Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2

被引：52

作者：

Chaste, Pauline ^{[1
,2
]}

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

Mohan, Kommu N. ^{[5
,6
]}

Klei, Lambertus ^{[1
]}

Song, Youeun ^{[1
]}

Murtha, Michael T. ^{[7
]}

Hus, Vanessa ^{[8
]}

Lowe, Jennifer K. ^{[9
,10
]}

Willsey, A. Jeremy ^{[3
,4
]}

Moreno-De-Luca, Daniel ^{[11
]}

Yu, Timothy W. ^{[12
]}

Fombonne, Eric ^{[13
]}

Geschwind, Daniel ^{[9
,10
]}

Grice, Dorothy E. ^{[14
]}

Ledbetter, David H. ^{[15
]}

Lord, Catherine ^{[16
]}

Mane, Shrikant M. ^{[17
]}

Martin, Donna M. ^{[7
,18
,19
]}

Morrow, Eric M. ^{[20
,21
]}

Walsh, Christopher A. ^{[22
,23
,24
]}

Sutcliffe, James S. ^{[25
,26
]}

State, Matthew W. ^{[3
,4
]}

Martin, Christa Lese ^{[15
]}

Devlin, Bernie ^{[1
]}

Beaudet, Arthur L. ^{[6
]}

Cook, Edwin H., Jr. ^{[27
]}

Kim, Soo-Jeong ^{[28
]}

机构：

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

[2] FondaMental Fdn, Creteil, France

[3] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[4] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA

[5] BITS Pilani Hyderabad Campus, Dept Biol Sci, Hyderabad, Andhra Pradesh, India

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

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

[8] Univ Michigan, Dept Psychol, Ann Arbor, MI USA

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

[10] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Ctr Autism Res & Treatment, Los Angeles, CA 90095 USA

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

[12] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Genet, Boston, MA USA

[13] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA

[14] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[15] Geisinger Hlth Syst, Autism & Dev Med Inst, Danville, PA USA

[16] Weill Cornell Med Coll, Ctr Autism & Dev Brain, White Plains, NY USA

[17] Yale Univ, Yale Ctr Genome Anal, Orange, CT USA

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

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

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

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

[22] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA

[23] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Genet, Boston, MA USA

[24] Harvard Univ, Sch Med, Ctr Life Sci, Boston, MA USA

[25] Vanderbilt Univ, Vanderbilt Brain Inst, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA

[26] Vanderbilt Univ, Vanderbilt Brain Inst, Dept Psychiat, Nashville, TN 37235 USA

[27] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA

[28] Univ Washington, Dept Psychiat & Behav Sci, Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98195 USA

来源：

AUTISM RESEARCH | 2014年 / 7卷 / 03期

关键词：

15q11.2; deletion; duplication; penetrance; autism; HIDDEN-MARKOV MODEL; RECURRENT MICRODELETIONS; CRITICAL REGION; ARRAY-CGH; DELETION; GENES; MAP; MICRODUPLICATION; IDENTIFICATION; PENETRANCE;

D O I：

10.1002/aur.1378

中图分类号：

B84 [心理学]; C [社会科学总论]; Q98 [人类学];

学科分类号：

03 ; 0303 ; 030303 ; 04 ; 0402 ;

摘要：

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n=2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, 7: 355-362. (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.

引用

页码：355 / 362

页数：8

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