Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.


Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

DOI: 10.1016/j.ajhg.2013.06.012
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@article{Jiang2013DetectionOC, title={Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.}, author={Yong-hui Jiang and Ryan K. C. Yuen and Xin Jin and Mingbang Wang and Nong Chen and Xueli Wu and Jia Ju and Junpu Mei and Yujian Shi and Mingze He and Guangbiao Wang and Jieqin Liang and Zhe Wang and Dandan Cao and Melissa T. Carter and Christina Chrysler and Irene E Drmic and Jennifer L. Howe and Lynette Lau and Christian Marshall and Daniele Merico and Thomas Nalpathamkalam and Bhooma Thiruvahindrapuram and Ann P. Thompson and Mohammed Zahir Uddin and Susan Walker and Jun Luo and Evdokia Anagnostou and Lonnie Zwaigenbaum and Robert H Ring and Jian Wang and Clara M. Lajonchere and Jun Wang and Andy Y. Shih and Peter Szatmari and Huanming Yang and Geraldine Dawson and Yingrui Li and Stephen W. Scherer}, journal={American journal of human genetics}, year={2013}, volume={93 2}, pages={249-63} }