Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA
| Autor: | Sarah A. McClymont, Carl Baker, Joshua D. Smith, Richard Sandstrom, John A. Stamatoyannopoulos, John Huddleston, Evan E. Eichler, Archana Raja, Elaine M. Faustman, Robert B. Darnell, Ivan Iossifov, Bradley J. Nelson, David S. Hanna, Fereydoun Hormozdiari, Deborah A. Nickerson, Tychele N. Turner, Paul W. Hook, Michael H. Duyzend, Kendra Hoekzema, Holly A.F. Stessman, Michael C. Zody, Michael J. Bamshad, Andrew S. McCallion, James M. Swanson |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Autism Intellectual and Developmental Disabilities (IDD) Biology Medical and Health Sciences Genome Polymorphism Single Nucleotide DNA sequencing Article 03 medical and health sciences Genetics medicine 2.1 Biological and endogenous factors Humans Genetics(clinical) Exome Polymorphism Aetiology Autistic Disorder Gene Genetics (clinical) Exome sequencing Pediatric Genetics & Heredity Whole genome sequencing Genome Human Human Genome Single Nucleotide DNA Biological Sciences medicine.disease Brain Disorders Pedigree Mental Health 030104 developmental biology Human genome Female Human Biotechnology |
| Zdroj: | American journal of human genetics, vol 98, iss 1 |
| ISSN: | 1537-6605 |
| Popis: | We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism. |
| Databáze: | OpenAIRE |
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