Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder

Abstract

Objective: Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci.

Method: Analyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains.

Results: Children with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences).

Conclusions: Children with ASD with de novo mutations may exhibit a "muted" symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first.

Keywords: Autism Spectrum Disorder; De Novo Mutations; Idiopathic ASD; Phenotype; Simons Simplex Collection; Syndromic ASD.

Figure 1

Process for including participants in the HC and MAC groups

Figure 2

Phenotypic profiles. Variables were Z-normalized using the mean and standard deviation in the full SSC sample (reference). Mean z-scores in each group are plotted. Gray markers indicate a significant difference between cases and controls (see Table 1) and a dagger (†) next to the measure name indicates that a higher value is more severe/more atypical.

Figure 3

Profiles of individual conditions. De novo events found in at least four participants are shown alongside the full High Confidence (HC) sample and the Matched Autism Controls (MAC) sample. Variables were Z-normalized using the mean and standard deviation in the full SSC sample, and the colors in the heat map represent Z scores above (green) or below (red) the SSC mean. A dagger (†) next to the measure name indicates that a higher value is more severe/more atypical. Hierarchical clustering for purpose of presentation (indicated by dendrogram on left Y axis) was performed using Ward’s method and Euclidian distance.