Format

Send to

Choose Destination
Am J Hum Genet. 2016 Jan 7;98(1):58-74. doi: 10.1016/j.ajhg.2015.11.023. Epub 2015 Dec 31.

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

Author information

1
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
2
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; New York Genome Center, New York, NY 10013, USA.
4
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
5
New York Genome Center, New York, NY 10013, USA.
6
Department of Pediatrics, University of California, Irvine, CA 92612, USA.
7
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA.
8
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
9
New York Genome Center, New York, NY 10013, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Rockefeller University, New York, NY 10065, USA.
10
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: eee@gs.washington.edu.

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.

PMID:
26749308
PMCID:
PMC4716689
DOI:
10.1016/j.ajhg.2015.11.023
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center