Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

被引：915

作者：

Sanders, Stephan J. ^{[1
,2
,3
,4
]}

Ercan-Sencicek, A. Gulhan ^{[1
,2
,3
,4
]}

Hus, Vanessa ^{[5
]}

Luo, Rui ^{[6
]}

Murtha, Michael T. ^{[1
,2
,3
,4
]}

Moreno-De-Luca, Daniel ^{[7
]}

Chu, Su H. ^{[8
]}

Moreau, Michael P. ^{[9
]}

Gupta, Abha R. ^{[2
,10
]}

Thomson, Susanne A. ^{[11
]}

Mason, Christopher E. ^{[12
,13
]}

Bilguvar, Kaya ^{[1
,4
,14
,15
]}

Celestino-Soper, Patricia B. S. ^{[16
]}

Choi, Murim ^{[4
,30
]}

Crawford, Emily L. ^{[11
]}

Davis, Lea ^{[17
]}

Wright, Nicole R. Davis ^{[2
]}

Dhodapkar, Rahul M. ^{[2
]}

DiCola, Michael ^{[9
]}

DiLullo, Nicholas M. ^{[2
]}

Fernandez, Thomas V. ^{[2
]}

Fielding-Singh, Vikram ^{[18
]}

Fishman, Daniel O. ^{[19
]}

Frahm, Stephanie ^{[9
]}

Garagaloyan, Rouben ^{[20
]}

Goh, Gerald S. ^{[4
]}

Kammela, Sindhuja ^{[2
]}

Klei, Lambertus ^{[21
]}

Lowe, Jennifer K. ^{[22
]}

Lund, Sabata C. ^{[5
]}

McGrew, Anna D. ^{[11
]}

Meyer, Kyle A. ^{[23
]}

Moffat, William J. ^{[2
]}

Murdoch, John D. ^{[4
]}

O'Roak, Brian J. ^{[24
]}

Ober, Gordon T. ^{[2
]}

Pottenger, Rebecca S. ^{[25
]}

Raubeson, Melanie J. ^{[24
]}

Song, Youeun ^{[2
]}

Wang, Qi ^{[9
]}

Yaspan, Brian L. ^{[11
]}

Yu, Timothy W. ^{[26
]}

Yurkiewicz, Liana R. ^{[2
]}

Beaudet, Arthur L. ^{[16
]}

Cantor, Rita M. ^{[6
,27
]}

Curland, Martin ^{[20
]}

Grice, Dorothy E. ^{[28
,29
]}

Guenel, Murat ^{[1
,4
,14
,15
]}

Lifton, Richard P. ^{[4
,30
]}

Mane, Shrikant M. ^{[31
]}

机构：

[1] Yale Univ, Sch Med, Program Neurogenet, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06520 USA

[3] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA

[4] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA

[5] Univ Michigan, Autism & Commun Disorders Ctr, Ann Arbor, MI 48109 USA

[6] Univ Calif Los Angeles, Dept Human Genet, David Geffen Sch Med, Los Angeles, CA 90095 USA

[7] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[8] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

[9] Rutgers State Univ, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA

[10] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA

[11] Vanderbilt Univ, Ctr Mol Neurosci, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[12] Weill Cornell Med Coll, Dept Physiol Biophys, New York, NY 10021 USA

[13] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10021 USA

[14] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT 06510 USA

[15] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA

[16] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[17] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60608 USA

[18] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[19] Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA

[20] Microangelo Associates LLC, Pacific Palisades, CA 90272 USA

[21] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA

[22] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA

[23] Yale Univ, Interdept Neurosci Program, New Haven, CT 06510 USA

[24] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[25] Princeton Univ, Princeton, NJ 08544 USA

[26] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Childrens Hosp Boston,Dept Neurol,Div Genet, Boston, MA 02115 USA

[27] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA

[28] Columbia Univ, Dept Psychiat, Div Child & Adolescent Psychiat, New York, NY 10032 USA

[29] New York State Psychiat Inst & Hosp, New York, NY 10032 USA

[30] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA

[31] Yale Ctr Genome Anal, Orange, CT 06477 USA

[32] Univ Michigan, Med Ctr, Dept Pediat, Ann Arbor, MI 48109 USA

[33] Univ Michigan, Med Ctr, Dept Human Genet, Ann Arbor, MI 48109 USA

[34] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA

[35] Rutgers State Univ, Inst Human Genet, Piscataway, NJ 08854 USA

[36] Harvard Univ, Sch Med, Ctr Life Sci, Howard Hughes Med Inst, Boston, MA 02115 USA

[37] Harvard Univ, Sch Med, Ctr Life Sci, Div Genet,Childrens Hosp Boston, Boston, MA 02115 USA

[38] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA

[39] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA

[40] Geisinger Hlth Syst, Danville, PA 17822 USA

[41] McGill Univ, Montreal Childrens Hosp, Dept Psychiat, Montreal, PQ H3Z 1P2, Canada

[42] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA

[43] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA

[44] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA

[45] Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA

来源：

NEURON | 2011年 / 70卷 / 05期

关键词：

COPY NUMBER VARIATION; HIDDEN-MARKOV MODEL; EARLY-ONSET; 16P11.2; RISK; MICRODELETIONS; REARRANGEMENTS; DELETIONS; VARIANTS; GENES;

D O I：

10.1016/j.neuron.2011.05.002

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 x 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.

引用

页码：863 / 885

页数：23

共 71 条

[1] Genetic Mapping in Human Disease [J].

Altshuler, David ;

Daly, Mark J. ;

Lander, Eric S. .

SCIENCE, 2008, 322 (5903) :881-888

[2] A genome-wide scan for common alleles affecting risk for autism [J].

Anney, Richard ;

Klei, Lambertus ;

Pinto, Dalila ;

Regan, Regina ;

Conroy, Judith ;

Magalhaes, Tiago R. ;

Correia, Catarina ;

Abrahams, Brett S. ;

Sykes, Nuala ;

Pagnamenta, Alistair T. ;

Almeida, Joana ;

Bacchelli, Elena ;

Bailey, Anthony J. ;

Baird, Gillian ;

Battaglia, Agatino ;

Berney, Tom ;

Bolshakova, Nadia ;

Boelte, Sven ;

Bolton, Patrick F. ;

Bourgeron, Thomas ;

Brennan, Sean ;

Brian, Jessica ;

Carson, Andrew R. ;

Casallo, Guillermo ;

Casey, Jillian ;

Chu, Su H. ;

Cochrane, Lynne ;

Corsello, Christina ;

Crawford, Emily L. ;

Crossett, Andrew ;

Dawson, Geraldine ;

de Jonge, Maretha ;

Delorme, Richard ;

Drmic, Irene ;

Duketis, Eftichia ;

Duque, Frederico ;

Estes, Annette ;

Farrar, Penny ;

Fernandez, Bridget A. ;

Folstein, Susan E. ;

Fombonne, Eric ;

Freitag, Christine M. ;

Gilbert, John ;

Gillberg, Christopher ;

Glessner, Joseph T. ;

Goldberg, Jeremy ;

Green, Jonathan ;

Guter, Stephen J. ;

Hakonarson, Hakon ;

Heron, Elizabeth A. .

HUMAN MOLECULAR GENETICS, 2010, 19 (20) :4072-4082

[3] Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile [J].

Antonell, A. ;

Del Campo, M. ;

Magano, L. F. ;

Kaufmann, L. ;

Martinez de la Iglesia, J. ;

Gallastegui, F. ;

Flores, R. ;

Schweigmann, U. ;

Fauth, C. ;

Kotzot, D. ;

Perez-Jurado, L. A. .

JOURNAL OF MEDICAL GENETICS, 2010, 47 (05) :312-320

[4] AUTISM AS A STRONGLY GENETIC DISORDER - EVIDENCE FROM A BRITISH TWIN STUDY [J].

BAILEY, A ;

LECOUTEUR, A ;

GOTTESMAN, I ;

BOLTON, P ;

SIMONOFF, E ;

YUZDA, E ;

RUTTER, M .

PSYCHOLOGICAL MEDICINE, 1995, 25 (01) :63-77

[5] Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region [J].

Berg, Jonathan S. ;

Brunetti-Pierri, Nicola ;

Peters, Sarika U. ;

Kang, Sung-Hae L. ;

Fong, Chin-to ;

Salamone, Jessica ;

Freedenberg, Debra ;

Hannig, Vickie L. ;

Prock, Lisa Albers ;

Miller, David T. ;

Raffalli, Peter ;

Harris, David J. ;

Erickson, Robert P. ;

Cunniff, Christopher ;

Clark, Gary D. ;

Blazo, Maria A. ;

Peiffer, Daniel A. ;

Gunderson, Kevin L. ;

Sahoo, Trilochan ;

Patel, Ankita ;

Lupski, James R. ;

Beaudet, Arthur L. ;

Cheung, Sau Wai .

GENETICS IN MEDICINE, 2007, 9 (07) :427-441

[6] Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals [J].

Bijlsma, E. K. ;

Gijsbers, A. C. J. ;

Schuurs-Hoeijmakers, J. H. M. ;

van Haeringen, A. ;

van de Putte, D. E. Fransen ;

Anderlid, B. -M. ;

Lundin, J. ;

Lapunzina, P. ;

Perez Jurado, L. A. ;

Delle Chiaie, B. ;

Loeys, B. ;

Menten, B. ;

Oostra, A. ;

Verhelst, H. ;

Amor, D. J. ;

Bruno, D. L. ;

van Essen, A. J. ;

Hordijk, R. ;

Sikkema-Raddatz, B. ;

Verbruggen, K. T. ;

Jongmans, M. C. J. ;

Pfundt, R. ;

Reeser, H. M. ;

Breuning, M. H. ;

Ruivenkamp, C. A. L. .

EUROPEAN JOURNAL OF MEDICAL GENETICS, 2009, 52 (2-3) :77-87

[7] Large, rare chromosomal deletions associated with severe early-onset obesity [J].

Bochukova, Elena G. ;

Huang, Ni ;

Keogh, Julia ;

Henning, Elana ;

Purmann, Carolin ;

Blaszczyk, Kasia ;

Saeed, Sadia ;

Hamilton-Shield, Julian ;

Clayton-Smith, Jill ;

O'Rahilly, Stephen ;

Hurles, Matthew E. ;

Farooqi, I. Sadaf .

NATURE, 2010, 463 (7281) :666-670

[8] Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes [J].

Bucan, Maja ;

Abrahams, Brett S. ;

Wang, Kai ;

Glessner, Joseph T. ;

Herman, Edward I. ;

Sonnenblick, Lisa I. ;

Retuerto, Ana I. Alvarez ;

Imielinski, Marcin ;

Hadley, Dexter ;

Bradfield, Jonathan P. ;

Kim, Cecilia ;

Gidaya, Nicole B. ;

Lindquist, Ingrid ;

Hutman, Ted ;

Sigman, Marian ;

Kustanovich, Vlad ;

Lajonchere, Clara M. ;

Singleton, Andrew ;

Kim, Junhyong ;

Wassink, Thomas H. ;

McMahon, William M. ;

Owley, Thomas ;

Sweeney, John A. ;

Coon, Hilary ;

Nurnberger, John I., Jr. ;

Li, Mingyao ;

Cantor, Rita M. ;

Minshew, Nancy J. ;

Sutcliffe, James S. ;

Cook, Edwin H. ;

Dawson, Geraldine ;

Buxbaum, Joseph D. ;

Grant, Struan F. A. ;

Schellenberg, Gerard D. ;

Geschwind, Daniel H. ;

Hakonarson, Hakon .

PLOS GENETICS, 2009, 5 (06)

[9]

Bugge M, 2000, J MED GENET, V37, P858, DOI 10.1136/jmg.37.11.858

[10] ESTIMATING THE NUMBER OF SPECIES - A REVIEW [J].

BUNGE, J ;

FITZPATRICK, M .

JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION, 1993, 88 (421) :364-373

← 1 2 3 4 5 6 7 8 →