Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

Islam Oguz Tuncay, Nancy L. Parmalee, Raida Khalil, Kiran Kaur, Ashwani Kumar, Mohamed Jimale, Jennifer L. Howe, Kimberly Goodspeed, Patricia Evans, Loai Alzghoul, Chao Xing, Stephen W. Scherer, Maria H. Chahrour

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders characterized by deficits in social communication and restricted, repetitive patterns of behavior or interests. ASD is highly heritable, but genetically and phenotypically heterogeneous, reducing the power to identify causative genes. We performed whole genome sequencing (WGS) in an ASD cohort of 68 individuals from 22 families enriched for recent shared ancestry. We identified an average of 3.07 million variants per genome, of which an average of 112,512 were rare. We mapped runs of homozygosity (ROHs) in affected individuals and found an average genomic homozygosity of 9.65%, consistent with expectations for multiple generations of consanguineous unions. We identified potentially pathogenic rare exonic or splice site variants in 12 known (including KMT2C, SCN1A, SPTBN1, SYNE1, ZNF292) and 12 candidate (including CHD5, GRB10, PPP1R13B) ASD genes. Furthermore, we annotated noncoding variants in ROHs with brain-specific regulatory elements and identified putative disease-causing variants within brain-specific promoters and enhancers for 5 known ASD and neurodevelopmental disease genes (ACTG1, AUTS2, CTNND2, CNTNAP4, SPTBN4). We also identified copy number variants in two known ASD and neurodevelopmental disease loci in two affected individuals. In total we identified potentially etiological variants in known ASD or neurodevelopmental disease genes for ~61% (14/23) of affected individuals. We combined WGS with homozygosity mapping and regulatory element annotations to identify candidate ASD variants. Our analyses add to the growing number of ASD genes and variants and emphasize the importance of leveraging recent shared ancestry to map disease variants in complex neurodevelopmental disorders.

Original languageEnglish (US)
Article number13
Journalnpj Genomic Medicine
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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