TARP Syndrome via the RBM10 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.

TARP syndrome (TARPS), also known as Robin’s syndrome, is a severe form of X-linked syndromic ID that often leads to early lethality due to liver failure, kidney failure, hyaline membrane disease, and respiratory failure (Johnston et al. 2014. PubMed ID: 24259342). The clinical features of TARP syndrome often include Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava. Affected individuals have been reported with variable multiple congenital anomalies, such as abnormal corpus callosum, cerebellar vermis hypoplasia, developmental delay, hypotonia, lethargy, seizures, failure to thrive, and abnormalities of the head, neck, respiratory, cardiovascular, gastrointestinal, genitourinary and skeletal systems (Johnston et al. 2010. PubMed ID: 20451169; Johnston et al. 2014. PubMed ID: 24259342).

TARP syndrome is an X-linked disorder caused by pathogenic variants in RNA-binding motif protein 10 gene (RBM10). Along with de novo events, there are also reports of maternal heterozygosity and maternal mosaicism (Johnston et al. 2014. PubMed ID: 24259342). RBM10 maps to chromosome Xp11.3 and consists of 23 coding exons that encode the 930 amino acid polypeptide RBM10. RBM10 is a member of RNA-binding motif (RBM) family and is predicted to include one zinc finger motif, one G-patch domain, and two RNA recognition motif (RRM) domains (Johnston et al. 2010. PubMed ID: 20451169). To date, the mutational reports of RBM10 include small frameshift deletions, nonsense and missense variants and a large deletion (Human Gene Mutation Database). The disease transmission pattern is 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). Analytical sensitivity should be high because most pathogenic variants reported within this gene to date are detectable by sequencing. To date, only one gross deletion involving RBM10 has been reported.

This test provides full coverage of all coding exons of the RBM10 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).