The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

被引：216

作者：

Redin, Claire ^{[1
,2
,3
,4
]}

Brand, Harrison ^{[1
,2
,3
,4
]}

Collins, Ryan L. ^{[1
,2
,3
,4
,5
]}

Kammin, Tammy ^{[6
]}

Mitchell, Elyse ^{[7
]}

Hodge, Jennelle C. ^{[7
,8
,9
]}

Hanscom, Carrie ^{[1
,2
,3
,4
]}

Pillalamarri, Vamsee ^{[1
,2
,3
,4
]}

Seabra, Catarina M. ^{[1
,2
,3
,4
,10
]}

Abbott, Mary-Alice ^{[11
]}

Abdul-Rahman, Omar A. ^{[12
]}

Aberg, Erika ^{[13
]}

Adley, Rhett ^{[1
]}

Alcaraz-Estrada, Sofia L. ^{[14
]}

Alkuraya, Fowzan S. ^{[15
]}

An, Yu ^{[1
,16
,17
]}

Anderson, Mary-Anne ^{[18
]}

Antolik, Caroline ^{[1
,2
,3
,4
]}

Anyane-Yeboa, Kwame ^{[19
]}

Atkin, Joan F. ^{[20
,21
]}

Bartell, Tina ^{[22
]}

Bernstein, Jonathan A. ^{[23
]}

Beyer, Elizabeth ^{[24
,25
]}

Blumenthal, Ian ^{[1
]}

Bongers, Ernie M. H. F. ^{[26
,27
]}

Brilstra, Eva H. ^{[28
]}

Brown, Chester W. ^{[29
,30
,113
]}

Bruggenwirth, Hennie T. ^{[31
]}

Callewaert, Bert ^{[32
]}

Chiang, Colby ^{[1
]}

Corning, Ken ^{[33
]}

Cox, Helen ^{[34
]}

Cuppen, Edwin ^{[28
]}

Currall, Benjamin B. ^{[1
,6
,35
]}

Cushing, Tom ^{[36
]}

David, Dezso ^{[37
]}

Deardorff, Matthew A. ^{[38
,39
]}

Dheedene, Annelies ^{[32
]}

D'Hooghe, Marc ^{[40
]}

de Vries, Bert B. A. ^{[26
,27
]}

Earl, Dawn L. ^{[41
]}

Ferguson, Heather L. ^{[6
]}

Fisher, Heather ^{[42
]}

FitzPatrick, David R. ^{[43
]}

Gerrol, Pamela ^{[6
]}

Giachino, Daniela ^{[44
]}

Glessner, Joseph T. ^{[1
,2
,3
,4
]}

Gliem, Troy ^{[7
]}

Grady, Margo ^{[45
]}

Graham, Brett H. ^{[29
,30
]}

机构：

[1] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Psychiatr & Neurodev Genet Unit, Boston, MA 02114 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[5] Harvard Med Sch, Div Med Sci, Program Bioinformat & Integrat Gen, Boston, MA USA

[6] Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA

[7] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[8] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA

[9] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA

[10] Univ Porto, GABBA Program, Porto, Portugal

[11] Baystate Med Ctr, Med Genet, Springfield, MA USA

[12] Univ Mississippi, Med Ctr, Dept Pediat, Jackson, MS 39216 USA

[13] IWK Hlth Ctr, Maritime Med Genet Serv, Halifax, NS, Canada

[14] ISSSTE, Ctr Med Nacl Noviembre 20, Med Genom Div, Mexico City, DF, Mexico

[15] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia

[16] Fudan Univ, Shanghai Med Sch, IBS, Shanghai, Peoples R China

[17] Fudan Univ, MOE Key Lab Contemporary Anthropol, Shanghai, Peoples R China

[18] Ctr Human Genet Res DNA & Tissue Culture Res, Boston, MA USA

[19] Columbia Univ, Med Ctr, Div Clin Genet, New York, NY USA

[20] Ohio State Univ, Coll Med, Dept Pediat, Columbus, OH 43210 USA

[21] Nationwide Childrens Hosp, Div Mol & Human Genet, Columbus, OH USA

[22] Kaiser Permanente, Dept Genet, Sacramento, CA USA

[23] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA

[24] Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA

[25] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA

[26] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Dept Human Genet, Med Ctr, Nijmegen, Netherlands

[27] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Med Ctr, Nijmegen, Netherlands

[28] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Genet, Div Biomed Genet, Utrecht, Netherlands

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

[30] Texas Childrens Hosp, Dept Genet, Houston, TX 77030 USA

[31] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands

[32] Univ Ghent, Ctr Med Genet, Ghent, Belgium

[33] Greenwood Genet Ctr, Columbia, SC USA

[34] Birmingham Womens Hosp, West Midlands Reg Clin Genet Unit, Birmingham, W Midlands, England

[35] Harvard Med Sch, Dept Genet, Boston, MA USA

[36] Univ New Mexico, Sch Med, Dept Pediat, Div Pediat Genet, Albuquerque, NM 87131 USA

[37] Natl Hlth Inst Doutor Ricardo Jorge, Dept Human Genet, Lisbon, Portugal

[38] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[39] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA

[40] Algemeen Ziekenhuis St Jan, Dept Neurol & Child Neurol, Brugge, Belgium

[41] Seattle Childrens, Seattle, WA USA

[42] Mt Sinai West Hosp, New York, NY USA

[43] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[44] Univ Torino, Dept Clin & Biol Sci, Med Genet Unit, Turin, Italy

[45] UW Canc Ctr ProHlth Care, Waukesha, WI USA

[46] Thomas Jefferson Univ, Sidney Kimmel Med Sch, Philadelphia, PA 19107 USA

[47] Childrens Natl Med Ctr, Div Neurogenet & Dev Pediat, Washington, DC 20010 USA

[48] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA

[49] Boston Childrens Hosp, Div Genet, Boston, MA USA

[50] Harvard Med Sch, Dept Pediat, Boston, MA USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 01期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

SEVERE MENTAL-RETARDATION; OF-FUNCTION MUTATIONS; DE-NOVO MUTATIONS; CHROMOSOME REARRANGEMENTS; MICRODELETION SYNDROME; INTELLECTUAL DISABILITY; STRUCTURAL VARIATION; DEVELOPMENTAL DELAY; SPECTRUM; EPILEPSY;

D O I：

10.1038/ng.3720

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21 % of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADS) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

引用

页码：36 / 45

页数：10

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