Autism Spectrum Disorders via the CACNA2D3 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. PubMed ID: 19819542). 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. PubMed ID: 27786181). Recent studies using whole exome trios have identified novel gene candidates, with familial and de novo variants from several hundred genes now implicated in the development of ASD (Bourgeron. 2016. PubMed ID: 27289453).

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. PubMed ID: 27790361; Karam et al. 2015. PubMed ID: 25728503). 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. PubMed ID: 25363768).

CACNA2D3 (calcium voltage-gated channel auxiliary subunit alpha2delta 3) is a component of the voltage-dependent calcium channel complex composed of alpha-1 pore subunit, alpha-2/delta auxiliary subunit, beta auxiliary subunit. CACNA2D3 encodes an auxiliary alpha-2/delta subunit of the multimeric calcium channel complex which modulates trafficking and surface expression of the calcium channel, and has also been implicated in synaptogenesis (Pirone et al. 2014. PubMed ID: 24403143). Disruption of CACNA2D3 in mice results in changes in auditory nerve fiber synapse function and morphology resulting in sensory processing defects (Pirone et al. 2014. PubMed ID: 24403143).

De novo likely gene disrupting variants including nonsense and splice-site variants have been reported at higher-than-expected frequencies in CACNA2D3 among individuals with autism spectrum disorder phenotypes (Yuen et al. 2017. PubMed ID: 28263302). Specifically, variants have been identified in simplex families within the Simons Simplex Collection, simplex ASD trios (n=2,270) (De Rubeis et al. 2014. PubMed ID: 25363760; Iossifov et al. 2012. PubMed ID: 22542183), and in at least 1/5,205 affected individuals within the autism-specific database MSSNG (Yuen et al. 2017. PubMed ID: 28263023). Taken together, these results suggest an autosomal dominant mode of inheritance for ASD.

Variants within CACNA2D3 have also been associated with chronic back pain and altered pain tolerance (nociception) (Neely et al. 2010. PubMed ID: 21074052).

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorders (ASD) risk is estimated to be approximately 50-60% (Krumm et al. 2015. PubMed ID: 25961944). CACNA2D3 is categorized as a ‘strong candidate’ regarding its association with ASD in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/database/human-gene/CACNA2D3). However, more than 700 genes have been associated with ASD features (Bourgeron. 2016. PubMed ID: 27289453), suggesting that the clinical sensitivity of any single gene sequencing or copy number variant test in the context of autism spectrum disorder phenotypes is minimal. For CACNA2D3, the true clinical sensitivity of sequence or copy number variant analyses is unknown.

Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads.

This test provides full coverage of all coding exons of the CACNA2D3 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).