TY - JOUR
T1 - Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA
AU - Turner, Tychele N.
AU - Hormozdiari, Fereydoun
AU - Duyzend, Michael H.
AU - McClymont, Sarah A.
AU - Hook, Paul W.
AU - Iossifov, Ivan
AU - Raja, Archana
AU - Baker, Carl
AU - Hoekzema, Kendra
AU - Stessman, Holly A.
AU - Zody, Michael C.
AU - Nelson, Bradley J.
AU - Huddleston, John
AU - Sandstrom, Richard
AU - Smith, Joshua D.
AU - Hanna, David
AU - Swanson, James M.
AU - Faustman, Elaine M.
AU - Bamshad, Michael J.
AU - Stamatoyannopoulos, John
AU - Nickerson, Deborah A.
AU - McCallion, Andrew S.
AU - Darnell, Robert
AU - Eichler, Evan E.
N1 - Funding Information:
We thank T. Brown for assistance in editing this manuscript. This work was supported by grants from the Simons Foundation (SFARI 336475 to E.E.E.), National Institute of Child Health and Development (HHSN267200700021C to J.M.S.), (HHSN275200800015C and HHSN267200700023C to E.M.F.), National Institute of Neurological Disorders and Stroke (NS062972 to A.S.M.), National Institute of General Medical Sciences (predoctoral training grant 5T32GM07814 to P.W.H.), and National Human Genome Research Institute (postdoctoral training grant 2T32HG000035 to T.N.T.). We also thank Dr. Daniela Witten for advice on statistical testing of regulatory elements and Dr. Bradley Coe for information on CNVs from his previous publication. We thank Natalia Volfovsky, Alex Lash, and Malcolm Mallardi from the Simons Foundation for help with depositing genome data to SFARI Base and Colleen Davis for help with depositing genome data to dbGaP. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate receiving access to phenotypic data on Simons Foundation Autism Research Initiative (SFARI) Base. Approved researchers can obtain the SSC population dataset described in this study by applying at SFARI Base (see Web Resources ). E.E.E. is an investigator of the Howard Hughes Medical Institute.
Funding Information:
We thank T. Brown for assistance in editing this manuscript. This work was supported by grants from the Simons Foundation (SFARI 336475 to E.E.E.), National Institute of Child Health and Development (HHSN267200700021C to J.M.S.), (HHSN275200800015C and HHSN267200700023C to E.M.F.), National Institute of Neurological Disorders and Stroke (NS062972 to A.S.M.), National Institute of General Medical Sciences (predoctoral training grant 5T32GM07814 to P.W.H.), and National Human Genome Research Institute (postdoctoral training grant 2T32HG000035 to T.N.T.). We also thank Dr. Daniela Witten for advice on statistical testing of regulatory elements and Dr. Bradley Coe for information on CNVs from his previous publication. We thank Natalia Volfovsky, Alex Lash, and Malcolm Mallardi from the Simons Foundation for help with depositing genome data to SFARI Base and Colleen Davis for help with depositing genome data to dbGaP. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate receiving access to phenotypic data on Simons Foundation Autism Research Initiative (SFARI) Base. Approved researchers can obtain the SSC population dataset described in this study by applying at SFARI Base (see Web Resources). E.E.E. is an investigator of the Howard Hughes Medical Institute.
Publisher Copyright:
© 2016 The American Society of Human Genetics.
PY - 2016/1/7
Y1 - 2016/1/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954403183&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2015.11.023
DO - 10.1016/j.ajhg.2015.11.023
M3 - Article
C2 - 26749308
AN - SCOPUS:84954403183
SN - 0002-9297
VL - 98
SP - 58
EP - 74
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -