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

Xiujuan Du,Yu Sun,Xin Liu,Huili Liu,Yongguo Yu,Kai Wang,Lixiao Shen,Xiaomei Luo,Lili Wang,Xueren Gao,Yu Wang,Fei Li,Jianguo Wang,Zhuwen Gong,Yanjie Fan

doi:10.3389/fgene.2018.00594

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.

Highlights

Autism spectrum disorder (ASD) is a group of highly heterogeneous neurodevelopmental disorders affecting 1 in 59 children aged 8 years, with boys four times more likely to be affected than girls (Baio et al, 2018)
Several genes identified by copy number variants (CNVs) screening and target sequencing for candidate genes were related to ASD susceptibility, such as PTCHD1, NRXN1, NLGN3, SHANK3, SHANK1 and so on (Jamain et al, 2003; Moessner et al, 2007; Kim et al, 2008; Noor et al, 2010; Sato et al, 2012; Dabell et al, 2013)
Among the patients with ASD, there were 23 children younger than 3 years, 30 children from 3 to 6 year of age and 12 children older than 6 years and the male/female ratio was 53/12. 41 out of 60 patients diagnosed as ASD with available behavioral assessments had Childhood Autism Rating Scale (CARS) scores 37, suggesting a severe autistic behavior

Summary

Introduction

Autism spectrum disorder (ASD) is a group of highly heterogeneous neurodevelopmental disorders affecting 1 in 59 children aged 8 years, with boys four times more likely to be affected than girls (Baio et al, 2018). The clinical and genetic heterogeneity of ASD has proved to be challenging to the diagnostic workup of affected patients. By using WES, ∼ 20.0% patients with sporadic ASD could be identified and this rate even reached to ∼90% because of the highly inbred nature of the Saudi population, making it useful in complementing CMA designed to detect CNVs, and better characterizing the genetic architecture for ASD in simplex families (O’Roak et al, 2011; Yu et al, 2013; Tammimies et al, 2015; Al-Mubarak et al, 2017). Far, there remains a gap in our knowledge of the diagnostic yield of trio-WES among Chinese children with autistic features when CMA is unable to detect risk-related variations, and its impacts on clinical practice

Methods

Results

Conclusion