Autism Spectrum Disorders and CTNND2-Related Disorders via the CTNND2 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. PubMed ID: 24670961). 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).

CTNND2 (delta-Catenin/neural plakophilin-related armadillo-repeat protein/neurojungin) encodes a delta-catenin that interacts with cadherins (cell-cell junction proteins), and in the neuronal context, synapse junction-associated proteins (Lu et al. 2016. PubMed ID: 27380241). CTNND2 also impacts neuronal structure/function and synapse morphogenesis during neuronal development (Lu et al. 2016. PubMed ID: 27380241). Copy number and sequence variation within CTNND2 have been associated with autism spectrum disorder (Turner et al. 2015. PubMed ID: 25807484), as well as other neurological disorders including Alzheimer’s disease (Jun et al. 2012. PubMed ID: 22984439), Cri-du-chat syndrome and intellectual disabilities (Hofmeister et al. 2015. PubMed ID: 25473103; Belcaro et al. 2015. PubMed ID: 25839933, Medina et al. 2000. PubMed ID: 10673328, Sardina et al. 2014. PubMed ID: 24677774), and schizophrenia (Sklar et al. 2008. PubMed ID: 18668038; Stefansson et al. 2008. PubMed ID: 18668039).

Missense variants within CTNND2 at conserved residues were reported to be significantly more frequent in ASD cohorts than controls, however whether these variants arose de novo was not reported (Turner et al. 2015. PubMed ID: 25807484). Furthermore, exon-disrupting copy number variants (CNVs) within CTNND2 are overall enriched in cohorts of individuals generally diagnosed with neurodevelopmental disorders compared to population-based control cohorts. For ASD specifically, exon-disrupting deletions are observed in excess, suggesting a haploinsufficient mechanism for ASD development and an autosomal dominant mode of inheritance (Turner et al. 2015. PubMed ID: 25807484).

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). CTNND2 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/CTNND2). 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. With respect to CNVs in probands diagnosed with a neurodevelopmental disorder, 25/19,556 (0.13%) cases had a CNV overlapping with a CTNND2 exonic region compared to 3/13,898 (0.02%) in population-based controls (Odds Ratio: 5.9, p=4.10x10^-4) (Turner et al. 2015. PubMed ID: 25807484).

This test provides full coverage of all coding exons of the CTNND2 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).