A Comparison of Head Circumference Growth Trajectories in the Context of the CHD8 Regulatory Network

Background: At least 30% of autism spectrum disorder (ASD) diagnoses are attributable to disruptive genetic events (Torre-Ubieta, Won, Stein, & Geschwind, 2016). Although no single genetic event explains the majority of ASD cases, functional genetic networks and shared deficiencies in neural growth pathways have been identified (Huguet, Ey, & Bourgeron, 2013). Research has examined converging regulatory networks, such as genes targeted by CHD8, a gene strongly associated with ASD (Cotney et al., 2015). One of the most prominent phenotypes in CHD8 is macrocephaly (Bernier et al., 2014; Barnard, Pomaville, & O’Roak, 2015). Despite the relevance of head size to brain development, growth trajectories have not been examined across functional gene classifications.

Objectives: Compare head circumference growth trajectories across functional genetic and clinical categories among individuals with disruptive genetic events associated with ASD either targeted or not targeted by CHD8.

Methods: Seventy-six participants with a disruptive mutation to an ASD-associated gene were included in the analyses (see Table 1). HC measurements were derived from medical record review and medical examination at the research visit. CHD8 target versus non-target functional gene groups were dichotomized based on prior research (Cotney et al., 2015). Participants were characterized as Macrocephalic or Microcephalic if they met criteria at any time point (i.e. +/- 2 population-based z-scores). Random effect, two-level models were tested in Mplus 7.3 with HC and age at the within level, and sex, gene functional category and clinical phenotype at the between level.

Results: Across the full sample, HC increased linearly (B = 2.71, SE = .28, p <.001) and showed quadratic deceleration (B = -.11, SE = .02, p < .001) with age, as shown in Figure 1. Females had smaller mean HC (B = -2.14, SE = .96, p = .026). Both functional gene group and clinical HC characterization moderated growth trajectories. The CHD8 Targets group had steeper linear growth (B = .22, SE = .08, p = .008) than non-Targets. The Macrocephaly group also had greater early linear growth (p < .001) relative to normal and Microcephaly groups. The Microcephaly group did not differ from the Normal group on growth rates (p > .10), indicating small and stable HC. Gene events in the Microcephaly and Macrocephaly groups were largely non-overlapping.

Conclusions: Growth patterns differ significantly within the population of individuals with ASD-associated gene disruptive events, and provide further evidence for discrete macrocephalic and microcephalic groups. Rapid early growth was characteristic of the broader CHD8 Target and Macrocephaly groups, indicating a shared phenotype and post-natal expression of this functional genetic class. In contrast, the Microcephalic group did not show atypical growth post-birth, suggesting related expression of these genes may be constrained to the prenatal period.

Grey matter overgrowth in the first years of life (Courchesne, Campbell, & Solso, 2011) and atypical levels of cerebral fluids (Shen et al., 2013) are common in ASD and may contribute to macro- and microcephalic phenotypes. HC phenotypes associated with genomic subtypes of ASD provide clues to the neurobiological and developmental etiology of neurodevelopmental disorders.