Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use

Thomas Husson,François Lecoquierre,Robert Olaso,Maud Rothärmel ,Antoine Rosier,Alice Goldenberg,Géraldine Joly‐Helas ,Thierry Frébourg ,Jean‐François Deleuze ,Anne-Claire Richard,Pascal Chambon,Maryam Soleimani,Anne‐Marie Guerrot ,Anne-Claire Bréhin ,Nathalie Le Meur,Camille Charbonnier,Kévin Cassinari ,Anne Boland,Romain Taton,Pascale Saugier-Veber,Valérie Drouin‐Garraud ,Gaël Nicolas ,Olivier Quenez,Olivier Guillin,Dominique Campion

doi:10.1038/s41398-020-0760-7

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component whose knowledge evolves quickly. Next-generation sequencing is the only effective technology to deal with the high genetic heterogeneity of ASD in a clinical setting. However, rigorous criteria to classify rare genetic variants conferring ASD susceptibility are currently lacking. We have performed whole-exome sequencing to identify both nucleotide variants and copy number variants (CNVs) in 253 ASD patients, including 68 patients with intellectual disability (ID) and 90 diagnosed as Asperger syndrome. Using explicit criteria to classify both susceptibility genes and susceptibility variants we prioritized 217 genes belonging to the following categories: syndromic genes, genes with an excess of de novo protein truncating variants and genes targeted by rare CNVs. We obtained a susceptibility variant detection rate of 19.7% (95% CI: [15–25.2%]). The rate for CNVs was 7.1% (95% CI: [4.3–11%]) and 12.6% (95% CI: [8.8–17.4%]) for nucleotide variants. The highest rate (30.1%, 95% CI: [20.2–43.2%]) was obtained in the ASD + ID subgroup. A strong contributor for at risk nucleotide variants was the recently identified set of genes (n = 81) harboring an excess of de novo protein truncating variants. Since there is currently no evidence that the genes targeted here are necessary and sufficient to cause ASD, we recommend to avoid the term “causative of ASD” when delivering the information about a variant to a family and to use instead the term “genetic susceptibility factor contributing to ASD”.

Highlights

Autism spectrum disorder (ASD), whose prevalence is estimated to be around 1 per 100 children, encompass a wide range of phenotypic manifestations ranging from severe behavioral impairment, often associated with intellectual disability (ID), to mild difficulties in social interaction
When the sample was split into three clinical subgroups, the rate of copy number variants (CNVs) and nucleotide susceptibility-variants was high in the ASD+ID subgroup (30.1%, 95% CI: [20.2–43.2%]) (Table 4)
The high frequency of de novo events is noteworthy: we identified 21/28 de novo nucleotide variants and 6/14 de novo CNVs among 42 patients from whom parental DNA was available

Summary

Introduction

Autism spectrum disorder (ASD), whose prevalence is estimated to be around 1 per 100 children, encompass a wide range of phenotypic manifestations ranging from severe behavioral impairment, often associated with intellectual disability (ID), to mild difficulties in social interaction. Chromosomal microarray analysis is usually used as the first-tier genetic test for individuals with autism with a diagnostic yield of 7–9%1,2. Such analysis cannot detect single nucleotide variations and small Indels but only loss or gain of genomic DNA material. Husson et al Translational Psychiatry (2020)10:77 susceptibility, each of them being present only in a very small proportion of cases[3]. In this context, nextgeneration sequencing is the only reasonable and costeffective approach to search for variants in these genes in a diagnostic perspective

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