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

Tychele N. Turner, Fereydoun Hormozdiari, Michael H. Duyzend, Sarah A. McClymont, Paul W. Hook, Ivan Iossifov, Archana Raja, Carl Baker, Kendra Hoekzema, Holly Stessman, Michael C. Zody, Bradley J. Nelson, John Huddleston, Richard Sandstrom, Joshua D. Smith, David Hanna, James M. Swanson, Elaine M. Faustman, Michael J. Bamshad, John Stamatoyannopoulos & 4 others Deborah A. Nickerson, Andrew S. McCallion, Robert Darnell, Evan E. Eichler

Research output: Contribution to journalArticle

99 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)58-74
Number of pages17
JournalAmerican Journal of Human Genetics
Volume98
Issue number1
DOIs
StatePublished - Jan 7 2016
Externally publishedYes

Fingerprint

Autistic Disorder
Genome
Exome
DNA
Mutation
Genes
Nucleotides
Gene Dosage
Nucleic Acid Regulatory Sequences
Deoxyribonuclease I
Exons
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Turner, T. N., Hormozdiari, F., Duyzend, M. H., McClymont, S. A., Hook, P. W., Iossifov, I., ... Eichler, E. E. (2016). Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. American Journal of Human Genetics, 98(1), 58-74. https://doi.org/10.1016/j.ajhg.2015.11.023

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; 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.

In: American Journal of Human Genetics, Vol. 98, No. 1, 07.01.2016, p. 58-74.

Research output: Contribution to journalArticle

Turner, TN, Hormozdiari, F, Duyzend, MH, McClymont, SA, Hook, PW, Iossifov, I, Raja, A, Baker, C, Hoekzema, K, Stessman, H, 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 2016, 'Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA', American Journal of Human Genetics, vol. 98, no. 1, pp. 58-74. https://doi.org/10.1016/j.ajhg.2015.11.023
Turner, Tychele N. ; Hormozdiari, Fereydoun ; Duyzend, Michael H. ; McClymont, Sarah A. ; Hook, Paul W. ; Iossifov, Ivan ; Raja, Archana ; Baker, Carl ; Hoekzema, Kendra ; Stessman, Holly ; 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. / Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 1. pp. 58-74.
@article{677fe4e7886941f6b1073d592ac6faba,
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.",
author = "Turner, {Tychele N.} and Fereydoun Hormozdiari and Duyzend, {Michael H.} and McClymont, {Sarah A.} and Hook, {Paul W.} and Ivan Iossifov and Archana Raja and Carl Baker and Kendra Hoekzema and Holly Stessman and Zody, {Michael C.} and Nelson, {Bradley J.} and John Huddleston and Richard Sandstrom and Smith, {Joshua D.} and David Hanna and Swanson, {James M.} and Faustman, {Elaine M.} and Bamshad, {Michael J.} and John Stamatoyannopoulos and Nickerson, {Deborah A.} and McCallion, {Andrew S.} and Robert Darnell and Eichler, {Evan E.}",
year = "2016",
month = "1",
day = "7",
doi = "10.1016/j.ajhg.2015.11.023",
language = "English (US)",
volume = "98",
pages = "58--74",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

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

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.

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

UR - http://www.scopus.com/inward/citedby.url?scp=84954403183&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2015.11.023

DO - 10.1016/j.ajhg.2015.11.023

M3 - Article

VL - 98

SP - 58

EP - 74

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -