1 Rebecca Foulger Source NHS GMS was added to SURF1.
Genetic epilepsy syndromes v1.190 SUCLA2 Rebecca Foulger Source NHS GMS was added to SUCLA2.
Genetic epilepsy syndromes v1.190 STAMBP Rebecca Foulger Source NHS GMS was added to STAMBP.
Genetic epilepsy syndromes v1.190 STAG1 Rebecca Foulger Source NHS GMS was added to STAG1.
Genetic epilepsy syndromes v1.190 ST3GAL5 Rebecca Foulger Source NHS GMS was added to ST3GAL5.
Genetic epilepsy syndromes v1.190 SNORD118 Rebecca Foulger Source NHS GMS was added to SNORD118.
Genetic epilepsy syndromes v1.190 SMS Rebecca Foulger Source NHS GMS was added to SMS.
Genetic epilepsy syndromes v1.190 SMARCA2 Rebecca Foulger Source NHS GMS was added to SMARCA2.
Genetic epilepsy syndromes v1.190 SLC6A8 Rebecca Foulger Source NHS GMS was added to SLC6A8.
Genetic epilepsy syndromes v1.190 SLC25A12 Rebecca Foulger Source NHS GMS was added to SLC25A12.
Genetic epilepsy syndromes v1.190 SLC1A4 Rebecca Foulger Source NHS GMS was added to SLC1A4.
Genetic epilepsy syndromes v1.190 SETBP1 Rebecca Foulger Source NHS GMS was added to SETBP1.
Genetic epilepsy syndromes v1.190 SEPSECS Rebecca Foulger Source NHS GMS was added to SEPSECS.
Genetic epilepsy syndromes v1.190 SCO2 Rebecca Foulger Source NHS GMS was added to SCO2.
Genetic epilepsy syndromes v1.190 SCO1 Rebecca Foulger Source NHS GMS was added to SCO1.
Genetic epilepsy syndromes v1.190 SCN3A Rebecca Foulger Source NHS GMS was added to SCN3A.
Genetic epilepsy syndromes v1.190 SAMHD1 Rebecca Foulger Source NHS GMS was added to SAMHD1.
Genetic epilepsy syndromes v1.190 RTTN Rebecca Foulger Source NHS GMS was added to RTTN.
Genetic epilepsy syndromes v1.190 RTN4IP1 Rebecca Foulger Source NHS GMS was added to RTN4IP1.
Genetic epilepsy syndromes v1.190 RORB Rebecca Foulger Source NHS GMS was added to RORB.
Genetic epilepsy syndromes v1.190 RORA Rebecca Foulger Source NHS GMS was added to RORA.
Genetic epilepsy syndromes v1.190 ROGDI Rebecca Foulger Source NHS GMS was added to ROGDI.
Genetic epilepsy syndromes v1.190 RNASET2 Rebecca Foulger Source NHS GMS was added to RNASET2.
Genetic epilepsy syndromes v1.190 RNASEH2C Rebecca Foulger Source NHS GMS was added to RNASEH2C.
Genetic epilepsy syndromes v1.190 RNASEH2B Rebecca Foulger Source NHS GMS was added to RNASEH2B.
Genetic epilepsy syndromes v1.190 RNASEH2A Rebecca Foulger Source NHS GMS was added to RNASEH2A.
Genetic epilepsy syndromes v1.190 RMND1 Rebecca Foulger Source NHS GMS was added to RMND1.
Genetic epilepsy syndromes v1.190 RHOBTB2 Rebecca Foulger Source NHS GMS was added to RHOBTB2.
Genetic epilepsy syndromes v1.190 RFT1 Rebecca Foulger Source NHS GMS was added to RFT1.
Genetic epilepsy syndromes v1.190 RELN Rebecca Foulger Source NHS GMS was added to RELN.
Genetic epilepsy syndromes v1.190 RARS2 Rebecca Foulger Source NHS GMS was added to RARS2.
Genetic epilepsy syndromes v1.190 RALA Rebecca Foulger Source NHS GMS was added to RALA.
Genetic epilepsy syndromes v1.190 RAB18 Rebecca Foulger Source NHS GMS was added to RAB18.
Genetic epilepsy syndromes v1.190 RAB11B Rebecca Foulger Source NHS GMS was added to RAB11B.
Genetic epilepsy syndromes v1.190 QDPR Rebecca Foulger Source NHS GMS was added to QDPR.
Genetic epilepsy syndromes v1.190 PTS Rebecca Foulger Source NHS GMS was added to PTS.
Genetic epilepsy syndromes v1.190 PTPN23 Rebecca Foulger Source NHS GMS was added to PTPN23.
Genetic epilepsy syndromes v1.190 PTEN Rebecca Foulger Source NHS GMS was added to PTEN.
Genetic epilepsy syndromes v1.190 PSAP Rebecca Foulger Source NHS GMS was added to PSAP.
Genetic epilepsy syndromes v1.190 PRMT7 Rebecca Foulger Source NHS GMS was added to PRMT7.
Genetic epilepsy syndromes v1.190 PRICKLE1 Rebecca Foulger Source NHS GMS was added to PRICKLE1.
Genetic epilepsy syndromes v1.190 PPT1 Rebecca Foulger Source NHS GMS was added to PPT1.
Genetic epilepsy syndromes v1.190 PPP3CA Rebecca Foulger Source NHS GMS was added to PPP3CA.
Genetic epilepsy syndromes v1.190 POMT1 Rebecca Foulger Source NHS GMS was added to POMT1.
Genetic epilepsy syndromes v1.190 POMGNT1 Rebecca Foulger Source NHS GMS was added to POMGNT1.
Genetic epilepsy syndromes v1.190 PMM2 Rebecca Foulger Source NHS GMS was added to PMM2.
Genetic epilepsy syndromes v1.190 PLAA Rebecca Foulger Source NHS GMS was added to PLAA.
Genetic epilepsy syndromes v1.190 PIK3R2 Rebecca Foulger Source NHS GMS was added to PIK3R2.
Genetic epilepsy syndromes v1.190 PIK3CA Rebecca Foulger Source NHS GMS was added to PIK3CA.
Genetic epilepsy syndromes v1.190 PIGW Rebecca Foulger Source NHS GMS was added to PIGW.
Genetic epilepsy syndromes v1.190 PIGO Rebecca Foulger Source NHS GMS was added to PIGO.
Genetic epilepsy syndromes v1.190 PIGG Rebecca Foulger Source NHS GMS was added to PIGG.
Genetic epilepsy syndromes v1.190 PHGDH Rebecca Foulger Source NHS GMS was added to PHGDH.
Genetic epilepsy syndromes v1.190 PHACTR1 Rebecca Foulger Source NHS GMS was added to PHACTR1.
Genetic epilepsy syndromes v1.190 PEX7 Rebecca Foulger Source NHS GMS was added to PEX7.
Genetic epilepsy syndromes v1.190 PEX6 Rebecca Foulger Source NHS GMS was added to PEX6.
Genetic epilepsy syndromes v1.190 PEX3 Rebecca Foulger Source NHS GMS was added to PEX3.
Genetic epilepsy syndromes v1.190 PEX2 Rebecca Foulger Source NHS GMS was added to PEX2.
Genetic epilepsy syndromes v1.190 PEX19 Rebecca Foulger Source NHS GMS was added to PEX19.
Genetic epilepsy syndromes v1.190 PEX13 Rebecca Foulger Source NHS GMS was added to PEX13.
Genetic epilepsy syndromes v1.190 PEX12 Rebecca Foulger Source NHS GMS was added to PEX12.
Genetic epilepsy syndromes v1.190 PEX10 Rebecca Foulger Source NHS GMS was added to PEX10.
Genetic epilepsy syndromes v1.190 PEX1 Rebecca Foulger Source NHS GMS was added to PEX1.
Genetic epilepsy syndromes v1.190 PET100 Rebecca Foulger Source NHS GMS was added to PET100.
Genetic epilepsy syndromes v1.190 PDHX Rebecca Foulger Source NHS GMS was added to PDHX.
Genetic epilepsy syndromes v1.190 PDHA1 Rebecca Foulger Source NHS GMS was added to PDHA1.
Genetic epilepsy syndromes v1.190 PCDH12 Rebecca Foulger Source NHS GMS was added to PCDH12.
Genetic epilepsy syndromes v1.190 PCCB Rebecca Foulger Source NHS GMS was added to PCCB.
Genetic epilepsy syndromes v1.190 PCCA Rebecca Foulger Source NHS GMS was added to PCCA.
Genetic epilepsy syndromes v1.190 PAH Rebecca Foulger Source NHS GMS was added to PAH.
Genetic epilepsy syndromes v1.190 PAFAH1B1 Rebecca Foulger Source NHS GMS was added to PAFAH1B1.
Genetic epilepsy syndromes v1.190 PACS2 Rebecca Foulger Source NHS GMS was added to PACS2.
Genetic epilepsy syndromes v1.190 PACS1 Rebecca Foulger Source NHS GMS was added to PACS1.
Genetic epilepsy syndromes v1.190 OTUD6B Rebecca Foulger Source NHS GMS was added to OTUD6B.
Genetic epilepsy syndromes v1.190 OPHN1 Rebecca Foulger Source NHS GMS was added to OPHN1.
Genetic epilepsy syndromes v1.190 OCLN Rebecca Foulger Source NHS GMS was added to OCLN.
Genetic epilepsy syndromes v1.190 NTRK2 Rebecca Foulger Source NHS GMS was added to NTRK2.
Genetic epilepsy syndromes v1.190 NSDHL Rebecca Foulger Source NHS GMS was added to NSDHL.
Genetic epilepsy syndromes v1.190 NSD1 Rebecca Foulger Source NHS GMS was added to NSD1.
Genetic epilepsy syndromes v1.190 NRXN1 Rebecca Foulger Source NHS GMS was added to NRXN1.
Genetic epilepsy syndromes v1.190 NPRL3 Rebecca Foulger Source NHS GMS was added to NPRL3.
Genetic epilepsy syndromes v1.190 NHLRC1 Rebecca Foulger Source NHS GMS was added to NHLRC1.
Genetic epilepsy syndromes v1.190 NGLY1 Rebecca Foulger Source NHS GMS was added to NGLY1.
Genetic epilepsy syndromes v1.190 NDUFV1 Rebecca Foulger Source NHS GMS was added to NDUFV1.
Genetic epilepsy syndromes v1.190 NDUFS8 Rebecca Foulger Source NHS GMS was added to NDUFS8.
Genetic epilepsy syndromes v1.190 NDUFS4 Rebecca Foulger Source NHS GMS was added to NDUFS4.
Genetic epilepsy syndromes v1.190 NDUFAF5 Rebecca Foulger Source NHS GMS was added to NDUFAF5.
Genetic epilepsy syndromes v1.190 NDUFAF2 Rebecca Foulger Source NHS GMS was added to NDUFAF2.
Genetic epilepsy syndromes v1.190 NDUFA10 Rebecca Foulger Source NHS GMS was added to NDUFA10.
Genetic epilepsy syndromes v1.190 NDUFA1 Rebecca Foulger Source NHS GMS was added to NDUFA1.
Genetic epilepsy syndromes v1.190 NDE1 Rebecca Foulger Source NHS GMS was added to NDE1.
Genetic epilepsy syndromes v1.190 NARS2 Rebecca Foulger Source NHS GMS was added to NARS2.
Genetic epilepsy syndromes v1.190 NAGA Rebecca Foulger Source NHS GMS was added to NAGA.
Genetic epilepsy syndromes v1.190 MTR Rebecca Foulger Source NHS GMS was added to MTR.
Genetic epilepsy syndromes v1.190 MTHFR Rebecca Foulger Source NHS GMS was added to MTHFR.
Genetic epilepsy syndromes v1.190 MPDU1 Rebecca Foulger Source NHS GMS was added to MPDU1.
Genetic epilepsy syndromes v1.190 MOCS2 Rebecca Foulger Source NHS GMS was added to MOCS2.
Genetic epilepsy syndromes v1.190 MOCS1 Rebecca Foulger Source NHS GMS was added to MOCS1.
Genetic epilepsy syndromes v1.190 MMADHC Rebecca Foulger Source NHS GMS was added to MMADHC.
Genetic epilepsy syndromes v1.190 MMACHC Rebecca Foulger Source NHS GMS was added to MMACHC.
Genetic epilepsy syndromes v1.190 MLC1 Rebecca Foulger Source NHS GMS was added to MLC1.
Genetic epilepsy syndromes v1.190 MFSD8 Rebecca Foulger Source NHS GMS was added to MFSD8.
Genetic epilepsy syndromes v1.190 MED12 Rebecca Foulger Source NHS GMS was added to MED12.
Genetic epilepsy syndromes v1.190 MAP2K2 Rebecca Foulger Source NHS GMS was added to MAP2K2.
Genetic epilepsy syndromes v1.190 MAP2K1 Rebecca Foulger Source NHS GMS was added to MAP2K1.
Genetic epilepsy syndromes v1.190 MAGI2 Rebecca Foulger Source NHS GMS was added to MAGI2.
Genetic epilepsy syndromes v1.190 MAF Rebecca Foulger Source NHS GMS was added to MAF.
Genetic epilepsy syndromes v1.190 MACF1 Rebecca Foulger Source NHS GMS was added to MACF1.
Genetic epilepsy syndromes v1.190 LYST Rebecca Foulger Source NHS GMS was added to LYST.
Genetic epilepsy syndromes v1.190 LIAS Rebecca Foulger Source NHS GMS was added to LIAS.
Genetic epilepsy syndromes v1.190 KRAS Rebecca Foulger Source NHS GMS was added to KRAS.
Genetic epilepsy syndromes v1.190 KIF5C Rebecca Foulger Source NHS GMS was added to KIF5C.
Genetic epilepsy syndromes v1.190 KIF2A Rebecca Foulger Source NHS GMS was added to KIF2A.
Genetic epilepsy syndromes v1.190 KIF1A Rebecca Foulger Source NHS GMS was added to KIF1A.
Genetic epilepsy syndromes v1.190 KCTD3 Rebecca Foulger Source NHS GMS was added to KCTD3.
Genetic epilepsy syndromes v1.190 KCNQ5 Rebecca Foulger Source NHS GMS was added to KCNQ5.
Genetic epilepsy syndromes v1.190 KCNK4 Rebecca Foulger Source NHS GMS was added to KCNK4.
Genetic epilepsy syndromes v1.190 KCNJ11 Rebecca Foulger Source NHS GMS was added to KCNJ11.
Genetic epilepsy syndromes v1.190 KCNA1 Rebecca Foulger Source NHS GMS was added to KCNA1.
Genetic epilepsy syndromes v1.190 KARS Rebecca Foulger Source NHS GMS was added to KARS.
Genetic epilepsy syndromes v1.190 IRF2BPL Rebecca Foulger Source NHS GMS was added to IRF2BPL.
Genetic epilepsy syndromes v1.190 IKBKG Rebecca Foulger Source NHS GMS was added to IKBKG.
Genetic epilepsy syndromes v1.190 IFIH1 Rebecca Foulger Source NHS GMS was added to IFIH1.
Genetic epilepsy syndromes v1.190 HSD17B4 Rebecca Foulger Source NHS GMS was added to HSD17B4.
Genetic epilepsy syndromes v1.190 HRAS Rebecca Foulger Source NHS GMS was added to HRAS.
Genetic epilepsy syndromes v1.190 HLCS Rebecca Foulger Source NHS GMS was added to HLCS.
Genetic epilepsy syndromes v1.190 HEXA Rebecca Foulger Source NHS GMS was added to HEXA.
Genetic epilepsy syndromes v1.190 HEPACAM Rebecca Foulger Source NHS GMS was added to HEPACAM.
Genetic epilepsy syndromes v1.190 HCN2 Rebecca Foulger Source NHS GMS was added to HCN2.
Genetic epilepsy syndromes v1.190 HCFC1 Rebecca Foulger Source NHS GMS was added to HCFC1.
Genetic epilepsy syndromes v1.190 HAX1 Rebecca Foulger Source NHS GMS was added to HAX1.
Genetic epilepsy syndromes v1.190 HACE1 Rebecca Foulger Source NHS GMS was added to HACE1.
Genetic epilepsy syndromes v1.190 GTPBP2 Rebecca Foulger Source NHS GMS was added to GTPBP2.
Genetic epilepsy syndromes v1.190 GRIN2D Rebecca Foulger Source NHS GMS was added to GRIN2D.
Genetic epilepsy syndromes v1.190 GRIA4 Rebecca Foulger Source NHS GMS was added to GRIA4.
Genetic epilepsy syndromes v1.190 GPHN Rebecca Foulger Source NHS GMS was added to GPHN.
Genetic epilepsy syndromes v1.190 GOSR2 Rebecca Foulger Source NHS GMS was added to GOSR2.
Genetic epilepsy syndromes v1.190 GNB5 Rebecca Foulger Source NHS GMS was added to GNB5.
Genetic epilepsy syndromes v1.190 GNB1 Rebecca Foulger Source NHS GMS was added to GNB1.
Genetic epilepsy syndromes v1.190 GNAQ Rebecca Foulger Source NHS GMS was added to GNAQ.
Genetic epilepsy syndromes v1.190 GM2A Rebecca Foulger Source NHS GMS was added to GM2A.
Genetic epilepsy syndromes v1.190 GLUL Rebecca Foulger Source NHS GMS was added to GLUL.
Genetic epilepsy syndromes v1.190 GLUD1 Rebecca Foulger Source NHS GMS was added to GLUD1.
Genetic epilepsy syndromes v1.190 GLDC Rebecca Foulger Source NHS GMS was added to GLDC.
Genetic epilepsy syndromes v1.190 GLB1 Rebecca Foulger Source NHS GMS was added to GLB1.
Genetic epilepsy syndromes v1.190 GFM1 Rebecca Foulger Source NHS GMS was added to GFM1.
Genetic epilepsy syndromes v1.190 GFAP Rebecca Foulger Source NHS GMS was added to GFAP.
Genetic epilepsy syndromes v1.190 GCH1 Rebecca Foulger Source NHS GMS was added to GCH1.
Genetic epilepsy syndromes v1.190 GBA Rebecca Foulger Source NHS GMS was added to GBA.
Genetic epilepsy syndromes v1.190 GAMT Rebecca Foulger Source NHS GMS was added to GAMT.
Genetic epilepsy syndromes v1.190 GALC Rebecca Foulger Source NHS GMS was added to GALC.
Genetic epilepsy syndromes v1.190 GABRB2 Rebecca Foulger Source NHS GMS was added to GABRB2.
Genetic epilepsy syndromes v1.190 FUT8 Rebecca Foulger Source NHS GMS was added to FUT8.
Genetic epilepsy syndromes v1.190 FUCA1 Rebecca Foulger Source NHS GMS was added to FUCA1.
Genetic epilepsy syndromes v1.190 FRRS1L Rebecca Foulger Source NHS GMS was added to FRRS1L.
Genetic epilepsy syndromes v1.190 FOLR1 Rebecca Foulger Source NHS GMS was added to FOLR1.
Genetic epilepsy syndromes v1.190 FLNA Rebecca Foulger Source NHS GMS was added to FLNA.
Genetic epilepsy syndromes v1.190 FKTN Rebecca Foulger Source NHS GMS was added to FKTN.
Genetic epilepsy syndromes v1.190 FH Rebecca Foulger Source NHS GMS was added to FH.
Genetic epilepsy syndromes v1.190 FGFR3 Rebecca Foulger Source NHS GMS was added to FGFR3.
Genetic epilepsy syndromes v1.190 FGF12 Rebecca Foulger Source NHS GMS was added to FGF12.
Genetic epilepsy syndromes v1.190 FBXO11 Rebecca Foulger Source NHS GMS was added to FBXO11.
Genetic epilepsy syndromes v1.190 FBXL4 Rebecca Foulger Source NHS GMS was added to FBXL4.
Genetic epilepsy syndromes v1.190 FARS2 Rebecca Foulger Source NHS GMS was added to FARS2.
Genetic epilepsy syndromes v1.190 FAR1 Rebecca Foulger Source NHS GMS was added to FAR1.
Genetic epilepsy syndromes v1.190 EXOSC3 Rebecca Foulger Source NHS GMS was added to EXOSC3.
Genetic epilepsy syndromes v1.190 ETHE1 Rebecca Foulger Source NHS GMS was added to ETHE1.
Genetic epilepsy syndromes v1.190 EMX2 Rebecca Foulger Source NHS GMS was added to EMX2.
Genetic epilepsy syndromes v1.190 EIF3F Rebecca Foulger Source NHS GMS was added to EIF3F.
Genetic epilepsy syndromes v1.190 EIF2S3 Rebecca Foulger Source NHS GMS was added to EIF2S3.
Genetic epilepsy syndromes v1.190 EIF2B5 Rebecca Foulger Source NHS GMS was added to EIF2B5.
Genetic epilepsy syndromes v1.190 EIF2B4 Rebecca Foulger Source NHS GMS was added to EIF2B4.
Genetic epilepsy syndromes v1.190 EIF2B2 Rebecca Foulger Source NHS GMS was added to EIF2B2.
Genetic epilepsy syndromes v1.190 EFTUD2 Rebecca Foulger Source NHS GMS was added to EFTUD2.
Genetic epilepsy syndromes v1.190 EEF1A2 Rebecca Foulger Source NHS GMS was added to EEF1A2.
Genetic epilepsy syndromes v1.190 EARS2 Rebecca Foulger Source NHS GMS was added to EARS2.
Genetic epilepsy syndromes v1.190 DYNC1H1 Rebecca Foulger Source NHS GMS was added to DYNC1H1.
Genetic epilepsy syndromes v1.190 DPM1 Rebecca Foulger Source NHS GMS was added to DPM1.
Genetic epilepsy syndromes v1.190 DPAGT1 Rebecca Foulger Source NHS GMS was added to DPAGT1.
Genetic epilepsy syndromes v1.190 DNM1L Rebecca Foulger Source NHS GMS was added to DNM1L.
Genetic epilepsy syndromes v1.190 DHX30 Rebecca Foulger Source NHS GMS was added to DHX30.
Genetic epilepsy syndromes v1.190 DHDDS Rebecca Foulger Source NHS GMS was added to DHDDS.
Genetic epilepsy syndromes v1.190 DHCR7 Rebecca Foulger Source NHS GMS was added to DHCR7.
Genetic epilepsy syndromes v1.190 DENND5A Rebecca Foulger Source NHS GMS was added to DENND5A.
Genetic epilepsy syndromes v1.190 DEAF1 Rebecca Foulger Source NHS GMS was added to DEAF1.
Genetic epilepsy syndromes v1.190 DDX3X Rebecca Foulger Source NHS GMS was added to DDX3X.
Genetic epilepsy syndromes v1.190 DCX Rebecca Foulger Source NHS GMS was added to DCX.
Genetic epilepsy syndromes v1.190 D2HGDH Rebecca Foulger Source NHS GMS was added to D2HGDH.
Genetic epilepsy syndromes v1.190 CTSD Rebecca Foulger Source NHS GMS was added to CTSD.
Genetic epilepsy syndromes v1.190 CSTB Rebecca Foulger Source NHS GMS was added to CSTB.
Genetic epilepsy syndromes v1.190 CREBBP Rebecca Foulger Source NHS GMS was added to CREBBP.
Genetic epilepsy syndromes v1.190 COQ9 Rebecca Foulger Source NHS GMS was added to COQ9.
Genetic epilepsy syndromes v1.190 COQ4 Rebecca Foulger Source NHS GMS was added to COQ4.
Genetic epilepsy syndromes v1.190 COQ2 Rebecca Foulger Source NHS GMS was added to COQ2.
Genetic epilepsy syndromes v1.190 COL4A2 Rebecca Foulger Source NHS GMS was added to COL4A2.
Genetic epilepsy syndromes v1.190 COL4A1 Rebecca Foulger Source NHS GMS was added to COL4A1.
Genetic epilepsy syndromes v1.190 COL18A1 Rebecca Foulger Source NHS GMS was added to COL18A1.
Genetic epilepsy syndromes v1.190 COG7 Rebecca Foulger Source NHS GMS was added to COG7.
Genetic epilepsy syndromes v1.190 CNNM2 Rebecca Foulger Source NHS GMS was added to CNNM2.
Genetic epilepsy syndromes v1.190 CLN3 Rebecca Foulger Source NHS GMS was added to CLN3.
Genetic epilepsy syndromes v1.190 CLCN4 Rebecca Foulger Source NHS GMS was added to CLCN4.
Genetic epilepsy syndromes v1.190 CC2D2A Rebecca Foulger Source NHS GMS was added to CC2D2A.
Genetic epilepsy syndromes v1.190 CASK Rebecca Foulger Source NHS GMS was added to CASK.
Genetic epilepsy syndromes v1.190 CAD Rebecca Foulger Source NHS GMS was added to CAD.
Genetic epilepsy syndromes v1.190 CACNA1G Rebecca Foulger Source NHS GMS was added to CACNA1G.
Genetic epilepsy syndromes v1.190 CACNA1E Rebecca Foulger Source NHS GMS was added to CACNA1E.
Genetic epilepsy syndromes v1.190 CACNA1A Rebecca Foulger Source NHS GMS was added to CACNA1A.
Genetic epilepsy syndromes v1.190 C12orf57 Rebecca Foulger Source NHS GMS was added to C12orf57.
Genetic epilepsy syndromes v1.190 BTD Rebecca Foulger Source NHS GMS was added to BTD.
Genetic epilepsy syndromes v1.190 BRAF Rebecca Foulger Source NHS GMS was added to BRAF.
Genetic epilepsy syndromes v1.190 BOLA3 Rebecca Foulger Source NHS GMS was added to BOLA3.
Genetic epilepsy syndromes v1.190 BCS1L Rebecca Foulger Source NHS GMS was added to BCS1L.
Genetic epilepsy syndromes v1.190 BCKDHB Rebecca Foulger Source NHS GMS was added to BCKDHB.
Genetic epilepsy syndromes v1.190 BCKDHA Rebecca Foulger Source NHS GMS was added to BCKDHA.
Genetic epilepsy syndromes v1.190 ATP7A Rebecca Foulger Source NHS GMS was added to ATP7A.
Genetic epilepsy syndromes v1.190 ATP6V1A Rebecca Foulger Source NHS GMS was added to ATP6V1A.
Genetic epilepsy syndromes v1.190 ATP1A1 Rebecca Foulger Source NHS GMS was added to ATP1A1.
Genetic epilepsy syndromes v1.190 ASPA Rebecca Foulger Source NHS GMS was added to ASPA.
Genetic epilepsy syndromes v1.190 ARV1 Rebecca Foulger Source NHS GMS was added to ARV1.
Genetic epilepsy syndromes v1.190 ARID1B Rebecca Foulger Source NHS GMS was added to ARID1B.
Genetic epilepsy syndromes v1.190 ARG1 Rebecca Foulger Source NHS GMS was added to ARG1.
Genetic epilepsy syndromes v1.190 ARFGEF2 Rebecca Foulger Source NHS GMS was added to ARFGEF2.
Genetic epilepsy syndromes v1.190 AP3B2 Rebecca Foulger Source NHS GMS was added to AP3B2.
Genetic epilepsy syndromes v1.190 AMT Rebecca Foulger Source NHS GMS was added to AMT.
Genetic epilepsy syndromes v1.190 AMPD2 Rebecca Foulger Source NHS GMS was added to AMPD2.
Genetic epilepsy syndromes v1.190 ALPL Rebecca Foulger Source NHS GMS was added to ALPL.
Genetic epilepsy syndromes v1.190 ALG9 Rebecca Foulger Source NHS GMS was added to ALG9.
Genetic epilepsy syndromes v1.190 ALG8 Rebecca Foulger Source NHS GMS was added to ALG8.
Genetic epilepsy syndromes v1.190 ALG6 Rebecca Foulger Source NHS GMS was added to ALG6.
Genetic epilepsy syndromes v1.190 ALG3 Rebecca Foulger Source NHS GMS was added to ALG3.
Genetic epilepsy syndromes v1.190 ALG1 Rebecca Foulger Source NHS GMS was added to ALG1.
Genetic epilepsy syndromes v1.190 ALDH5A1 Rebecca Foulger Source NHS GMS was added to ALDH5A1.
Genetic epilepsy syndromes v1.190 AKT3 Rebecca Foulger Source NHS GMS was added to AKT3.
Genetic epilepsy syndromes v1.190 AKT1 Rebecca Foulger Source NHS GMS was added to AKT1.
Genetic epilepsy syndromes v1.190 AIMP1 Rebecca Foulger Source NHS GMS was added to AIMP1.
Genetic epilepsy syndromes v1.190 ADPRHL2 Rebecca Foulger Source NHS GMS was added to ADPRHL2.
Genetic epilepsy syndromes v1.190 ADGRG1 Rebecca Foulger Source NHS GMS was added to ADGRG1.
Genetic epilepsy syndromes v1.190 ADAR Rebecca Foulger Source NHS GMS was added to ADAR.
Genetic epilepsy syndromes v1.190 ACOX1 Rebecca Foulger Source NHS GMS was added to ACOX1.
Genetic epilepsy syndromes v1.190 ABAT Rebecca Foulger Source NHS GMS was added to ABAT.
Genetic epilepsy syndromes v1.190 ZEB2 Rebecca Foulger Source NHS GMS was added to ZEB2.
Genetic epilepsy syndromes v1.190 WWOX Rebecca Foulger Source NHS GMS was added to WWOX.
Genetic epilepsy syndromes v1.190 WDR45B Rebecca Foulger Source NHS GMS was added to WDR45B.
Genetic epilepsy syndromes v1.190 WDR45 Rebecca Foulger Source NHS GMS was added to WDR45.
Genetic epilepsy syndromes v1.190 UBE3A Rebecca Foulger Source NHS GMS was added to UBE3A.
Genetic epilepsy syndromes v1.190 UBE2A Rebecca Foulger Source NHS GMS was added to UBE2A.
Genetic epilepsy syndromes v1.190 TRPM6 Rebecca Foulger Source NHS GMS was added to TRPM6.
Genetic epilepsy syndromes v1.190 TRAK1 Rebecca Foulger Source NHS GMS was added to TRAK1.
Genetic epilepsy syndromes v1.190 TPP1 Rebecca Foulger Source NHS GMS was added to TPP1.
Genetic epilepsy syndromes v1.190 TCF4 Rebecca Foulger Source NHS GMS was added to TCF4.
Genetic epilepsy syndromes v1.190 TBC1D24 Rebecca Foulger Source NHS GMS was added to TBC1D24.
Genetic epilepsy syndromes v1.190 SZT2 Rebecca Foulger Source NHS GMS was added to SZT2.
Genetic epilepsy syndromes v1.190 SYNJ1 Rebecca Foulger Source NHS GMS was added to SYNJ1.
Genetic epilepsy syndromes v1.190 SYNGAP1 Rebecca Foulger Source NHS GMS was added to SYNGAP1.
Genetic epilepsy syndromes v1.190 SUOX Rebecca Foulger Source NHS GMS was added to SUOX.
Genetic epilepsy syndromes v1.190 STXBP1 Rebecca Foulger Source NHS GMS was added to STXBP1.
Genetic epilepsy syndromes v1.190 STX1B Rebecca Foulger Source NHS GMS was added to STX1B.
Genetic epilepsy syndromes v1.190 STRADA Rebecca Foulger Source NHS GMS was added to STRADA.
Genetic epilepsy syndromes v1.190 SPTAN1 Rebecca Foulger Source NHS GMS was added to SPTAN1.
Genetic epilepsy syndromes v1.190 SLC9A6 Rebecca Foulger Source NHS GMS was added to SLC9A6.
Genetic epilepsy syndromes v1.190 SLC6A19 Rebecca Foulger Source NHS GMS was added to SLC6A19.
Genetic epilepsy syndromes v1.190 SLC6A1 Rebecca Foulger Source NHS GMS was added to SLC6A1.
Genetic epilepsy syndromes v1.190 SLC35A2 Rebecca Foulger Source NHS GMS was added to SLC35A2.
Genetic epilepsy syndromes v1.190 SLC2A1 Rebecca Foulger Source NHS GMS was added to SLC2A1.
Genetic epilepsy syndromes v1.190 SLC25A22 Rebecca Foulger Source NHS GMS was added to SLC25A22.
Genetic epilepsy syndromes v1.190 SLC25A1 Rebecca Foulger Source NHS GMS was added to SLC25A1.
Genetic epilepsy syndromes v1.190 SLC1A2 Rebecca Foulger Source NHS GMS was added to SLC1A2.
Genetic epilepsy syndromes v1.190 SLC16A2 Rebecca Foulger Source NHS GMS was added to SLC16A2.
Genetic epilepsy syndromes v1.190 SLC13A5 Rebecca Foulger Source NHS GMS was added to SLC13A5.
Genetic epilepsy syndromes v1.190 SLC12A5 Rebecca Foulger Source NHS GMS was added to SLC12A5.
Genetic epilepsy syndromes v1.190 SIK1 Rebecca Foulger Source NHS GMS was added to SIK1.
Genetic epilepsy syndromes v1.190 SETD5 Rebecca Foulger Source NHS GMS was added to SETD5.
Genetic epilepsy syndromes v1.190 SCN9A Rebecca Foulger Source NHS GMS was added to SCN9A.
Genetic epilepsy syndromes v1.190 SCN8A Rebecca Foulger Source NHS GMS was added to SCN8A.