Autism Spectrum Disorders via the DSCAM Gene

Autism Spectrum Disorders (ASD) include several neurodevelopmental disorders characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) (Levy et al. 2009). ASD usually presents by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); McPartland et al. 2016). Comorbidities occur in more than 70% of cases and include intellectual disability (ID), epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi 2016). Recent studies using whole exome trio studies have identified novel gene candidates, with familial and de novo variants from several hundred genes now implicated in the development of ASD (Bourgeron 2016).

Genetic aberrations are reported to be responsible for 50%-90% and 15%-50% of ASD and ID cases, respectively, and inheritance overall is multifactorial (Larsen et al. 2016; Karam et al. 2015). Incidence of ASD is approximately 1 in 68 individuals with a male-to-female ratio of 4:1 (Center for Disease Control 2014). De novo missense and likely gene disrupting variants are 15% and 75% more frequent in ASD patients than unaffected controls, respectively (Iossifov et al. 2014).

DSCAM (down syndrome cell adhesion molecule) is a neuronal cell adhesion molecule with homology to members of the immunoglobulin superfamily. DSCAM is expressed in most neuronal cells and functions in neuron generation and growth, dendrite self/non-self recognition, and synapse formation and plasticity (Jia et al. 2011). DSCAM is located in chromosome region 21q22.2-q22.3 within the Down syndrome (DS) critical region (DSCR). This region includes genes that, because of increased dosage, are believed to result in the clinical phenotypes of DS (Jia et al. 2011). Known targets of DSCAM are p21-associated kinases (PAKs) which mediate neuron cytoskeletal organization, morphogenesis, and synaptic plasticity via DSCAM activation (Kreis and Barnier 2009; Pérez-Núñez et al. 2016).

The human DSCAM gene contains 33 protein-coding exons which encode a 2,012 amino acid protein. DSCAM alternative splicing is extensive in non-vertebrates (such as arthropods) and is believed to contribute to neuron self/non-self recognition. However, vertebrate genomes encode only two DSCAM homologs (DSCAM & DSCAML1) and neither is reported to be alternatively spliced to as significant an extent (Hattori et al. 2008; Schmucker and Chen 2009). The human DSCAM protein contains 10 Ig domains and 6 fibronectin type III repeats (Schmucker and Chen 2009). At least 6 de novo loss-of-function variants have been reported in individuals presenting with ASD features from multiple ASD cohorts (Iossifov et al. 2014; DeRubeis et al. 2014; Wang et al. 2016), supporting an autosomal dominant mode of inheritance.

Currently, the contribution of de novo and inherited factors to ASD risk is estimated to be approximately 50-60% (Krumm et al. 2015). DSCAM is categorized as a gene with ‘high confidence’ regarding its susceptibility for ASD in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/GeneDetail/DSCAM). However, more than 700 genes have been associated with ASD features (Bourgeron 2016). Based on large whole exome sequencing studies, de novo loss-of-function variants in DSCAM were identified in approximately 6/6,300 individuals from multiple ASD cohorts (Iossifov et al. 2014; De Rubeis et al. 2014; Wang et al. 2016). Recent investigations identified 2 additional ASD individuals with de novo likely gene disrupting variants in DSCAM from a cohort of 13,407 trios (Stessman et al. 2017).

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