Inherited
variation contributes to autism
About one-quarter of
genetic variants that are associated with autism spectrum disorder (ASD) are
due to de novo mutations in protein-coding genes. Brandler et al. wanted to
determine whether changes in noncoding regions of the genome are associated
with autism. They applied whole-genome sequencing to ∼2600 families with at least one affected
child. Children with ASD had inherited structural variants in noncoding regions
from their father. Regulatory regions of some specific genes were disrupted
among multiple families, supporting the idea that a component of autism risk
involves inherited noncoding variation.
Abstract
The genetic basis of
autism spectrum disorder (ASD) is known to consist of contributions from de
novo mutations in variant-intolerant genes. We hypothesize that rare inherited
structural variants in cis-regulatory elements (CRE-SVs) of these genes also
contribute to ASD. We investigated this by assessing the evidence for natural
selection and transmission distortion of CRE-SVs in whole genomes of 9274
subjects from 2600 families affected by ASD. In a discovery cohort of 829
families, structural variants were depleted within promoters and untranslated
regions, and paternally inherited CRE-SVs were preferentially transmitted to
affected offspring and not to their unaffected siblings. The association of
paternal CRE-SVs was replicated in an independent sample of 1771 families. Our
results suggest that rare inherited noncoding variants predispose children to
ASD, with differing contributions from each parent.
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