Clinical Phenotype of De Novo Mutations in CHD2

Background: De novo mutations in CHD2, a chromatin-remodeling gene, are associated with increased risk for autism spectrum disorder (ASD) and epileptic encephalopathy (Carvill et al., 2013; O’Roak et al., 2014). Case reports have identified individuals with CHD2 mutations who present with neurodevelopmental problems including ASD, intellectual disability (ID), seizures, and challenging behavior, but substantial diversity is present across phenotypes (Chénier et al., 2014; Kim et al., 2018). Mice with CHD2 mutations present with reduced body weight and spinal curvature, and these features have been reported in some humans; however, a characteristic physical phenotype of CHD2 mutations has not been established in humans (Chénier et al., 2014; Kim et al., 2018). Quantitative phenotyping of individuals with de novo CHD2 mutations is necessary to understand how these events contribute to neurodevelopmental disorders and comorbid behavioral and medical problems.

Objectives: To characterize the human phenotype of CHD2 mutations using quantitative data from medical and behavioral evaluations.

Methods: Participants were 10 individuals with disruptive de novo CHD2 mutations: Four individuals drawn from an ongoing genetics-first study, two individuals from the Simons Simplex Collection (SSC), and four individuals from published studies identified through denovo-db (2018; Epi4K Consortium et al., 2013; O’Roak et al., 2014; Rauch et al., 2012; Willsey et al., 2017). Participants in SSC and the ongoing study completed diagnostic assessments, medical history interviews, and physical and dysmorphology exams.

Results: 70% of individuals with disruptive de novo CHD2 mutations were diagnosed with ASD, 60% were diagnosed with ID, and 56% were diagnosed with an anxiety disorder. 75% reported seizures. Gastrointestinal problems were reported by 100% of participants who completed a medical history interview; sleep problems were also reported by 100% of participants with a medical history. Spinal problems were not reported in any cases. Internalizing behavior problems were in the clinical range, while externalizing problems were in the borderline range; a history of aggression toward caregivers is reported for 83% of participants. Substantial variability is present in verbal IQ, nonverbal IQ, and adaptive behavior. 83% of individuals presented with a body mass index (BMI) one or more standard deviations below the mean, and 50% had a BMI below the 5^th percentile.

Conclusions: CHD2 mutations in humans are characterized by low BMI, sleep and GI problems, internalizing and externalizing behavior problems, high rates of ASD and seizures, and variability in IQ and adaptive behavior. Significant sleep and GI problems are also reported in humans with CHD8 mutations (Bernier et al., 2014), suggesting that the role of chromatin remodeling in ASD-associated sleep and GI disturbances should be further examined. Other features of the CHD2 phenotype in humans, such as low body weight and elevated rates of internalizing disorders, differ notably from the CHD8 phenotype (Bernier et al., 2014). Future research should evaluate associations between de novo mutations and comorbid internalizing disorders as well as the impact of intron mutations in chromatin-remodeling genes.