Autism Spectrum Disorders via the TRIP12 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).

TRIP12 (thyroid hormone receptor interactor 12) is an E3 ubiquitin-protein ligase that guards against excessive spreading of ubiquitinated chromatin at sites of DNA damage through an ubiquitin fusion degradation pathway (Lelieveld et al. 2016; Liu et al. 2016; Poulsen et al. 2012). Errors in ubiquitination that result in the accumulation of protein aggregates are well documented in many neurological diseases (Popovic et al. 2014) yet the precise role of TRIP12 in ASD and ID is unknown. The majority of individuals with pathogenic TRIP12 variants present with both ASD and mild to moderate ID (IQ range 53-72), have difficulty falling asleep, and are delayed in speech and language development (O’Roak et al. 2014; Bramswig et al. 2017).

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). While TRIP12 plays a clear role in DNA repair and protein ubiquitination, little is known with respect to neurodevelopment (O’Roak et al. 2014). It appears TRIP12 pathogenic variants lead to ASD/ID symptoms in an autosomal dominant manner, likely through haploinsufficiency (Bramswig et al. 2017).

There are 4 different TRIP12 transcript isoforms that use identical translation start and stop sites, but differ in the usage of internal exons and in-frame splice sites. All transcripts share an identical C-terminal HECT domain, which is characteristic of E3 ubiquitin ligases, but vary in the size of the WWE domain, which mediates protein-protein interactions involving ubiquitin. Thus, the TRIP12 protein ranges between 1,722-2,040 amino acids in length (Bramswig et al. 2017). The majority of affected individuals have a de novo TRIP12 pathogenic variant (nonsense, splice-site, frameshift, or missense) (Wang et al. 2016; Bramswig et al. 2017; O’Roak et al. 2014). Familial missense variants do occur, but with varying penetrance (Bramswig 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). TRIP12 is categorized as a ‘strong candidate’ for ASD in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/GeneDetail/TRIP12). However, more than 700 genes have been associated with ASD features (Bourgeron 2016). Based on recent large whole exome sequencing studies, causative variants in TRIP12 were identified in approximately 1/500 to 1/900 ASD probands (Wang et al. 2016; O’Roak et al. 2014).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the TRIP12 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.