Nonphotosensitive Trichothiodystrophy 5 (X-linked Intellectual Disability) via the RNF113A Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD). X-linked Intellectual Disability (XLID) contributes almost 10-15% of intellectual disability (ID) cases in males.

Deficiency of the RING finger protein 113A (RNF113A) leads to nonphotosensitive trichothiodystrophy type 5 (TTD5), a syndromic form of X-linked intellectual disability. TTD5 is primarily characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The clinical features may include (but may not be limited to) profound intellectual disability, developmental delay, speech problem, cerebellar atrophy, seizures, structural brain malformations such as hypoplastic corpus callosum and cerebellum, Dandy-Walker malformation, and also gait abnormalities, short stature, intrauterine growth restriction, progressive microcephaly, minimal body hair, recurrent infections, dysmorphic facies, aged appearance, and abnormalities of the head, neck, skin, hair, muscle and gastrointestinal, ophthalmological and genitourinary systems (Corbett et al. 2015. PubMed ID: 25612912).

Pathogenic variants in RNF113A (also known as ZNF183) cause X-linked nonphotosensitive Trichothiodystrophy type 5, a syndromic form of intellectual disability. RNF113A consists of one coding exon and maps to chromosome Xq24, encoding a 343 amino acid polypeptide. RNF113A, an E3 ligase of ubiquitin-dependent pathway, contains a C3HC4-type RING finger domain and a Zinc-finger domain and is predicted to play a role in gene regulation and DNA repair (Frattini et al. 1997. PubMed ID: 9224902; Brickner et al. 2017. PubMed ID: 29144457). To date, one missense and one nonsense pathogenic variant have been reported (Tarpey et al. 2009. PubMed ID: 19377476; Corbett et al. 2015. PubMed ID: 25612912). The disease transmission pattern is primarily X-linked recessive.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795).

This test provides full coverage of all coding exons of the RNF113A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).