ID

45460

Descripción

Principal Investigator: Evan E. Eichler, PhD, Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA; Howard Hughes Medical Institute, Seattle, WA, USA MeSH: Autistic Disorder,Child Development Disorders, Pervasive https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000482 It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 617 individual exomes from 209 families deposited in dbGaP. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

Link

dbGap-study=phs000482

Palabras clave

Versiones (2)

1. 20/10/22 20/10/22 - Simon Heim
2. 12/12/22 12/12/22 - Kristina Keller

Titular de derechos de autor

Evan E. Eichler, PhD, Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA; Howard Hughes Medical Institute, Seattle, WA, USA

Subido en

12 de diciembre de 2022

DOI

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Licencia