Brandler WM, Antaki D, Gujral M, Kleiber ML, Whitney J, Maile MS, Hong O, Chapman TR, Tan S, Tandon P, Pang T, Tang SC, Vaux KK, Yang Y, Harrington E, Juul S, Turner DJ, Thiruvahindrapuram B, Kaur G, Wang Z, Kingsmore SF, Gleeson JG, Bisson D, Kakaradov B, Telenti A, Venter JC, Corominas R, Toma C, Cormand B, Rueda I, Guijarro S, Messer KS, Nievergelt CM, Arranz MJ, Courchesne E, Pierce K, Muotri AR, Iakoucheva LM, Hervas A, Scherer SW, Corsello C, Sebat J
Paternally inherited cis-regulatory structural variants are associated with autism.
Science (New York, N.Y.). 2018-04-20; 360.6386: 327-331.
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.