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

TitleGenome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.
Publication TypeJournal Article
Year of Publication2016
AuthorsTurner, TN, Hormozdiari, F, Duyzend, MH, McClymont, SA, Hook, PW, Iossifov, I, Raja, A, Baker, C, Hoekzema, K, Stessman, HA, Zody, MC, Nelson, BJ, Huddleston, J, Sandstrom, R, Smith, JD, Hanna, D, Swanson, JM, Faustman, EM, Bamshad, MJ, Stamatoyannopoulos, J, Nickerson, DA, McCallion, AS, Darnell, R, Eichler, EE
JournalAm J Hum Genet
Volume98
Issue1
Pagination58-74
Date Published2016 Jan 07
ISSN1537-6605
KeywordsAutistic Disorder, DNA, Exome, Female, Genome, Human, Humans, Male, Pedigree, Polymorphism, Single Nucleotide
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.

DOI10.1016/j.ajhg.2015.11.023
Alternate JournalAm. J. Hum. Genet.
PubMed ID26749308
PubMed Central IDPMC4716689
Grant ListU54 HD083091 / HD / NICHD NIH HHS / United States
HHSN267200700021C / HD / NICHD NIH HHS / United States
T32 GM007814 / GM / NIGMS NIH HHS / United States
HHSN275200800015C / HD / NICHD NIH HHS / United States
5T32GM07814 / GM / NIGMS NIH HHS / United States
UM1 HG008901 / HG / NHGRI NIH HHS / United States
T32 HG000035 / HG / NHGRI NIH HHS / United States
2T32HG000035 / HG / NHGRI NIH HHS / United States
R01 NS062972 / NS / NINDS NIH HHS / United States
NS062972 / NS / NINDS NIH HHS / United States
HHSN267200700023C / HD / NICHD NIH HHS / United States
/ / Howard Hughes Medical Institute / United States