Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development

Background: Autism spectrum disorder (ASD) is a heterogeneous disorder with significant genotypic and phenotypic complexity (Geschwind, 2009). While various behaviorally defined subtypes have been proposed, these have not been tied to genetic etiology, linked to treatment indicators, nor been diagnosed consistently by expert clinicians (King et al, 2014). Indeed, with the transition to the DSM-5, all behaviorally defined subtypes have been subsumed by the umbrella term Autism Spectrum Disorder, allowing for identification of subtypes more closely aligned to biological mechanisms (APA, 2013). The genetic etiology of ASD is no less varied. Over 100 genes and genomic regions have been suggested as candidates or associated with ASD (Betancur, 2011), and over 800 genes have been predicted to play a role in ASD (Iossifov et al, 2012; Neale et al, 2012; O’Roak et al, 2012a; Sanders et al, 2012). Given that parsing the behavioral heterogeneity has yielded limited utility, genetically defined subtypes may prove more beneficial in illuminating molecular mechanisms underlying ASD, the course and prognosis of a subgroup of individuals with ASD, and individualized treatment targets. Severe disruptive mutations in chromodomain helicase DNA binding protein 8 (CHD8) have been strongly associated with ASD and provide a likely candidate for a specific subtype of ASD (O’Roak et al, 2012b; Talkowski et al, 2012; Neale et al, 2012).  

Objectives: To determine if CHD8 mutations define a specific subtype of ASD through the identification of patients, comprehensive follow up evaluation, and extensive phenotype-genotype correlations.

Methods: Expanding upon our description of individuals with truncating mutations to CHD8 reported in Bernier et al, 2014, we identified a total of 25 independent mutations through targeted sequencing (N=22) of 7,097 individuals with autism or developmental delay from multiple research cohorts as well as through clinical referral (N=3); no truncating events were identified in 8,916 controls, including 2,413 unaffected siblings. We re-contacted all patients and their families who were willing to participate in follow up assessment (N=18) and collected medical records for those unavailable for assessment (N=7). In-depth, structured clinical assessment, review of medical records, and medical/dysmorphological evaluation was conducted. Clinical assessment included diagnostic assessment and evaluation of cognitive, adaptive, language, motor, and executive functioning abilities. 

Results: ASD was the most common diagnosis observed in our cohort. Of the 25 identified individuals evaluated, 23 meet strict diagnostic criteria for ASD.  Although patients varied in age from 4-41 years of age, we observed striking similarities in their facial characteristics. Predominant features included increased occipitofrontal circumference (OFC), pronounced supraorbital brow ridges, hypertelorism with down-slanted palpebral fissures, broad nose with full nasal tip, and pointed chin. Other recurrent physical features included slender, tall build and large, flat feet, which were reported in several individuals. 80% of individuals reported significant GI problems, characterized as recurrent and consistent problems with constipation. Cognitive ability ranged from intellectual disability to average functioning. Sleep problems were common as was precocious puberty in the female patients.  

Conclusions: Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal comorbidities between brain development and enteric innervation.