X-linked Intellectual Disability via the RPL10 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 ID cases in males.

Deficiency of ribosomal protein 10 (RPL10) leads to a syndromic form of ID, known as Mental Retardation, X-linked syndromic 35 (MRXS35). The clinical features of RPL10-related ribosomopathy are variable and may include (but may not be limited to) delayed psychomotor development, delayed or absent speech, intellectual disability, seizures, autism, short stature, poor growth, premature birth, muscular hypotonia, gastroesophageal reflux disease, cardiac and genitourinary anomalies, abnormalities of the head, neck (including dysmorphic features and progressive microcephaly) and skeletal systems (Brooks et al. 2014. PubMed ID: 25316788; Thevenon et al. 2015. PubMed ID: 25846674; Zanni et al. 2015. PubMed ID: 26290468; Bourque et al. 2017. PubMed ID: 29066376; Chiocchetti et al. 2011. PubMed ID: 21567917). Unaffected carrier females have been reported with favorably, fully skewed X-inactivation of the pathogenic variant-bearing X chromosomes (Brooks et al. 2014. PubMed ID: 25316788).

Pathogenic variants in human ribosomal protein 10 gene (RPL10) lead to MRXS35. RPL10 maps to chromosome Xq28 and consists of 6 coding exons that translate a 214 amino acid polypeptide RPL10, a highly conserved component of the large (60S) ribosome subunit that plays an essential role in protein synthesis. Combined genetic, functional, and biochemical assays suggest that pathogenic variants in RPL10 can potentially leads to defects in bulk translation and increased apoptosis in the brain; thereby causing syndromic central nervous system defects (Brooks et al. 2014. PubMed ID: 25316788). To date, only five missense variants have been reported in the human RPL10 gene and there is no report of any gross deletion/duplication that includes RPL10 (Human gene Mutation database). 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). Analytical sensitivity should be high because all pathogenic variants reported within this gene to date are detectable by sequencing.

This test provides full coverage of all coding exons of the RPL10 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).