Autism Spectrum Disorders via the KATNAL2 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). Multiple independent de novo sequence variants in the same gene among unrelated probands has been reported as a potential means to identify ASD risk alleles (Sanders et al. 2012. PubMed ID: 22495306).

KATNAL2 (Katanin P60 subunit A-like 2) is a putative microtubule-severing ATPase that, in mice, has been shown to impact dendritic branch formation in the developing brain (Williams et al. 2016. PubMed ID: 27161796). KATNAL2 may also play a role in ciliogenesis and centriole activity (Dunleavy et al. 2017. PubMed ID: 29136647).

De novo variants in KATNAL2 have been reported in individuals with ASD features from simplex families (Sanders et al. 2012. PubMed ID: 22495306; O'Roak et al. 2012. PubMed ID: 22495309; Stessman et al. 2017. PubMed ID: 28191889), supporting an autosomal dominant mode of inheritance. Maternally-inherited KATNAL2 likely gene disrupting variants (nonsense and splice site) have also been reported in individuals with ASD phenotypes (Yuen et al. 2015. PubMed ID: 25621899; Stessman et al. 2017. PubMed ID: 28191889). Of note, females are reported to have more variants in ASD risk genes than males, but require a greater mutational burden than males before clinical manifestation of ASD features (Jacquemont et al. 2014. PubMed ID: 24581740). Furthermore, variants predicted to disrupt KATNAL2 protein function (splice site, nonsense, frameshift) have also been reported in population databases composed of presumably unaffected individuals (Supplementary Table 18, Stessman et al. 2017. PubMed ID: 28191889) which may be related to sex-specific difference in ASD manifestations or incomplete penetrance.

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). KATNAL2 is categorized as a gene with ‘high confidence’ regarding its association with ASD in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/database/human-gene/KATNAL2). 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 small. For KATNAL2, the true clinical sensitivity of sequence or copy number variant analyses is unknown.

This test provides full coverage of all coding exons of the KATNAL2 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).