De Novo Variants in Chinese Asd Trios Reveal Distinct Genetic Basis Underlying Autism with and Without Developmental Delay

Jincheng Wang,Fei Li,Jinyu Wu,Xiujuan Du,Mengdi Wang,Xiaoqun Wang,Lingli Zhang,Zilong Qiu,Juehua Yu,Kan Yang

doi:10.2139/ssrn.3946571

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder causing social communication and stereotypical behavioral impairments, often with developmental delay or intellectual disabilities (DD/ID). Here, we performed whole-exome sequencing on 772 Chinese ASD trios, combining with a previous 369 ASD trios, to identify de novo variants in 1141 ASD trios. We found that ASD without DD/ID carried less disruptive de novo variants than ASD with DD/ID. Surprisingly, we found that expression of genes with de novo variants in ASD without DD/ID were enriched in a subtype of human neural progenitor cells. Importantly, some ASD risk genes identified in this study are not present in the current ASD gene database, suggesting that there are ubique genetic contributors to ASD in East Asian populations. Together, this work nominates novel ASD risk genes and indicates that ASD genetic studies in different geographic populations are essential to reveal the comprehensive genetic architecture of ASD.

Highlights

Autism spectrum disorders (ASD) refers to a collection of severe neurodevelopmental disorders, mostly occurred before 3 years old or during the toddler stage, associated with impairments in social communication and prominent stereotypical or repetitive behaviors 1
We found that genes with de novo variants in LFA probands exhibited enrichment in precentral cortex (PRC), postcentral cortex (PC) and banks of superior temporal cortex (BST) regions (Fig. 3e, Table S2), which was consistent with our previous report 13 and suggested that dysfunction of primary somatosensory and motor cortex may be associated with LFA probands
Studying ASD risk genes primarily contributing to social interaction behaviors but not cognitive functions may reveal the neurobiology of social behaviors of mammalian animals

Summary

Introduction

Autism spectrum disorders (ASD) refers to a collection of severe neurodevelopmental disorders, mostly occurred before 3 years old or during the toddler stage, associated with impairments in social communication and prominent stereotypical or repetitive behaviors 1. Numerous new ASD candidate genes emerged, including SLC35G1, in which we identified recurrent mutations in HFA probands. We identified de novo rare non-synonymous variants (including LGD and missense) in 62% (259 of 415) of families having LFA probands, and 54% (180 of 334) of families having HFA probands (Fig. 1h).

Results

Conclusion