Abstract:
Background: Autism spectrum disorder (ASD) is a neurodevelopmental
disorder (NDD) that affects about 1 in 54 children worldwide, imposing
enormous economic and socioemotional burden on families and
communities. Genetic studies of ASD have identified de novo copy number
variants (CNVs) and point mutations that contribute significantly to the genetic architecture, but the majority of these studies were conducted in
populations unsuited for detecting autosomal recessive (AR) inheritance.
However, several ASD studies in consanguineous populations point towards
AR as an under-appreciated source of ASD variants.
Methods: We used whole exome sequencing to look for rare variants for
ASD in 115 proband-mother-father trios from populations with high rates of
consanguinity, namely Pakistan, Iran, and Saudi Arabia. Consanguinity was
assessed through microarray genotyping. Results: We report 77 candidate single nucleotide variants and indels, with
62% homozygous, 22% autosomal dominant/de novo , and 16% X-linked, in
55 trios. 56% of the variants were loss of function (LoF) or putative LoF
(pLoF), and 44% nonsynonymous. We found an enrichment of homozygous
variants, both in 16 genes previously reported for AR ASD and/or intellectual
disability (ID) and 32 previously unreported AR candidate genes (including DAGLA, ENPP6 , FAXDC2 , ILDR2 , KSR2 , PKD1L1 , SCN10A, SHH, and SLC36A1).
We also identified seven candidate homozygous exonic loss CNVs.
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Biallelic variants for autism….
Conclusions: The significant enrichment for homozygous variants among individuals with high Froh coefficients, compared with low Froh, either in
known or candidate AR genes, confirms that genetic architecture for ASD
among consanguineous populations is different to non-consanguineous
populations. Assessment of consanguinity may assist in the genetic
diagnostic process for ASD.
