21915
Familial Contribution to Clinical Variability in Social Responsiveness for Individuals with Disruptive Mutations to CHD8 and CHD8 Target Genes
Chromodomain helicase protein 8 (CHD8) is one of the most frequently identified de novo likely gene disrupting mutations (LGDM) occurring in simplex ASD (Iossifov et al, 2014; O’Roak et al, 2012). CHD8 is a key regulator for a network of associated ASD risk genes involved in neurodevelopment (Cotney et al, 2014). Distinct phenotypic patterns have emerged for CHD8, yet considerable variability in ASD presentation remains (Bernier et al, 2014). Considering this variability in observed phenotype, the impact of CHD8 and associated LGDMs may be better captured by the extent that observed performance deviates from expected outcomes. Given high familial heritability of phenotypic traits such as social behavior (Constantino, 2005), parental functioning serves as a measurement of expected outcome and informs penetrance of de novo gene variants (Moreno-de-Luca et al, 2014). This promising approach can help quantify genetic contribution to phenotypic variability for mutations to CHD8 and CHD8-target genes.
Objectives:
First, to explore the genetic impact of disruptive events to CHD8 and CHD8-targets on phenotypic variability in social functioning by quantifying observed-expected (e.g., proband-parent) discrepancy. Second, to assess the observed-expected discrepancy for CHD8 and CHD8-targets relative to other ASD-associated gene-disrupting mutations and idiopathic ASD.
Methods:
Participants were simplex families of children who met strict criteria for ASD and either: (1) a de novo mutation of CHD8 and CHD8-target genes (via Cotney et al, 2014, n=45(9 female)), (2) other non-CHD8-related LGDM (n=313(53)), or (3) no known gene event (i.e. idiopathic, n=2073(264)). Identified families were participants of the Simons Simplex Collection, the Autism Simplex Collection, and an ongoing study of individuals with identified ASD-risk gene events. Social behavior was measured by the Social Responsiveness Scale (Constantino, 2005) for both probands and non-carrier parents. One-way ANOVAs compared group differences in observed-expected discrepancy between proband and parents for raw SRS scores.
Results:
Overall, participants with CHD8 and CHD8-target mutations had greater discrepancy in proband and paternal SRS than those with a non-CHD8 LGDM and those with no gene event. More specifically, children with CHD8 and CHD8-target mutations showed a decrement in social ability relative to expected ability as assessed by mean parental social ability (standard deviation, SD = 3.01), father social ability (SD = 2.71), and mother social ability (SD= 2.86). Preliminary analyses indicated that groups differed significantly in proband-father SRS difference score (F(2, 2411) = 3.25, p =0.039, see Figure 1), but not in proband-mother or proband-parental average difference score.
Conclusions:
Individuals with CHD8 and CHD8-target gene events show greater impairment in social responsiveness relative to expected (based on parental ability) than individuals with a non-CHD8 LGDM or no gene event. The presence of this effect for paternal but not maternal comparisons may indicate a differential genetic contribution to social behavior. Overall, findings suggest a unique pattern of penetrance for de novo CHD8-related events compared to other LGDMs, which may enhance understanding of symptom severity and treatment.