Autism Spectrum Disorders via the KMT5B (SUV420H1) 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). Several studies have identified de novo missense, nonsense, and frameshift variants in KMT5B within individuals presenting with a neurodevelopmental disorder (Iossifov et al. 2012; Sanders et al. 2012; De Rubeis et al. 2014; Stessman et al. 2017). Based on the large number of reported heterozygous de novo variants in affected individuals, it appears KMT5B pathogenic variants lead to ASD/ID symptoms in an autosomal dominant manner. However, the precise molecular mechanism is unclear (Stessman et al. 2017).

KMT5B (lysine (K)-specific methyltransferase 5B) (also known as SUV420H1, suppressor of variegation 4-20 homolog 1) is a histone lysine N-methyltransferase involved in chromatin modifications and gene regulation. The role of KMT5B in brain development is unclear; however histone H4 K20 trimethylation via KMT5B has been shown to regulate the cell cycle of baboon neural stem progenitor cells (Rhodes et al. 2016). RNAi knockdown studies of the Drosophila KMT5B homolog also suggest an impact on habitual learning (Stessman et al. 2017). Individuals with likely gene disrupting variants in KMT5B present with intellectual disability/developmental delay (100% of cases to date), ASD (83%), language delay (75%), motor delay (60%), febrile seizures (60%), and in some cases attention deficits (Stessman et al. 2017).

In human cells, the KMT5B (SUV420H1) gene encodes two alternatively splice isoforms, the longest including 10 exons that encode an 885 amino acid protein. Both isoforms contain a SET domain (residues 191-303). This domain is present in all known human histone methyltransferases and hypothesized to mediate interactions with dual-specificity phosphatase-like proteins (Lachner and Jenuwein 2002; Wu et al. 2013). At least 4 de novo variants have been reported within the SET domain, however, likely gene disrupting variants upstream and downstream of the SET domain have been reported (Stessman et al. 2017).

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorder (ASD) risk is estimated to be approximately 50%-60% (Krumm et al. 2015). KMT5B is categorized as a ‘high confidence’ gene candidate for ASD in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/GeneDetail/KMT5B). However, more than 700 genes have been associated with ASD features (Bourgeron 2016). Based on multiple recent large sequencing studies, causative variants in KMT5B were collectively identified in approximately 0.07% of ASD probands (14/19,778) (Iossifov et al. 2014; DeRubies et al. 2014; Stessman et al. 2017).

This test provides full coverage of all coding exons of the KMT5B 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).