Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA

Turner, Tychele N, Hormozdiari, Fereydoun, Duyzend, Michael H, McClymont, Sarah A, Hook, Paul W, Iossifov, Ivan, Raja, Archana, Baker, Carl, Hoekzema, Kendra, Stessman, Holly A, Zody, Michael C, Nelson, Bradley J, Huddleston, John, Sandstrom, Richard, Smith, Joshua D, Hanna, David, Swanson, James M, Faustman, Elaine M, Bamshad, Michael J, Stamatoyannopoulos, John, Nickerson, Deborah A, McCallion, Andrew S, Darnell, Robert, Eichler, Evan E (2016) Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. The American Journal of Human Genetics, 98 (1). pp. 58-74. ISSN 0002-9297

URL: http://www.ncbi.nlm.nih.gov/pubmed/26749308
DOI: 10.1016/j.ajhg.2015.11.023

Abstract

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.

Item Type: Paper
Subjects: diseases & disorders > mental disorders > personality disorders > autism
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation

Investigative techniques and equipment > assays > whole genome sequencing
CSHL Authors:
Communities: CSHL labs > Iossifov lab
Depositing User: Matt Covey
Date Deposited: 05 Jan 2016 20:20
Last Modified: 16 Jun 2017 18:05
PMCID: PMC4716689
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32204

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