X-linked Intellectual Disability via the DLG3 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 synapse-associated protein 102 (SAP102) leads to X-linked Mental Retardation-90 (MRX90). The clinical features of MRX90 are variable from nonsyndromic to syndromic and may include (but may not be limited to) delayed psychomotor development, delayed speech development, limited speech, mild to severe ID, learning disability, seizures, obesity, behavioral problems (anxiety, attention-deficit hyperactivity disorder), muscular hypotonia, narrow-thorax, enuresis and abnormalities of the head and neck, including dysmorphic features such as high-arched palate, molar hypoplasia, short and upslanting palpebral fissures and strabismus (Tarpey et al. 2004. PubMed ID: 15185169; Philips et al. 2014. PubMed ID: 24721225; Kumar et al. 2016. PubMed ID: 27222290; Hu et al. 2016. PubMed ID: 25644381). Some carrier females have been observed with mild intellectual disability and seizures, although a random X-inactivation pattern has been reported in the majority of the female carriers (Tarpey et al. 2004. PubMed ID: 15185169; Gieldon et al. 2017. PubMed ID: 28777483).

Pathogenic variants in the human Discs large Drosophila homolog of 3 gene (DLG3) lead to MRX90. DLG3 maps to chromosome Xq13.1 and consists of 19 coding exons that translate into an 817 amino acid polypeptide of synapse-associated protein 102 (SAP102). SAP102, a member of the membrane-associated guanylate kinase (MAGUK) protein family, consists of three tandem PDZ domains, one src-homology (SH3) domain and one guanylate kinase (GK) domain. SAP102 is the major MAGUK expressed in the neurons during early brain development and is presumed to participate in early stages of NMDA receptor processing, and clustering and targeting of NMDA receptors in the postsynaptic density (PSD) of excitatory synapses (Tarpey et al. 2004. PubMed ID: 15185169). To date, several pathogenic variants (missense, nonsense, splice site, small frameshift deletions and duplications) have been reported, including two gross deletions/duplications involving DLG3 (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 the majority of pathogenic variants reported within this gene to date are detectable by sequencing.

To date, two gross deletions/duplications involving DLG3 have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the DLG3 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).