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

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. 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. 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. 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.

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Journal
Scientific Reports
Published
2026-03-21
DOI
https://doi.org/10.1038/s41598-026-44288-9
Primary Topic
Autism Spectrum Disorder Research
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article
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article

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

Nasim Vasli, Arsalan Hassan, Clinton Tran, Thulasi Thiruvallur Madanagopal et al.
Scientific Reports
Autism Spectrum Disorder Research
article

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

Nasim Vasli, Arsalan Hassan, Clinton Tran, Thulasi Thiruvallur Madanagopal, Ansa Rabia, Cassandra Stan, Bita Bozorgmehr, Ashlyn Rodrigues, Zehra Agha, Clement C. Zai, Aisha Nasir Hashmi, Ricardo Harripaul, Muhammad Ayub, Leon French, Saqib Mahmood, Stephen F. Pastore, Shreejoy J. Tripathy, Roksana Sasanfar, Majid Ghadami, Susan L. Santangelo, Katherine Aw, J. Vincent, Tahir Muhammad, Shazia Maqbool, Anna Mikhailov, Maleeha Azam, Raheel Qamar, Laila Al Ayadhi, James A. Knowles, Muhammad Iqbal, Abolfazl Heidari
article en

Abstract

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. 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. 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. 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.

Scientific Reports
Rutgers, The State University of New Jersey (US), Broad Institute (US), Tufts University (US), Mohammed V University (MA), Centre for Addiction and Mental Health (CA), Harvard University (US), COMSATS University Islamabad (PK), University of Toronto (CA), CMH Lahore Medical College and Institute of Dentistry (PK), King Saud University (SA), University of Health Sciences Lahore (PK), University of Peshawar (PK), Massachusetts General Hospital (US), Queens University (BD), Maine Medical Center Research Institute (US), Kingston Health Sciences Centre (CA), Nur International University (PK), University College London (GB), University at Buffalo, State University of New York (US), Qazvin University of Medical Sciences (IR), Farhangian University (IR)
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Autism Spectrum Disorder Research
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