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.
Highlights
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity
A causal relationship is often hard to prove for a number of reasons: (i) such events normally span large regions making it difficult to discern the role of single genes in the disorder; (ii) apparently identical alterations have variable phenotypic outcomes or expressivity; (iii) some of these changes are observed in typically developing individuals; (iv) very low rate of replication, as recurrent individual copy number variations (CNVs) were observed only in less than 1% of the cases[7]
We detected an average of 29120.333 total variants comprised of 27466.807 Single Nucleotide Variants (SNVs) and 1653.526 indels per exome (Supplementary Table S2)
Summary
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity. This is best exemplified by ASD, for which delivering a near complete genetic picture is hindered by many factors Examples of such factors include: (i) extensive clinical and genetic heterogeneity (in excess of 600 genes have been implicated in ASD, far)[2]; (ii) the absence of generalizable genetic risk factors as most of the mutations are extremely rare or private in nature; (iii) the variability in diagnosis and data analysis methodology; and (iv) the precise function of many of ASD-candidate genes and their possible impact on the central nervous system remains largely undetermined[3, 4]. As there is a growing appreciation for the important part transmitted and de novo mutations play in ASD, more studies assessing both types of events within a given cohort are needed to understand their precise role
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