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Paternally inherited cis-regulatory structural variants are associated with autism.


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.

SUBMITTER: Brandler WM 

PROVIDER: S-EPMC6449150 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Paternally inherited cis-regulatory structural variants are associated with autism.

Brandler William M WM   Antaki Danny D   Gujral Madhusudan M   Kleiber Morgan L ML   Whitney Joe J   Maile Michelle S MS   Hong Oanh O   Chapman Timothy R TR   Tan Shirley S   Tandon Prateek P   Pang Timothy T   Tang Shih C SC   Vaux Keith K KK   Yang Yan Y   Harrington Eoghan E   Juul Sissel S   Turner Daniel J DJ   Thiruvahindrapuram Bhooma B   Kaur Gaganjot G   Wang Zhuozhi Z   Kingsmore Stephen F SF   Gleeson Joseph G JG   Bisson Denis D   Kakaradov Boyko B   Telenti Amalio A   Venter J Craig JC   Corominas Roser R   Toma Claudio C   Cormand Bru B   Rueda Isabel I   Guijarro Silvina S   Messer Karen S KS   Nievergelt Caroline M CM   Arranz Maria J MJ   Courchesne Eric E   Pierce Karen K   Muotri Alysson R AR   Iakoucheva Lilia M LM   Hervas Amaia A   Scherer Stephen W SW   Corsello Christina C   Sebat Jonathan J  

Science (New York, N.Y.) 20180401 6386


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  ...[more]

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