NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits

被引：100

作者：

Dittwald, Piotr ^{[1
,2
,3
]}

Gambin, Tomasz ^{[1
,4
]}

Szafranski, Przemyslaw ^{[1
]}

Li, Jian ^{[1
]}

Amato, Stephen ^{[5
]}

Divon, Michael Y. ^{[6
]}

Rodriguez Rojas, Lisa Ximena ^{[7
]}

Elton, Lindsay E. ^{[8
]}

Scott, Daryl A. ^{[1
,9
]}

Schaaf, Christian P. ^{[1
]}

Torres-Martinez, Wilfredo ^{[10
]}

Stevens, Abby K. ^{[10
]}

Rosenfeld, Jill A. ^{[11
]}

Agadi, Satish ^{[12
]}

Francis, David ^{[13
]}

Kang, Sung-Hae L. ^{[1
]}

Breman, Amy ^{[1
]}

Lalani, Seema R. ^{[1
]}

Bacino, Carlos A. ^{[1
]}

Bi, Weimin ^{[1
]}

Milosavljevic, Aleksandar ^{[1
]}

Beaudet, Arthur L. ^{[1
]}

Patel, Ankita ^{[1
]}

Shaw, Chad A. ^{[1
]}

Lupski, James R. ^{[1
,14
,15
]}

Gambin, Anna ^{[2
,16
]}

Cheung, Sau Wai ^{[1
]}

Stankiewicz, Pawel ^{[1
]}

机构：

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

[2] Univ Warsaw, Inst Informat, PL-02097 Warsaw, Poland

[3] Univ Warsaw, Coll Interfac Individual Studies Math & Nat Sci, PL-02089 Warsaw, Poland

[4] Warsaw Univ Technol, Inst Comp Sci, PL-02665 Warsaw, Poland

[5] Phoenix Childrens Hosp, Phoenix, AZ 85006 USA

[6] Lenox Hill Hosp, New York, NY 10065 USA

[7] Fdn Clin Valle del Lili, Cali 76001000, Colombia

[8] Pediat Specialty Serv, Austin, TX 78723 USA

[9] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA

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

[11] PerkinElmer Inc, Signature Genom Labs, Spokane, WA 99207 USA

[12] Baylor Coll Med, Dept Pediat & Neurol, Houston, TX 77030 USA

[13] Murdoch Childrens Res Inst, Dept Cytogenet, Victorian Clin Genet Serv, Parkville, Vic 3052, Australia

[14] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[15] Texas Childrens Hosp, Houston, TX 77030 USA

[16] Polish Acad Sci, Mossakowski Med Res Ctr, PL-02106 Warsaw, Poland

来源：

GENOME RESEARCH | 2013年 / 23卷 / 09期

基金：

美国国家卫生研究院;

关键词：

17Q21.31 MICRODELETION SYNDROME; SEGMENTAL DUPLICATIONS; HOMOLOGOUS RECOMBINATION; DEVELOPMENTAL DELAY; RECIPROCAL DUPLICATIONS; RECURRENT DELETIONS; DNA REARRANGEMENTS; DPY19L2; DELETION; GENE; DISEASE;

D O I：

10.1101/gr.152454.112

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the similar to 25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.

引用

页码：1395 / 1409

页数：15

共 66 条

[1] Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome [J].

Albers, Cornelis A. ;

Paul, Dirk S. ;

Schulze, Harald ;

Freson, Kathleen ;

Stephens, Jonathan C. ;

Smethurst, Peter A. ;

Jolley, Jennifer D. ;

Cvejic, Ana ;

Kostadima, Myrto ;

Bertone, Paul ;

Breuning, Martijn H. ;

Debili, Najet ;

Deloukas, Panos ;

Favier, Remi ;

Fiedler, Janine ;

Hobbs, Catherine M. ;

Huang, Ni ;

Hurles, Matthew E. ;

Kiddle, Graham ;

Krapels, Ingrid ;

Nurden, Paquita ;

Ruivenkamp, Claudia A. L. ;

Sambrook, Jennifer G. ;

Smith, Kenneth ;

Stemple, Derek L. ;

Strauss, Gabriele ;

Thys, Chantal ;

van Geet, Chris ;

Newbury-Ecob, Ruth ;

Ouwehand, Willem H. ;

Ghevaert, Cedric .

NATURE GENETICS, 2012, 44 (04) :435-U248

[2] Recent segmental duplications in the human genome [J].

Bailey, JA ;

Gu, ZP ;

Clark, RA ;

Reinert, K ;

Samonte, RV ;

Schwartz, S ;

Adams, MD ;

Myers, EW ;

Li, PW ;

Eichler, EE .

SCIENCE, 2002, 297 (5583) :1003-1007

[3] Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: Is less more? [J].

Bejjani, BA ;

Saleki, R ;

Ballif, BC ;

Rorem, EA ;

Sundin, K ;

Theisen, A ;

Kashork, CD ;

Shaffer, LG .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2005, 134A (03) :259-267

[4] Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events [J].

Bi, Weimin ;

Probst, Frank J. ;

Wiszniewska, Joanna ;

Plunkett, Katie ;

Roney, Erin K. ;

Carter, Brian S. ;

Williams, Misti D. ;

Stankiewicz, Pawel ;

Patel, Ankita ;

Stevens, Cathy A. ;

Lupski, James R. ;

Cheung, Sau Wai .

JOURNAL OF MEDICAL GENETICS, 2012, 49 (11) :681-688

[5] Detection of Clinically Relevant Exonic Copy-Number Changes by Array CGH [J].

Boone, Philip M. ;

Bacino, Carlos A. ;

Shaw, Chad A. ;

Eng, Patricia A. ;

Hixson, Patricia M. ;

Pursley, Amber N. ;

Kang, Sung-Hae L. ;

Yang, Yaping ;

Wiszniewska, Joanna ;

Nowakowska, Beata A. ;

del Gaudio, Daniela ;

Xia, Zhilian ;

Simpson-Patel, Gayle ;

Immken, LaDonna L. ;

Gibson, James B. ;

Tsai, Anne C. -H. ;

Bowers, Jennifer A. ;

Reimschisel, Tyler E. ;

Schaaf, Christian P. ;

Potocki, Lorraine ;

Scaglia, Fernando ;

Gambin, Tomasz ;

Sykulski, Maciej ;

Bartnik, Magdalena ;

Derwinska, Katarzyna ;

Wisniowiecka-Kowalnik, Barbara ;

Lalani, Seema R. ;

Probst, Frank J. ;

Bi, Weimin ;

Beaudet, Arthur L. ;

Patel, Ankita ;

Lupski, James R. ;

Cheung, Sau Wai ;

Stankiewicz, Pawel .

HUMAN MUTATION, 2010, 31 (12) :1326-1342

[6] Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities [J].

Brunetti-Pierri, Nicola ;

Berg, Jonathan S. ;

Scaglia, Fernando ;

Belmont, John ;

Bacino, Carlos A. ;

Sahoo, Trilochan ;

Lalani, Seema R. ;

Graham, Brett ;

Lee, Brendan ;

Shinawi, Marwan ;

Shen, Joseph ;

Kang, Sung-Hae L. ;

Pursley, Amber ;

Lotze, Timothy ;

Kennedy, Gail ;

Lansky-Shafer, Susan ;

Weaver, Christine ;

Roeder, Elizabeth R. ;

Grebe, Theresa A. ;

Arnold, Georgianne L. ;

Hutchison, Terry ;

Reimschisel, Tyler ;

Amato, Stephen ;

Geragthy, Michael T. ;

Innis, Jeffrey W. ;

Obersztyn, Ewa ;

Nowakowska, Beata ;

Rosengren, Sally S. ;

Bader, Patricia I. ;

Grange, Dorothy K. ;

Naqvi, Sayed ;

Garnica, Adolfo D. ;

Bernes, Saunder M. ;

Fong, Chin-To ;

Summers, Anne ;

Walters, W. David ;

Lupski, James R. ;

Stankiewicz, Pawel ;

Cheung, Sau Wai ;

Patel, Ankita .

NATURE GENETICS, 2008, 40 (12) :1466-1471

[7] Gene Conversion in Human Genetic Disease [J].

Chen, Jian-Min ;

Ferec, Claude ;

Cooper, David N. .

GENES, 2010, 1 (03) :550-563

[8] Development and validation of a CGH microarray for clinical cytogenetic diagnosis [J].

Cheung, SW ;

Shaw, CA ;

Yu, W ;

Li, JZ ;

Ou, ZS ;

Patel, A ;

Yatsenko, SA ;

Cooper, ML ;

Furman, P ;

Stankiewicz, P ;

Lupski, JR ;

Chinault, AC ;

Beaudet, AL .

GENETICS IN MEDICINE, 2005, 7 (06) :422-432

[9] Gene Conversion Causing Human Inherited Disease: Evidence for Involvement of Non-B-DNA-Forming Sequences and Recombination-Promoting Motifs in DNA Breakage and Repair [J].

Chuzhanova, Nadia ;

Chen, Jian-Min ;

Bacolla, Albino ;

Patrinos, George P. ;

Ferec, Claude ;

Wells, Robert D. ;

Cooper, David N. .

HUMAN MUTATION, 2009, 30 (08) :1189-1198

[10] A copy number variation morbidity map of developmental delay [J].

Cooper, Gregory M. ;

Coe, Bradley P. ;

Girirajan, Santhosh ;

Rosenfeld, Jill A. ;

Vu, Tiffany H. ;

Baker, Carl ;

Williams, Charles ;

Stalker, Heather ;

Hamid, Rizwan ;

Hannig, Vickie ;

Abdel-Hamid, Hoda ;

Bader, Patricia ;

McCracken, Elizabeth ;

Niyazov, Dmitriy ;

Leppig, Kathleen ;

Thiese, Heidi ;

Hummel, Marybeth ;

Alexander, Nora ;

Gorski, Jerome ;

Kussmann, Jennifer ;

Shashi, Vandana ;

Johnson, Krys ;

Rehder, Catherine ;

Ballif, Blake C. ;

Shaffer, Lisa G. ;

Eichler, Evan E. .

NATURE GENETICS, 2011, 43 (09) :838-U44

← 1 2 3 4 5 6 7 →