Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

Abstract

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 1 in 55 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 of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies of ASD in consanguineous populations point towards AR as an under-appreciated source of ASD variants. Here, we used trio 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. We report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss), and 47% nonsynonymous. Our analysis indicates an enrichment of biallelic variants. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID) (AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335), and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified several candidate biallelic exonic loss CNVs. The enrichment shown here for biallelic variants confirms that the genetic architecture for ASD among consanguineous populations is different to non-consanguineous populations. However, as has been shown in many recessive disorders, the genes reported here may also be relevant to outbred populations.