title: Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.
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.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Tychele N
authors.initials: TN
authors.lastname: Turner
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Hormozdiari
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Duyzend
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: McClymont
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hook
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; New York Genome Center, New York, NY 10013, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Iossifov
authors.affiliation: 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.
authors.forename: Archana
authors.initials: A
authors.lastname: Raja
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Kendra
authors.initials: K
authors.lastname: Hoekzema
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Stessman
authors.affiliation: New York Genome Center, New York, NY 10013, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Zody
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Nelson
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Huddleston
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Department of Pediatrics, University of California, Irvine, CA 92612, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Swanson
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Faustman
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: John
authors.initials: J
authors.lastname: Stamatoyannopoulos
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Darnell
authors.affiliation: 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.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D059472:Exome; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D004247:DNA