Intellectual Disability via the TUSC3 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). Traditionally, ID can be both non-syndromic (NS-ID) and syndromic (S-ID). However, it is often difficult to rule out the presence of more subtle neurological anomalies and psychiatric disorders in NS-ID patients, and additionally, symptoms of some S-ID cases may be very subtle, blurring the distinction between S-ID and NS-ID (Kaufman et al. 2010. PubMed ID: 21124998).

Defects in a subunit of the oligosaccharyltransferase (OTase) complex lead to Mental Retardation 7 (MRT7) (Molinari et al. 2008. PubMed ID: 18455129). The clinical features of MRT7 are variable from nonsyndromic to syndromic and may include (but may not be limited to) moderate to severe ID, delayed psychomotor development, speech delay, short stature, dysmorphic features such as deep set eyes, long face, thin philtrum, pointed chin, hypertelorism, short frenulum and camptodactyly, syndactyly, and autism (Najmabadi et al. 2007. PubMed ID: 17120046; Molinari et al. 2008. PubMed ID: 18455129; Garshasbi et al. 2008. PubMed ID: 18452889; Garshasbi et al. 2011. PubMed ID: 21739581; Jones et al. 2013. PubMed ID: 23806237; Yavarna et al. 2015. PubMed ID: 26077850; Al-Amri et al. 2016. PubMed ID: 27148795).

Pathogenic variants in human Tumor Suppressor Candidate 3 gene (TUSC3) lead to MRT7. TUSC3 maps to chromosome 8p22 and consists of 10 coding exons that translate into a 348 amino acid polypeptide. TUSC3 protein, believed to be an ortholog of the yeast oligosaccharyltransferase 3 (Ost3), is a subunit of the oligosaccharyltransferase (OTase) complex. However, in vitro studies on cultured cells have showed normal glycosylation patterns with defective TUSC3, suggesting that human TUSC3 may not be involved in glycosylation (Garshasbi et al. 2008. PubMed ID: 18452889; Molinari et al. 2008. PubMed ID: 18455129). Later in vivo studies in mice have suggested that TUSC3 may play an important role in magnesium transportation into neurons (Zhou and Clapham. 2009. PubMed ID: 19717468). To date, out of fourteen pathogenic variants reported in human TUSC3 gene (Human gene Mutation database), almost 60% are gross deletions involving TUSC3, and the rest are frameshift, missense, and nonsense variants. The disease transmission pattern is autosomal 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). Approximately 40% of reported TUSC3 pathogenic variants are directly detectable by sequencing, whereas the remainder are gross deletions.

To date, eight gross deletions involving TUSC3 have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TUSC3 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).