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Intellectual disability

Gene: RNF113A

Green List (high evidence)

RNF113A (ring finger protein 113A)
EnsemblGeneIds (GRCh38): ENSG00000125352
EnsemblGeneIds (GRCh37): ENSG00000125352
OMIM: 300951, Gene2Phenotype
RNF113A is in 5 panels

5 reviews

Sarah Leigh (Genomics England Curator)

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, 4:41 p.m. | Last Modified: 23 Mar 2020, 4:41 p.m.
Panel Version: 3.15

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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) localised 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).

Tessarech et al (2019 - PMID: 31793730) also reported on Q301* which was identified in 2 male fetuses presenting microcephaly, genital, CNS (partial CCA) and endocrine abnormalities - all features of the disorder. TOP was elected. ARX, ATRX sequencing, 7-DHCR in amniotic fluid were performed, while karyotypes and SNP-arrays for both were normal. Trio exome revealed a maternally inherited Q301* variant in one fetus, also confirmed in the other. The variant had occurred de novo in the mother who had completely skewed (100%) XCI. qRT-PCR in thymus cells from both fetuses demonstrated increased mRNA levels.

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, 6:12 p.m. | Last Modified: 5 Jan 2020, 6:12 p.m.
Panel Version: 3.0

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Publications

Louise Daugherty (Genomics England Curator)

Red List (low evidence)

Probable gene in Developmental Disorders Genotype-Phenotype Database (DDG2P) associated to X-linked trichothiodystrophy. Currnetly not enough evidence to support promoting this gene.
Created: 18 Dec 2017, 3:39 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)

Phenotypes
X-linked trichothiodystrophy; Trichothiodystrophy 5, nonphotosensitive, 300953; Intellectual disability

Publications

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
X-LINKED TRICHOTHIODYSTROPHY

Publications

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
Phenotypes
  • X-linked trichothiodystrophy
  • Trichothiodystrophy 5, nonphotosensitive, 300953
  • Intellectual disability
Tags
Skewed X-inactivation
OMIM
300951
Clinvar variants
Variants in RNF113A
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

2 Jun 2020, Gel status: 3

Added Tag

Sarah Leigh (Genomics England Curator)

Tag Skewed X-inactivation tag was added to gene: RNF113A.

23 Mar 2020, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: rnf113a has been classified as Green List (High Evidence).

23 Mar 2020, Gel status: 1

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: RNF113A were set to 25612912; 29144457

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

5 Jan 2018, Gel status: 1

Set mode of inheritance, Set publications

Ellen McDonagh (Genomics England Curator)

Model 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 was set to ['25612912', '29144457']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

RNF113A was added to Intellectual disabilitypanel. Sources: Expert Review Red

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

RNF113A was created by ellenmcdonagh