Intellectual Disability (Syndromic and Non-Syndromic) via the UPF3B Gene

Intellectual Disability (ID) is a heterogeneous group of disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ below 70) and adaptive behavior, diagnosed in ~1–3% of the population before 18 years of age. ID can be presented as isolated cases (non-syndromic ID) or in combination with other malformations, dysmorphic features, and/or neurological abnormalities (syndromic ID). X-linked Intellectual Disability (XLID) contributes almost 10-15% of the ID cases in males, and non-syndromic XLID is more prevalent as it accounts for almost two third of the XLID cases (de Brouwer et al. 2007). Pathogenic variants in the UPF3B gene have been reported in several families with syndromic and non-syndromic XLID. The common clinical features of UPF3B-related syndromic XLID includes mild to severe intellectual disability with autistic features, slender build, poor musculature, long face, high-arched palate and pectus deformities, sometimes childhood-onset schizophrenia and/or attention deficit hyperactivity disorder (Tarpey et al. 2009; Jolly et al. 2013). UPF3B (Regulator of nonsense transcripts 3B) is a cytosolic protein and a part of a post-splicing multiprotein complex that is involved in the nonsense-mediated mRNA decay (NMD) pathway. Interestingly, the NMD pathway has recently been linked with neuronal differentiation and axon guidance (Colak et al. 2013), and pathogenic alterations in the NMD genes have been implicated in neurodevelopmental disorders (Nguyen et al. 2013).

UPF3B-related intellectual disability is inherited in X-linked recessive manner. Loss-of-function pathogenic variants in UPF3B result in neurodevelopmental disorders with variable clinical presentations, including syndromic and non-syndromic intellectual disability (Jolly et al. 2013). UPF3B is a core member of the highly conserved nonsense-mediated mRNA decay (NMD) pathway which is involved in the rapid degradation of transcripts with premature termination codons, as well as mRNA stability and regulation of gene expression (Alrahbeni et al. 2015). UPF3B consists of 11 exons and encodes a 483 amino acid polypeptide. Nonsense and missense pathogenic variants, as well as small deletions, have been reported in UPF3B.

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 in over 700 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity (Vissers et al. 2016). Analytical sensitivity should be high because all pathogenic variants reported to date are detectable by sequencing.

To date, there is no report of any large deletion or duplication involving this gene.

This test provides full coverage of all coding exons of the UPF3B 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).