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Early onset or syndromic epilepsy v5.6 PIGM Eleanor Williams changed review comment from: The rating of this gene has been updated togreenand the mode of inheritance set to'BIALLELIC, autosomal or pseudoautosomal'following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v5.6 PIGM Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: PIGM.
Early onset or syndromic epilepsy v5.6 PIGM Eleanor Williams reviewed gene: PIGM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v5.5 PIGM Achchuthan Shanmugasundram Source Expert Review Green was added to PIGM.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v4.184 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, 308300 to Incontinentia pigmenti, OMIM:308300
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh Tag Q4_23_NHS_review was removed from gene: PIGM.
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition.
To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations.
Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).
Absence seizures were apparent in 5/7 individuals from 5/6 families with OMIM:610293 biallelic for rs587776528 (table 1, PMID: 31445883).
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh Entity copied from Likely inborn error of metabolism - targeted testing not possible v4.77
Early onset or syndromic epilepsy v4.129 PIGM Sarah Leigh gene: PIGM was added
gene: PIGM was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber,London North GLH
promoter, non-coding-known-pathogenic, Q4_23_promote_green, Q4_23_NHS_review tags were added to gene: PIGM.
Mode of inheritance for gene: PIGM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGM were set to 27604308; 16767100; 25293775; 17442906; 31445883
Phenotypes for gene: PIGM were set to Glycosylphosphatidylinositol deficiency, OMIM:610293
Early onset or syndromic epilepsy v2.563 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from TFE3-related intellectual disability with pigmentary mosaicism to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
Early onset or syndromic epilepsy v2.530 PRPF8 Sarah Leigh gene: PRPF8 was added
gene: PRPF8 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q2_22_rating tags were added to gene: PRPF8.
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRPF8 were set to 20811066; 23714367; 30420816; 31696658; 35543142
Phenotypes for gene: PRPF8 were set to PRPF8-related developmental disorder (monoallelic); Retinitis pigmentosa 13, OMIM:600059
Penetrance for gene: PRPF8 were set to unknown
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Early onset or syndromic epilepsy v2.0 RNF113A Konstantinos Varvagiannis gene: RNF113A was added
gene: RNF113A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RNF113A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: RNF113A were set to 25612912; 31880405; 31793730; 29133357; 30506991; 15256591; 24026126; 23555887
Phenotypes for gene: RNF113A were set to ?Trichothiodystrophy 5, nonphotosensitive, 300953
Penetrance for gene: RNF113A were set to Complete
Review for gene: RNF113A was set to GREEN
Added comment: The gene has been reviewed for the ID panel. Seizures have been reported in 4 affected males from 3 families.

From the ID panel:
Nonphotosensitive trichothiodystrophy-5 (TTD5 - #300953) is caused by mutation in the RNF113A gene on Xq24. DD, ID and seizures are part of the phenotype in males. (Several) heterozygous females have not been reported to exhibit these features (DD/ID/seizures) although a single female in the first report had speech/motor delay and learning difficulties.

Corbett et al (2015 - PMID: 25612912) reported on 2 cousins with profound ID and epilepsy among other principal features of the disorder. Linkage analysis (probably low(?) LOD score) localized the gene to a 7.75 Mb region on Xq and subsequent Sanger and exome sequencing identified an RNF113A stopgain variant in both (NM_006978.2:c.901C>T / p.Q301*). Other X-chr variants did not segregate with the disorder. Previously sequencing of other trichothiodystrophy genes (in both) and CMA (X-chromosome BAC array / ISCA CMA) were non-diagnostic. The variant in this family was identified in a previous study (Tarpey et al 2009 - PMID: 19377476) but was 'incorrectly' discarded at the time due to a sequencing error in a control DNA sample (analysis repeated by Corbett et al). The same variant was also reported in 2 fetuses in a later report (PMID: 31793730).

Mendelsohn et al (2019 - PMID: 31880405) reported on 2 unrelated affected males. The 1st presented with severe DD/ID (independent walking at 7y, single words/non-verbal with with special educational needs at 11y), seizures as well as typical features of the disorder. Metabolic work-up (incl. 7-DHCR) and genetic testing (Allagile, PFIC genes, CMA) were non-diagnostic. Duo WES revealed a frameshift variant [c.903_910delGCAGACCCA / p.(Gln302fs*12)] inherited from the mother. Maternal XCI was completely skewed (100:0). The 2nd individual (briefly reported as REQ18-0616 by Monies et al - PMID: 31130284) presented global DD and seizures along with all other core features of the disorder at the age of 16m. Karyotype was normal. Exome revealed a frameshift variant [NM_006978.3:c.897_898delTG / p.(Cys299*)].

Further evidence is based on the role of the RNA113A, being involved in mRNA splicing (/spiceosome function) [Gatti da Silva et al 2018 - PMID: 30506991 & many other Refs] as well in DNA repair (E3 ubiquitin-protein ligase in a mechanism for sensing DNA damage induced by alkylation) [Brickner et al 2017 - PMID: 29133357]. In the latter study, LCLs from individuals harboring Q301* were shown to be hypersensitive to an alkylating agent (MMS) which was also the case for an RNF113A knockdown cell line. The cells had reduced ASCC alkylation repair complex foci formation, which was rescued upon reconstitution of patient cells with wt RNF113A.

Animal models :
Disruption of rnf113a in zebrafish resulted among others in small head and underdeveloped gut (PMID cited : 15256591 - Amsterdam et al) similar to the microcephaly observed in several individuals and/or abnormal gut development/diarrhoea reported in few.
Knockdown of the Drosophila ortholog (mdlc) led to reduced proliferation of neuroblasts. Neuronal differentiation was initiated but not completed. Expression of the full-length human gene rescued the CNS defects (discussed by Mendelsohn et al citing PMID: 24026126 - Carney et al). RNA-seq data from the same study were analyzed by Corbett et al, and differentialy expressed genes were enriched for genes involved in DNA damage response and repair.
Knockdown of RNF-113 in C.elegans sensitises cells to UVA-induced DNA damage. RNF-113 was shown to be involved in interstrand DNA crosslink repair and interact with a RAD51C homolog (PMID cited: 23555887 - Lee et al).

[Please consider upgrade/inclusion in other relevant panels eg. the 'Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome panel' where the gene has red rating].
Sources: Literature
Early onset or syndromic epilepsy v2.0 TFE3 Konstantinos Varvagiannis reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595499, 31833172, https://doi.org/10.1126/scisignal.aax0926; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of skin pigmentation, Coarse facial features, Seizures; Mode of inheritance: Other
Early onset or syndromic epilepsy v1.213 IKBKG Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists XLD inheritance for Incontinentia pigmenti (MIM:308300).
Early onset or syndromic epilepsy v1.188 POMGNT1 Tracy Lester reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 15466003; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 3 253280, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation)type B, 3 613151, Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 3 613157 , Retinitis pigmentosa 76 617123; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.188 IKBKG Tracy Lester reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: ; Publications: 28870493, 28870493 ; Phenotypes: Incontinentia pigmenti, 308300, Immunodeficiency , 300636; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.188 DHDDS Tracy Lester reviewed gene: DHDDS: Rating: GREEN; Mode of pathogenicity: ; Publications: 29100083; Phenotypes: ?Congenital disorder of glycosylation, 613861 , Developmental delay and seizures with or without movement abnormalities, 617836, Retinitis pigmentosa, 613861; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1111 TELO2 Konstantinos Varvagiannis gene: TELO2 was added
gene: TELO2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review
Mode of inheritance for gene: TELO2 was set to BIALLELIC, autosomal or pseudoautosomal
Penetrance for gene: TELO2 were set to Complete
Added comment: Biallelic mutations in TELO2 cause You-Hoover-Fong syndrome (MIM 616954). //

PMID: 27132593 reports on 6 patients (from 4 non-consanguineous families) with biallelic TELO2 variants and a similar phenotype.

Intellectual disability and microcephaly were universal features (6/6). Abnormal hearing (3/6), cortical visual impairment (3/6), abnormality of the cardiovascular system (3/6), behavioral problems (laughter outbursts in 3/6) and abnormal balance and movement disorder (6/6) were part of the phenotype. One individual had seizures.

5 missense variants and a complex allele with a stopgain variant localized in cis with a splice-site variant (NM_016111.3:c.514C>T or p.Gln172* in cis with c.2034+1G>A) are reported.

As a result heterozygosity for the complex variant may be confounded with compound heterozygous state until segregation studies are performed.

Functional studies support pathogenicity of the missense variants (reduced protein steady-state levels of TELO2 as well as TTI1 and TTI2 - the 2 other members of the TTT complex) suggesting loss of function.

PMID: 28944240 reports on 2 sisters born to non-consanguineous parents. Both were compound heterozygous for 2 novel variants, a missense and a frameshift one. Severe microcephaly (-8.5 SD and -10.7 SD) and seizures were noted in both. The first sister passed away at the age of 2 months due to a respiratory infection. The other sister demonstrated a compatible, though much more severe phenotype (ID and microcephaly) with additional features (dwarfism, renal anomalies, retinitis pigmentosa, etc) compared to previously reported patients. //

As a result this gene could possibly be considered for inclusion in this panel as amber (seizures in 3/8 patients reported to date - these individuals belonged to 2 different families) .
Sources: Literature, Expert Review
Early onset or syndromic epilepsy v0.924 IKBKG Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. Incontinentia pigmenti is confirmed by OMIM and Gene2Phenotype. There are >3 unrelated families with a variant in this gene diagnosed with incontinentia pigmenti who have seizures (PMID: 30151858,28794079,24339369). Neurological symptoms (including seizures) are affect ~30% of patients with incontinentia pigmenti (PMID:28870493).
Early onset or syndromic epilepsy v0.894 IKBKG Ivone Leong Phenotypes for gene: IKBKG were changed from to Incontinentia pigmenti, 308300