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Front Genet. 2018 Nov 30;9:594. doi: 10.3389/fgene.2018.00594. eCollection 2018.

Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder.

Author information

1
Developmental and Behavioral Pediatric Department - Child Primary Care Department, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Department of Pediatric Endocrinology and Genetics, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3
Developmental and Behavioral Pediatric Department - Child Primary Care Department, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4
Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Autism spectrum disorder (ASD) is a group of clinically and genetically heterogeneous neurodevelopmental disorders. Recent tremendous advances in the whole exome sequencing (WES) enable rapid identification of variants associated with ASD including single nucleotide variations (SNVs) and indels. To further explore genetic etiology of ASD in Chinese children with negative findings of copy number variants (CNVs), we applied WES in 80 simplex families with a single affected offspring with ASD or suspected ASD, and validated variations predicted to be damaging by Sanger sequencing. The results showed that an overall diagnostic yield of 8.8% (9.2% in the group of ASD and 6.7% in the group of suspected ASD) was observed in our cohort. Among patients with diagnosed ASD, developmental delay or intellectual disability (DD/ID) was the most common comorbidity with a diagnostic yield of 13.3%, followed by seizures (50.0%) and craniofacial anomalies (40.0%). All of identified de novo SNVs and indels among patients with ASD were loss of function (LOF) variations and were slightly more frequent among female (male vs. female: 7.3% vs. 8.5%). A total of seven presumed causative genes (CHD8, AFF2, ADNP, POGZ, SHANK3, IL1RAPL1, and PTEN) were identified in this study. In conclusion, WES is an efficient diagnostic tool for diagnosed ASD especially those with negative findings of CNVs and other neurological disorders in clinical practice, enabling early identification of disease related genes and contributing to precision and personalized medicine.

KEYWORDS:

autism spectrum disorder; comorbidity; diagnostic yield; genetic etiology; whole exome sequencing

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