A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

被引：461

作者：

Girirajan, Santhosh ^{[1
]}

Rosenfeld, Jill A. ^{[2
]}

Cooper, Gregory M. ^{[1
]}

Antonacci, Francesca ^{[1
]}

Siswara, Priscillia ^{[1
]}

Itsara, Andy ^{[1
]}

Vives, Laura ^{[1
]}

Walsh, Tom ^{[3
]}

McCarthy, Shane E. ^{[4
]}

Baker, Carl ^{[1
]}

Mefford, Heather C. ^{[1
]}

Kidd, Jeffrey M. ^{[1
]}

Browning, Sharon R. ^{[5
]}

Browning, Brian L. ^{[5
]}

Dickel, Diane E. ^{[1
]}

Levy, Deborah L. ^{[6
,7
]}

Ballif, Blake C. ^{[2
]}

Platky, Kathryn ^{[8
]}

Farber, Darren M. ^{[9
]}

Gowans, Gordon C. ^{[8
]}

Wetherbee, Jessica J. ^{[8
]}

Asamoah, Alexander ^{[8
]}

Weaver, David D. ^{[10
]}

Mark, Paul R. ^{[10
]}

Dickerson, Jennifer ^{[11
]}

Garg, Bhuwan P. ^{[11
]}

Ellingwood, Sara A. ^{[12
]}

Smith, Rosemarie ^{[12
]}

Banks, Valerie C. ^{[12
]}

Smith, Wendy ^{[12
]}

McDonald, Marie T. ^{[13
]}

Hoo, Joe J. ^{[14
,15
]}

French, Beatrice N. ^{[14
,15
]}

Hudson, Cindy ^{[16
]}

Johnson, John P. ^{[16
]}

Ozmore, Jillian R. ^{[17
]}

Moeschler, John B. ^{[17
]}

Surti, Urvashi ^{[18
]}

Escobar, Luis F. ^{[19
]}

El-Khechen, Dima ^{[19
]}

Gorski, Jerome L. ^{[20
]}

Kussmann, Jennifer ^{[20
]}

Salbert, Bonnie ^{[21
]}

Lacassie, Yves ^{[22
,23
]}

Biser, Alisha ^{[24
,25
]}

McDonald-McGinn, Donna M. ^{[24
,25
]}

Zackai, Elaine H. ^{[24
,25
]}

Deardorff, Matthew A. ^{[24
,25
]}

Shaikh, Tamim H. ^{[24
,25
]}

Haan, Eric ^{[26
,27
]}

机构：

[1] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[2] Signature Genom Labs, Spokane, WA USA

[3] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA

[4] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[5] Univ Auckland, Dept Stat, Fac Sci, Auckland 1, New Zealand

[6] McLean Hosp, Psychol Res Lab, Belmont, MA 02178 USA

[7] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA

[8] Univ Louisville, Dept Pediat, Weisskopf Child Evaluat Ctr, Louisville, KY 40292 USA

[9] Univ Louisville, Sch Med, Dept Neurol, Div Child Neurol, Louisville, KY 40292 USA

[10] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[11] Indiana Univ, Sch Med, Dept Neurol, Div Pediat Neurol, Indianapolis, IN 46202 USA

[12] Maine Med Ctr, Div Genet, Portland, ME 04102 USA

[13] Duke Univ, Med Ctr, Div Med Genet, Durham, NC USA

[14] Univ Toledo, Coll Med, Dept Pediat, Toledo, OH 43606 USA

[15] NW Ohio Reg Genet Ctr, Toledo, OH USA

[16] Shodair Childrens Hosp, Helena, MT USA

[17] Dartmouth Hitchcock Med Ctr, Div Clin Genet, Lebanon, NH 03766 USA

[18] Univ Pittsburgh, Magee Womens Hosp, Med Ctr, Pittsburgh, PA 15213 USA

[19] St Vincent Childrens Hosp, Med Genet & Neurodev Ctr, Indianapolis, IN USA

[20] Univ Missouri, Div Med Genet, Columbia, MO USA

[21] Geisinger Med Ctr, Danville, PA 17822 USA

[22] Louisiana State Univ, Hlth Sci Ctr, Div Genet, Dept Pediat, New Orleans, LA USA

[23] Childrens Hosp, New Orleans, LA USA

[24] Univ Penn, Dept Pediat & Genet, Philadelphia, PA 19104 USA

[25] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[26] S Australian Pathol Womens & Childrens Hosp, S Australian Clin Genet Serv, Adelaide, SA, Australia

[27] Univ Adelaide, Dept Paediat, Adelaide, SA, Australia

[28] Oasi Inst Res & Care Mental Retardat & Brain Ag, Troina, Italy

[29] VA Boston Healthcare Syst, Brockton, MA USA

[30] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[31] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[32] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 03期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; COPY NUMBER VARIATIONS; COMORBID SCHIZOPHRENIA; CHROMOSOMAL IMBALANCE; LEARNING-DISABILITY; MENTAL-RETARDATION; DELETION SYNDROME; INCREASE RISK; COSTA-RICA; ARRAY CGH;

D O I：

10.1038/ng.534

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

引用

页码：203 / U24

页数：8

共 47 条

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