Paternally inherited cis-regulatory structural variants are associated with autism

• Published in: Science (American Association for the Advancement of Science) Vol. 360; no. 6386; pp. 327 - 331
• Main Authors: Brandler, William M., Antaki, Danny, Gujral, Madhusudan, Kleiber, Morgan L., Whitney, Joe, Maile, Michelle S., Hong, Oanh, Chapman, Timothy R., Tan, Shirley, Tandon, Prateek, Pang, Timothy, Tang, Shih C., Vaux, Keith K., Yang, Yan, Harrington, Eoghan, Juul, Sissel, Turner, Daniel J., Thiruvahindrapuram, Bhooma, Kaur, Gaganjot, Wang, Zhuozhi, Kingsmore, Stephen F., Gleeson, Joseph G., Bisson, Denis, Kakaradov, Boyko, Telenti, Amalio, Venter, J. Craig, Corominas, Roser, Toma, Claudio, Cormand, Bru, Rueda, Isabel, Guijarro, Silvina, Messer, Karen S., Nievergelt, Caroline M., Arranz, Maria J., Courchesne, Eric, Pierce, Karen, Muotri, Alysson R., Iakoucheva, Lilia M., Hervas, Amaia, Scherer, Stephen W., Corsello, Christina, Sebat, Jonathan
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 20.04.2018
• Subjects: Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorders; Children; Coding; Exons; Family (Sociological Unit); Gene Expression Regulation; Gene sequencing; Genes; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genome, Human; Genomes; Humans; Mutation; Natural selection; Offspring; Paternal Inheritance; Pedigree; Promoter Regions, Genetic - genetics; Regulatory sequences; RNA, Untranslated - genetics; Selection, Genetic; Sequence Deletion; Transcription Factors - genetics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aan2261

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. Science , this issue p. 327 Whole-genome sequencing identifies inherited noncoding variants in families affected by autism spectrum disorder. 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.