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Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development
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.