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Cited by 93Genomic variations and chromosomal abnormalitiesGenomics and Rare DiseasesCongenital heart defects research

Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield

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Geng, Juan, Picker, Jonathan, Zheng, Zhaojing, Zhang, Xiaoqing, Wang, Jian, Hisama, Fuki, Brown, David W, Mullen, Mary P +7 more·2014·BMC Genomics
DOI 10.1186/1471-2164-15-1127PMC PMC4378009
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Abstract

BACKGROUND: Congenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Children's Hospital (BCH) and a 92-case research cohort from Shanghai Children's Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification. RESULTS: Based on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis. CONCLUSION: The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.

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  1. [1]Kaminsky EB Kaul V Paschall J Church DM Bunke B Kunig D Moreno-De-Luca D Moreno-De-Luca A Mulle JG Warren ST Richard G Compton JG Fuller AE Gliem TJ Huang S Collinson MN Beal SJ Ackley T Pickering DL Golden DM Aston E Whitby H Shetty S Rossi MR Rudd MK South ST Brothman AR Sanger WG Iyer RK Crolla JA An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities Genet Med 2011 13 9 777 784 10.1097/GIM.0b013e31822c79f9 21844811 PMC3661946 · DOI · Paper page
  2. [2]Riggs ER Jackson L Miller DT Van Vooren S Phenotypic information in genomic variant databases enhances clinical care and research: The international standards for cytogenomic arrays consortium experience Hum Mutat 2012 33 5 787 796 10.1002/humu.22052 22331816 PMC3327820 · DOI
  3. [3]Miller DT Adam MP Aradhya S Biesecker LG Brothman AR Carter NP Church DM Crolla JA Eichler EE Epstein CJ Faucett WA Feuk L Friedman JM Hamosh A Jackson L Kaminsky EB Kok K Krantz ID Kuhn RM Lee C Ostell JM Rosenberg C Scherer SW Spinner NB Stavropoulos DJ Tepperberg JH Thorland EC Vermeesch JR Waggoner DJ Watson MS Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies Am J Hum Genet 2010 86 5 749 764 10.1016/j.ajhg.2010.04.006 20466091 PMC2869000 · DOI · Paper page
  4. [4]Manning M Hudgins L Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities Gen Med 2010 12 11 742 745 10.1097/GIM.0b013e3181f8baad PMC3111046 20962661 · DOI
  5. [5]van der Linde D Konings EEM Slager MA Witsenburg M Helbing WA Takkenberg JJM Roos-Hesselink JW Birth prevalence of congenital heart disease worldwide J Am Coll Cardiol 2011 58 21 2241 2247 10.1016/j.jacc.2011.08.025 22078432 · DOI · Paper page
  6. [6]Reller MD Strickland MJ Riehle-Colarusso T Mahle WT Correa A Prevalence of congenital heart defects in Metropolitan Atlanta, 1998–2005 J Pediatr 2008 153 6 807 813 10.1016/j.jpeds.2008.05.059 18657826 PMC2613036 · DOI · Paper page
  7. [7]Fahed A Gelb B Seidman J Seidman C Genetics of congenital heart disease: the glass half empty Circ Res 2013 112 4 707 720 10.1161/CIRCRESAHA.112.300853 23410880 PMC3827691 · DOI
  8. [8]Soemedi R Wilson Ian J Bentham J Darlay R Töpf A Zelenika D Cosgrove C Setchfield K Thornborough C Granados-Riveron J Blue GM Breckpot J Hellens S Zwolinkski S Glen E Mamasoula C Rahman TJ Hall D Rauch A Devriendt K Gewillig M O' Sullivan J Winlaw DS Bu'Lock F Brook JD Bhattacharya S Lathrop M Santibanez-Koref M Cordell HJ Goodship JA Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease Am J Hum Genet 2012 91 3 489 501 10.1016/j.ajhg.2012.08.003 22939634 PMC3511986 · DOI · Paper page
  9. [9]Pierpont ME Basson CT Benson DW Gelb BD Giglia TM Goldmuntz E McGee G Sable CA Srivastava D Webb CL Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American heart association congenital cardiac defects committee, council on cardiovascular disease in the young: endorsed by the american academy of pediatrics Circulation 2007 115 23 3015 3038 10.1161/CIRCULATIONAHA.106.183056 17519398 · DOI
  10. [10]Soemedi R Topf A Wilson IJ Darlay R Rahman T Glen E Hall D Huang N Bentham J Bhattacharya S Cosgrove C Brook JD Granados-Riveron J Setchfield K Bu'lock F Thornborough C Devriendt K Breckpot J Hofbeck M Lathrop M Rauch A Blue GM Winlaw DS Hurles M Santibanez-Koref M Cordell HJ Goodship JA Keavney BD Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls Hum Mol Genet 2011 21 7 1513 1520 10.1093/hmg/ddr589 22199024 PMC3298277 · DOI
  11. [11]Greenway SC Pereira AC Lin JC DePalma SR Israel SJ Mesquita SM Ergul E Conta JH Korn JM McCarroll SA Gorham JM Gabriel S Altshuler DM Quintanilla-Dieck Mde L Artunduaga MA Eavey RD Plenge RM Shadick NA Weinblatt ME De Jager PL Hafler DA Breitbart RE Seidman JG Seidman CE De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot Nat Genet 2009 41 8 931 935 10.1038/ng.415 19597493 PMC2747103 · DOI
  12. [12]Thienpont B Mertens L de Ravel T Eyskens B Boshoff D Maas N Fryns J Gewillig M Vermeesch J Devriendt K Submicroscopic chromosomal imbalances detected by array-CGH are a frequent cause of congenital heart defects in selected patients Eur Heart J 2007 22 2778 2784 10.1093/eurheartj/ehl560 17384091 · DOI
  13. [13]Richards A Santos L Nichols H Crider B Elder F Hauser N Zinn A Garg V Cryptic chromosomal abnormalities identified in children with congenital heart disease Pediatr Res 2008 64 4 358 363 10.1203/PDR.0b013e31818095d0 18535492 · DOI
  14. [14]Erdogan F Larsen L Zhang L Tumer Z Tommerup N Chen W Jacobsen J Schubert M Jurkatis J Tzschach A Ropers HH Ullmann R High frequency of submicroscopic genomic aberrations detected by tiling path array comparative genome hybridisation in patients with isolated congenital heart disease J Med Genet 2008 45 11 704 709 10.1136/jmg.2008.058776 18713793 · DOI
  15. [15]Breckpot J Thienpont B Peeters H de Ravel T Singer A Rayyan M Allegaert K Vanhole C Eyskens B Vermeesch JR Gewillig M Devriendt K Array comparative genomic hybridization as a diagnostic tool for syndromic heart defects J Pediatr 2010 156 5 810 817 10.1016/j.jpeds.2009.11.049 20138633 · DOI
  16. [16]Goldmuntz E Paluru P Glessner J Hakonarson H Biegel J White P Gai X Shaikh T Microdeletions and microduplications in patients with congenital heart disease and multiple congenital anomalies Congenit Heart Dis 2011 6 6 592 602 10.1111/j.1747-0803.2011.00582.x 22010865 PMC4575121 · DOI
  17. [17]Breckpot J Thienpont B Arens Y Tranchevent LC Vermeesch JR Moreau Y Gewillig M Devriendt K Challenges of interpreting copy number variation in syndromic and non-syndromic congenital heart defects Cytogenet Genome Res 2011 135 3–4 251 259 10.1159/000331272 21921585 · DOI
  18. [18]Connor J Hinton R Miller E Sund K Ruschman J Ware SM Genetic testing practices in infants with congenital heart disease Congenit Heart Dis 2013 1 1 23782710
  19. [19]Syrmou A Tzetis M Fryssira H Kosma K Oikonomakis V Giannikou K Makrythanasis P Kitsiou-Tzeli S Kanavakis E Array comparative genomic hybridization as a clinical diagnostic tool in syndromic and nonsyndromic congenital heart disease Pediatr Res 2013 73 6 772 776 10.1038/pr.2013.41 23481551 · DOI
  20. [20]Rasmussen SA Olney RS Holmes LB Lin AE Keppler-Noreuil KM Moore CA Guidelines for case classification for the national birth defects prevention study Birth Defects Res Part A Clin Mol Teratol 2003 67 3 193 201 10.1002/bdra.10012 12797461 · DOI
  21. [21]Cooper GM Coe BP Girirajan S Rosenfeld JA Vu TH Baker C Williams C Stalker H Hamid R Hannig V Abdel-Hamid H Bader P McCracken E Niyazov D Leppig K Thiese H Hummel M Alexander N Gorski J Kussmann J Shashi V Johnson K Rehder C Ballif BC Shaffer LG Eichler EE A copy number variation morbidity map of developmental delay Nat Genet 2011 43 9 838 846 10.1038/ng.909 21841781 PMC3171215 · DOI · Paper page
  22. [22]Repnikova EA Rosenfeld JA Bailes A Weber C Erdman L McKinney A Ramsey S Hashimoto S Lamb Thrush D Astbury C Reshmi SC Shaffer LG Gastier-Foster JM Pyatt RE Characterization of copy number variation in genomic regions containing STR loci using array comparative genomic hybridization Forensic Sci Int 2013 7 5 475 481 10.1016/j.fsigen.2013.05.008 23948316 · DOI
  23. [23]Miller DT Shen Y Wu B-L Oligonucleotide microarrays for clinical diagnosis of copy number variation and zygosity status Curr Protoc Hum Genet 2012 22786613
  24. [24]Kearney HM Thorland EC Brown KK Quintero-Rivera F South ST American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants Gen Med 2011 13 7 680 685 10.1097/GIM.0b013e3182217a3a 21681106 · DOI · Paper page
  25. [25]Xu W Ahmad A Dagenais S Iyer RK Innis JW Chromosome 4q deletion syndrome: narrowing the cardiovascular critical region to 4q32.2-q34.3 Am J Med Genet A 2012 158A 3 635 640 10.1002/ajmg.a.34425 22302627 · DOI
  26. [26]Shen Y Dies KA Holm IA Bridgemohan C Sobeih MM Caronna EB Miller KJ Frazier JA Silverstein I Picker J Weissman L Raffalli P Jeste S Demmer LA Peters HK Brewster SJ Kowalczyk SJ Rosen-Sheidley B McGowan C Duda AW 3rd Lincoln SA Lowe KR Schonwald A Robbins M Hisama F Wolff R Becker R Nasir R Urion DK Milunsky JM Clinical genetic testing for patients with autism spectrum disorders Pediatrics 2010 125 4 e727 e735 10.1542/peds.2009-1684 20231187 PMC4247857 · DOI · Paper page
  27. [27]Sagoo GS Butterworth AS Sanderson S Shaw-Smith C Higgins JPT Burton H Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects Gen Med 2009 11 3 139 146 10.1097/GIM.0b013e318194ee8f 19367186 · DOI
  28. [28]Rossi MR DiMaio MS Xiang B Lu K Kaymakcalan H Seashore M Mahoney MJ Li P Clinical and genomic characterization of distal duplications and deletions of chromosome 4q: Study of two cases and review of the literature Am J Med Genet A 2009 149A 12 2788 2794 10.1002/ajmg.a.33088 19921640 PMC2788106 · DOI
  29. [29]Maurin ML Labrune P Brisset S Le Lorc'h M Pineau D Castel C Romana S Tachdjian G Molecular cytogenetic characterization of a 4p15.1-pter duplication and a 4q35.1-qter deletion in a recombinant of chromosome 4 pericentric inversion Am J Med Genet A 2009 149A 2 226 231 10.1002/ajmg.a.32603 19161154 · DOI
  30. [30]Strehle E-M Yu L Rosenfeld JA Donkervoort S Zhou Y Chen T-J Martinez JE Fan Y-S Barbouth D Zhu H Vaglio A Smith R Stevens CA Curry CJ Ladda RL Fan ZJ Fox JE Martin JA Abdel-Hamid HZ McCracken EA McGillivray BC Masser-Frye D Huang T Genotype-phenotype analysis of 4q deletion syndrome: Proposal of a critical region Am J Med Genet A 2012 158A 9 2139 2151 10.1002/ajmg.a.35502 22847869 · DOI
  31. [31]Pashmforoush M Pomiès P Peterson KL Kubalak S Ross J Jr Hefti A Aebi U Beckerle MC Chien KR Adult mice deficient in actininassociated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathy Nat Med 2001 7 5 591 597 10.1038/87920 11329061 · DOI
  32. [32]Pomies P Pashmforoush M Vegezzi C Chien KR Auffray C Beckerle MC The Cytoskeleton-associated PDZ-LIM Protein, ALP, Acts on Serum Response Factor Activity to Regulate Muscle Differentiation Mol Biol Cell 2007 18 5 1723 1733 10.1091/mbc.E06-09-0815 17332502 PMC1855033 · DOI
  33. [33]Strauss KA DuBiner L Simon M Zaragoza M Sengupta PP Li P Narula N Dreike S Platt J Procaccio V Ortiz-González XR Puffenberger EG Kelley RI Morton DH Narula J Wallace DC Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup Proc Natl Acad Sci 2013 110 9 3453 3458 10.1073/pnas.1300690110 23401503 PMC3587196 · DOI
  34. [34]Burnside RD Pasion R Mikhail FM Carroll AJ Robin NH Youngs EL Gadi IK Keitges E Jaswaney VL Papenhausen PR Potluri VR Risheg H Rush B Smith JL Schwartz S Tepperberg JH Butler MG Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay Hum Genet 2011 130 4 517 528 10.1007/s00439-011-0970-4 21359847 PMC6814187 · DOI · Paper page
  35. [35]Stefansson H Rujescu D Cichon S Pietiläinen OPH Ingason A Steinberg S Fossdal R Sigurdsson E Sigmundsson T Buizer-Voskamp JE Hansen T Jakobsen KD Muglia P Francks C Matthews PM Gylfason A Halldorsson BV Gudbjartsson D Thorgeirsson TE Sigurdsson A Jonasdottir A Jonasdottir A Bjornsson A Mattiasdottir S Blondal T Haraldsson M Magnusdottir BB Giegling I Möller HJ Hartmann A Large recurrent microdeletions associated with schizophrenia Nature 2008 455 7210 232 236 10.1038/nature07229 18668039 PMC2687075 · DOI · Paper page
  36. [36]Vassos E Collier DA Holden S Patch C Rujescu D St Clair D Lewis CM Penetrance for copy number variants associated with schizophrenia Hum Mol Genet 2010 19 17 3477 3481 10.1093/hmg/ddq259 20587603 · DOI · Paper page
  37. [37]Antonacci F Kidd JM Marques-Bonet T Teague B Ventura M Girirajan S Alkan C Campbell CD Vives L Malig M Rosenfeld JA Ballif BC Shaffer LG Graves TA Wilson RK Schwartz DC Eichler EE A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk Nat Genet 2010 42 9 745 750 10.1038/ng.643 20729854 PMC2930074 · DOI
  38. [39]El-Maarri O Abdul-Sater Z Yehya A Beresian J Salem E Kamar A Baydoun S Shibbani K Soubra A Bitar F Nemer G Two Heterozygous Mutations in NFATC1 in a Patient with Tricuspid Atresia PLoS One 2012 7 11 e49532 10.1371/journal.pone.0049532 23226213 PMC3511479 · DOI
  39. [40]Zhao W Niu G Shen B Zheng Y Gong F Wang X Lee J Mulvihill JJ Chen X Li S High-resolution analysis of copy number variants in adults with simple-to-moderate congenital heart disease Am J Med Genet A 2013 161A 12 3087 3094 10.1002/ajmg.a.36177 24115576 · DOI

Cited by

Sorted by citations

Authors
Geng, J., Picker, J., Zheng, Z., Zhang, X., Wang, J., Hisama, F., Brown, D. W., Mullen, M. P., Harris, D., Stoler, J., Seman, A., Miller, D. T., Fu, Q., Roberts, A. E., & Shen, Y.
Affiliations
  • Boston Children's Hospital (US)
  • Shanghai Jiao Tong University (CN)
Corresponding author
  • Fu, Qihua
  • Roberts, Amy E
  • Shen, Yiping
ORCID
Venue
BMC Genomics
Publisher
Springer Science and Business Media LLC
Published
2014-12
Volume
15
Issue
1
Pages
1127-1127
ISSN
1471-2164 (ISSN-L)
DOI
10.1186/1471-2164-15-1127
PMC
PMC4378009
OpenAlex
W2140643766
Cited by
93
References
1
Citations by year
2026: 6 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 10 · 2021: 15 · 2020: 6 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 15 · 2015: 1
FWCI
5.25
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Genomics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • National Natural Science Foundation of China
  • Science and Technology Commission of Shanghai Municipality
  • Shanghai Municipal Health Bureau
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
congenital heart disease, copy number variation, diagnostic yield, isolated congenital heart defects, candidate gene identification, 15q11.2
MeSH terms
Adolescent, Child, Child, Preschool, Chromosome Aberrations, Chromosome Mapping, Female, Gene Frequency, Heart Defects, Congenital, Humans, Infant, Male, Phenotype, Quantitative Trait Loci, Comparative Genomic Hybridization, Genetic Association Studies, DNA Copy Number Variations

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