Whole Exome Sequencing of Autism Spectrum Disorder Reveals Novel De Novo Variants in Korean Population
Objectives: The objective of this family-based whole exome sequencing (WES) is to examine genetic variants of autism spectrum disorder (ASD) in Korean population.
Methods: The probands with ASD and their biological parents were recruited in this study. We ascertained diagnosis based on DSM-5TMcriteria, using Autism Diagnostic Observation Schedule and Autism Diagnostic Interview – Revised. We selected probands with typical phenotypes of ASD both in social interaction/communication and repetitive behaviour/limited interest domains, with intellectual disability (IQ<70), for attaining homogeneity of the phenotypes. First, we performed WES minimum 50x for 13 probands and high-coverage pooled sequencing for their parents. We performed additional WES for 38 trio families, at least 100x depth. De novo mutations were confirmed by Sanger sequencing. All the sequence reads were mapped onto the human reference genome (hg19 without Y chromosome). Bioinformatics analyses were performed by BWA-MEM, Picard, GATK, and snpEff for variant annotation. We selected mutation candidates from probands, which are neither detected in two pooled samples nor both parents.
Results: Fifty one subjects with ASD (5 females, 40~175 months, mean IQ 42) and their families were included in this study. We discovered 109 de novo variants from 46 families. Twenty nine variants are expected to be amino acid changing, potentially causing deleterious effects. We assume CELSR3, MYH1, ATXN1, IDUA, NFKB1, ADCY7 and DLEC1 may have adverse effect on central nerve system. Additionally KCNE3, previously observed in deleterious mutation in periodic paralysis, may be related with ASD.
Conclusions: We observed novel variants which are assumed to contribute to development of ASD with typical phenotypes and low intelligence in WES study.