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<p>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 <i>de novo</i> 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/<i>de novo</i>, 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 <i>DAGLA</i>, <i>ENPP6</i>, <i>FAXDC2</i>, <i>ILDR2</i>, <i>KSR2</i>, <i>PKD1L1</i>, <i>SCN10A</i>, <i>SHH</i>, and <i>SLC36A1</i>). We also identified seven candidate homozygous exonic loss CNVs. The significant enrichment for homozygous variants among individuals with high F<sub>roh</sub> coefficients, compared with low F<sub>roh</sub>, 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.</p>

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

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  • 发表日期：

    2026年3月21日

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

摘要

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.