Autism Spectrum Disorders/Intellectual Disability via the ASH1L 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).

ASH1L (absent, small, or homeotic 1-like homolog, also known as KMT2H) is a histone lysine methyltransferase that occupies and modifies promoter region chromatin to influence gene regulation and development through H3K36me2 methylation. ASH1L protein levels are enriched in the hippocampus; however ASH1L’s role(s) in the brain are still poorly understood (Zhu et al. 2016). ASH1L has been shown to mediate activity-dependent repression of NRXN1, which encodes the synaptic cell adhesion molecule neurexin 1. Activity-dependent synapse elimination is believed to refine neuronal wiring during the late stages of postnatal development. Mice homozygous for disrupting variants in ASH1L are apparently not viable, while heterozygous mice do not show any abnormalities of the brain (Zhu et al. 2016).

ASH1L pathogenic variants result in ASD/ID symptoms in an autosomal dominant manner, as all affected individuals reported to date are heterozygous and several de novo variants have been implicated with disease development. The human ASH1L gene contains 27 protein-coding exons which encode a 2,964 amino acid protein. ASH1L contains a SET domain, four AT hooks, bromodomain, bromo-adjacent homology domain, PHD finger, and a MYND ligand domain (Gregory et al. 2007). At least 1 nonsense and 3 missense (two de novo) variants have been reported in individuals presenting with intellectual disability (100%), ASD (25%), facial dysmorphism (50%), abnormal behavior (75%), gastrointestinal problems (50%), eye anomalies (50%), myelination delay (1 case), and skeletal abnormalities (50%) (Okamoto et al. 2017). The nonsense variant occurred before the multidomain region of ASH1L and only one missense variant has been reported in the bromo-adjacent homology domain (most C-terminal domain) (Okamoto et al. 2017).

Currently, the contribution of de novo and inherited factors to ASD risk is estimated to be approximately 50-60% (Krumm et al. 2015). ASH1L 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/ASH1L). However, more than 700 genes have been associated with ASD features (Bourgeron 2016). Based on recent large whole exome sequencing studies, causative variants in ASH1L were identified in approximately 1/1000 individuals within multiple ASD and ID cohorts (De Rubeis et al. 2014; Grozeva et al. 2015; Wang et al. 2016). However, one study focused specifically on an ID cohort identified 7/765 individuals with missense variants in ASH1L (de Ligt et al. 2012).

This test provides full coverage of all coding exons of the ASH1L 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).