Genetic epilepsy syndromesGene: RNF113A
Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for X-linked trichothiodystrophy. At least 3 terminating variants reported in unrelated cases. Supportive functional studies also reported.
Created: 23 Mar 2020, 4:33 p.m. | Last Modified: 23 Mar 2020, 4:33 p.m.
Panel Version: 2.13
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].
Created: 5 Jan 2020, 6:19 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
?Trichothiodystrophy 5, nonphotosensitive, 300953
Gene: rnf113a has been classified as Green List (High Evidence).
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