Syndromic Intellectual Disability via the PURA 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). Mental retardation, autosomal dominant 31 (MRD31, syndromic ID) is a neurodevelopmental disorder that is primarily characterized by moderate to severe developmental delay, poor or absent speech, learning disability, early-onset feeding difficulties, significant hypotonia, seizures, encephalopathy, respiratory issues, dysmorphic facial features (including frontal bossing and epicanthal folds), and eye abnormalities (Tanaka et al. 2015). Abnormal EEGs have been documented in most of the affected individuals and many are reported with hypomyelination or myelin-maturation delay in brain-MRI; with frequent myoclonic jerks in infancy, leading to epilepsy (Lalani et al. 2014).

Mental retardation, autosomal dominant 31 (MRD31) is a neurodevelopmental disorder, associated with intellectual disability that results from heterozygous de novo pathogenic variants in PURA (Hunt et al. 2014). PURA is a single-exon gene that maps to chromosome 5q31.3 and encodes a 322 amino acid polypeptide of PURα. Purine-rich element-binding protein A (PUR-alpha, PURα) is a ubiquitously expressed, highly conserved multifunctional protein (28-kDa) and a member of the Pur-family of nucleic acid binding proteins. PURα contains an N-terminal glycine-rich region, three Pur-repeats and a C-terminal glutamine-glutamate rich domain. It acts as a regulatory protein in DNA replication, gene transcription, RNA transport and mRNA translation (Hunt et al. 2014), and thus plays an important role in development, proliferation and maturation of the neural system (Tanaka et al. 2015). To date, only de novo missense, nonsense, and frameshift pathogenic variants have been reported in the human PURA gene. There are two incidences of gross deletions (5q31.3 microdeletion syndrome) including PURA and multiple additional genes. The disease transmission pattern is consistent with autosomal dominant inheritance.

Earlier, in vivo studies have shown that Purine-rich element-binding protein A (PURα) is essential for postnatal brain development (Khalili et al. 2003). The authors have demonstrated that Pura-/- mice appear normal at birth, but develop tremors and seizures at 2 weeks, then die by 4 weeks of age. PURA is the leading candidate gene responsible for the developmental phenotype of the 5q31.3 microdeletion syndrome, and the clinical features of MRD31 are similar to it (Lalani et al. 2014; Tanaka et al. 2015).

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). 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 PURA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.