X-Linked Intellectual Disability via the CLCN4 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. Mental Retardation, X-linked 49, MRX49 (also known as MRX15) leads to borderline to profound intellectual disability, which can be both non-syndromic and syndromic. In syndromic forms, the affected individuals may present with additional features like poor or absent speech, congenital and progressive hypotonia, delayed psychomotor development, and slender build (Raynaud et al., 1996. PubMed ID: 8826458; Claes et al., 1997. PubMed ID: 9415477; Veeramah et al., 2013. PubMed ID: 23647072). Sometimes patients also suffer from eye and skeletal abnormalities, epileptic encephalopathy, seizures, cortical atrophy, behavioral problems, autism, mood disorders, obsessive-compulsive behaviors, hetero and auto aggression, dystonia, facial dysmorphism and microcephaly (Veeramah et al., 2013. PubMed ID: 23647072; Hu et al., 2016. PubMed ID: 25644381; Palmer et al., 2016. PubMed ID: 27550844). Heretozygous females can be asymptomatic or can develop mild intellectual disability and/or behavioral problems. Severely affected females have also been reported (Claes et al., 1997. PubMed ID: 9415477; Palmer et al., 2016. PubMed ID: 27550844).

Pathogenic variants (familial and de novo) in human ‘Chloride Channel 4’ (CLCN4) have been reported in several cases with MRX49, a form of X-linked intellectual disability. CLCN4 maps to chromosome Xp22.3 and consists of 11 coding exons that encode a 760 amino acid polypeptide of electrogenic chloride/proton exchanger ClC-4 (CLCN4). This gene is a member of the CLCN family of voltage-dependent chloride channel genes that have significant sequence homology (Fisher et al., 1995. PubMed ID: 8575751). To date, a small frameshift deletion and missense variants have been reported, but there are no reports of any gross deletions/duplications that include CLCN4. Using in vivo mouse models, Hu et al. has shown that pathogenic variants in CLCN4 impair normal protein function (Hu et al., 2016. PubMed ID: 25644381). The disease transmission pattern is X-linked recessive as well as X-linked dominant (Palmer et al., 2016. PubMed ID: 27550844).

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 CLCN4 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.