Narrow Versus Broad Phenotype Definitions Affect Genetic Analysis of Language More than Other Broad Autism Phenotype...

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition that displays heterogeneity in both presentation and etiology, and often presents with concomitant communication difficulties. The hypothesis behind the New Jersey Language and Autism Genetic Study is that genetic heterogeneity for component phenotypes of ASD may be reduced relative to the disorder as a whole. We previously published an initial phase of this study with family recruitment that used very restricted inclusion/exclusion criteria for both autism and language deficits. Here, we present an expanded sample that includes a wider range of phenotypic presentations in the autism and language domains.

Bioinformatics tools focusing on variant prioritization were used to identify candidate risk genes.

Our previous findings on 15q and 16q, connecting ASD and oral/written communication, are only relevant to the narrow ASD and language impairment phenotypes, though addition of families did reduce both critical regions. After variant and gene prioritization, we determined a set of ten and six top candidate risk genes with a strong association with language impairment and reading impairment, respectively. The top candidate genes include both genes previously implicated in neurodevelopmental disorders (e.g., ZNF774 and DNAH3) and genes not previously reported but with strong evidence of being involved in neurodevelopmental phenotypes.

Our analysis elucidates the genetic architecture and interaction of ASD and language-related phenotypes. In addition, we reported a number of high-confidence candidate genes within the top linkage regions. These genes will provide insights into the genetic etiology of neurodevelopmental disorders.