Abstract
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.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a current population prevalence estimated at 1 in 44 individuals in the USA1
copy number variants (CNVs) that were larger than the median size of the corresponding segments shared between two to four affected individuals, all Simons Foundation Autism Research Initiative (SFARI) CNV, and we identified 4 such CNVs, 2 amplifications and 2 smaller than 0.1 Mb
RPGRIP1L mutations are known to cause Joubert (MIM #213300)[48], Meckel (MIM #611561), and COACH (MIM #216360)[46] syndromes, characterized by DISCUSSION We performed whole genome sequencing (WGS) in a consanguineous cohort consisting of 68 intellectual disability and gross brain defects
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a current population prevalence estimated at 1 in 44 individuals in the USA1. Previous studies have successfully analyzed runs of homozygosity in consanguineous families to discover rare variants contributing to recessive disease[18,19,20,21,22] This has proved to be an effective strategy to identify genes that were previously not known to be involved in ASD18,23–25, contributing to the understanding of the underlying biology of the disorder. We ascertained a familial cohort through probands with ASD and aimed to utilize the recent shared ancestry within the cohort to detect rare and ultra-rare pathogenic biallelic variants, which would be difficult to identify in nonconsanguineous cohorts This unique collection of ancestrally diverse families had representation from the Middle East (47 individuals), South Asia (12 individuals), and Europe (5 individuals), in addition to one East Asian individual, one Hispanic individual, one individual of mixed European and East Asian ancestry, and one. After applying read depth and quality filters, 3,071,060
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