Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia

被引：262

作者：

Moreno-De-Luca, Daniel ^{[1
]}

Mulle, Jennifer G. ^{[1
]}

Kaminsky, Erin B. ^{[1
]}

Sanders, Stephan J. ^{[2
]}

Myers, Scott M. ^{[3
]}

Adam, Margaret P. ^{[1
]}

Pakula, Amy T. ^{[4
]}

Eisenhauer, Nancy J. ^{[3
]}

Uhas, Kim ^{[1
]}

Weik, LuAnn ^{[5
]}

Guy, Lisa ^{[4
]}

Care, Melanie E. ^{[6
,7
]}

Morel, Chantal F. ^{[6
,7
]}

Boni, Charlotte ^{[3
]}

Salbert, Bonnie Anne ^{[3
]}

Chandrareddy, Ashadeep ^{[8
]}

Demmer, Laurie A. ^{[8
]}

Chow, Eva W. C. ^{[9
]}

Surti, Urvashi ^{[10
]}

Aradhya, Swaroop ^{[11
]}

Pickering, Diane L. ^{[12
]}

Golden, Denae M. ^{[12
]}

Sanger, Warren G. ^{[12
]}

Aston, Emily ^{[13
]}

Brothman, Arthur R. ^{[13
]}

Gliem, Troy J. ^{[14
]}

Thorland, Erik C. ^{[14
]}

Ackley, Todd ^{[15
]}

Iyer, Ram ^{[15
]}

Huang, Shuwen ^{[16
]}

Barber, John C. ^{[16
]}

Crolla, John A. ^{[16
]}

Warren, Stephen T. ^{[1
,17
,18
]}

Martin, Christa L. ^{[1
]}

Ledbetter, David H. ^{[1
]}

机构：

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

[2] Yale Univ, Sch Med, Ctr Child Study, Dept Genet, New Haven, CT 06504 USA

[3] Geisinger Med Ctr, Danville, PA 17821 USA

[4] Emory Univ, Sch Med, Marcus Autism Ctr, Dept Pediat, Atlanta, GA 30329 USA

[5] Childrens Hosp Wisconsin, Milwaukee, WI 53233 USA

[6] Univ Hlth Network, Fred A Litwin Family Ctr Genet Med, Toronto, ON M5T 3I9, Canada

[7] Mt Sinai Hosp, Toronto, ON M5T 3I9, Canada

[8] Tufts Univ, Div Genet, Boston, MA 02111 USA

[9] Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON M6J 1H4, Canada

[10] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA

[11] GeneDx, Gaithersburg, MD 20877 USA

[12] Univ Nebraska Med Ctr, Human Genet Lab, Omaha, NE 68102 USA

[13] Univ Utah, ARUP Labs, Salt Lake City, UT 84108 USA

[14] Mayo Clin, Rochester, MN 55905 USA

[15] Michigan Med Genet Labs, Ann Arbor, MI 48109 USA

[16] Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England

[17] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA

[18] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2010年 / 87卷 / 05期

关键词：

HIDDEN-MARKOV MODEL; GENOME-WIDE SCAN; SPECTRUM DISORDERS; COMMON VARIANTS; GENETICS; MICRODELETION; ASSOCIATION; POPULATION; DUPLICATIONS; CRITERIA;

D O I：

10.1016/j.ajhg.2010.10.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing We detected a recurrent 1 4 Mb deletion at 17q12 which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients including several with ASD, but 0/4 519 controls We identified additional shared phenotypic features among nine patients available for clinical assessment including macrocephaly characteristic facial features renal anomalies, and neurocognitive impairments In a large follow up sample the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6 340 schizophrenia patients, but in 0/47 929 controls (corrected p = 7 37 x 10(-5)) These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted Interval is dosage sensitive and essential for normal brain development and function In addition the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD which is caused by HNF1B mutations only

引用

页码：618 / 630

页数：13

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