De NovoMutation in an Enhancer ofEBF3in simplex autism

Abstract

Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of de novo protein-coding variants within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2,671 families with autism, with a specific focus on de novo variation in enhancers with previously characterized in vivo activity. We identified three independent de novo mutations limited to individuals with autism in the enhancer hs737. These mutations result in similar phenotypic characteristics, affect enhancer activity in vitro, and preferentially occur in AAT motifs in the enhancer with predicted disruptions of transcription factor binding. We also find that hs737 is enriched for copy number variation in individuals with NDDs, is dosage sensitive in the human population, is brain-specific, and targets the NDD gene EBF3 that is genome-wide significant for protein coding de novo variants, demonstrating the importance of understanding all forms of variation in the genome.One Sentence SummaryWhole-genome sequencing in thousands of families reveals variants relevant to simplex autism in a brain enhancer of the well-established neurodevelopmental disorder gene EBF3.

The Role of Genetics, Epigenetics, and the Environment in ASD: A Mini Review

“…Finally, interactions between the genome and epigenome will allow scientists to enhance methylation studies through increased genomic coverage, expanding our knowledge of the role of ASD-specific biomarkers. For instance, changes in specific epigenetic markers (CpG methylation) in noncoding regions, including promoters, enhancers, silencers, insulators, intergenic regions, and ncRNAs, have been observed during neurogenesis [ 105 , 106 , 107 , 108 , 109 , 110 ]. Most importantly, alternative types of methylation (non-CpG methylation (CpH, where H = A, C, or T) and 5-hydroxymethylcytosine (5-hmC)) have been reported in the pathogenesis of ASD.…”