Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity. The interplay of de novo and inherited rare variants has been suspected in the development of ASD. Here, we applied whole exome sequencing (WES) on 19 trios from singleton Saudi families with ASD. We developed an analysis pipeline that allows capturing both de novo and inherited rare variants predicted to be deleterious. A total of 47 unique rare variants were detected in 17 trios including 38 which are newly discovered. The majority were either autosomal recessive or X-linked. Our pipeline uncovered variants in 15 ASD-candidate genes, including 5 (GLT8D1, HTATSF1, OR6C65, ITIH6 and DDX26B) that have not been reported in any human condition. The remaining variants occurred in genes formerly associated with ASD or other neurological disorders. Examples include SUMF1, KDM5B and MXRA5 (Known-ASD genes), PRODH2 and KCTD21 (implicated in schizophrenia), as well as USP9X and SMS (implicated in intellectual disability). Consistent with expectation and previous studies, most of the genes implicated herein are enriched for biological processes pertaining to neuronal function. Our findings underscore the private and heterogeneous nature of the genetic architecture of ASD even in a population with high consanguinity rates.

Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission

“…For the majority of cases, at least two variants were found per proband. The presence of multiple candidate variants per case, is something that we and others have encountered in similar complex disorders (ASD and Parkinson's disease) [22,34,35]. This reinforces the plausibility of a polygenic model whereby several genes/loci may harbor risk variants collectively contributing to the disease burden.…”

“…All variants described in this study have been submitted to LOVD [https://databases.lovd.nl/shared/genes] public repository. Sample processing and all three stages of data analysis (primary, secondary, and tertiary) were performed as previously described [22]. The WES workflow applied in this study is summarized in Fig.…”

“…At the gene level, intolerance to variation (missense and LoF) metrics (pLI and Z score) were extracted for each identified gene with validated variant(s). However, although these metrics can be helpful when combined with other prediction tools, they are inadequate to infer or exclude pathogenicity when used solely [22]. In addition, publicly available variants or gene databases such as dbSNP, SFARI Gene [https://gene.sfari.org/autdb/ Welcome.do], AutismKB [http://autismkb.cbi.pku.edu.cn/], and ADHDgene [http://adhd.psych.ac.cn/] were checked for previous reports of the variants/genes identified herein.…”

Effect of inbreeding on intellectual disability revisited by trio sequencing

“…18 and refs therein): between the first and the most recent study of this kind, 18,19 the percentage of multiplex families with mutations in known ARID genes has only risen from one-third to about one half 18 while the number of known ARID genes has increased from about a dozen to about 800 today. 18,20,21 In a recent study of the British Deciphering Developmental Defects (DDD) project, 22 [19][20][21] ), did not quantify consanguinity or autozygosity, or were simply too small 23 .…”

“…In a recent study of the British Deciphering Developmental Defects (DDD) project, whole‐exome sequencing (WES) identified bi‐allelic (recessive) mutations in 3.6% of the patients with developmental disorders (DD) and European ancestry, compared to 49.9% DNMS in known DD genes. To date, no comparable molecular data have been published for countries where PC is common, because most sequencing studies performed in Iran, Turkey, Saudi Arabia or Pakistan focused on recessive gene defects and were not designed to capture DNM (eg,), did not quantify consanguinity or autozygosity, or were simply too small.…”