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Clinical application of SNP array analysis in fetuses with ventricular septal defects and normal karyotypes

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

The present study aims to evaluate the utility of high-resolution single-nucleotide polymorphism (SNP) arrays in fetuses with ventricular septal defects (VSDs) with or without other structural anomalies but with normal karyotypes and to investigate the outcomes of cases of prenatal VSDs via clinical follow-up.

Methods

We analyzed 144 fetuses with VSDs and normal karyotypes using Affymetrix CytoScan HD arrays and the analyses were carried out a year after birth.

Results

Clinically significant CNVs were detected in 12 fetuses (8.3%). The most common pathogenic CNV was a 22q11.2 deletion with a detection rate of 2.8% (4/144). Well-known microdeletion or microduplication syndromes, including Smith–Magenis, Miller–Dieker, 9q subtelomeric deletion, 1p36 microdeletion, 1q21.1 microduplication, and terminal 4q deletion syndrome, were identified in six cases. Three regions of chromosomal imbalance were also identified: microduplication at 12q24.32q24.33, microdeletion at 16p13.13p13.12 and microdeletion at Xp21.1. The genes TBX1, SKI, GJA5, EHMT1, NOTCH1 were identified as established genes and LZTR1, PRDM26, YWHAE, FAT1, AKAP10, ERCC4, and ULK1 were identified as potential candidate genes of fetal VSDs. There was no significant difference in pathogenic CNVs between isolated VSDs and VSDs with additional structural abnormalities. Ninety-five (74.8%) pregnant women with fetuses with benign CNVs chose to continue the pregnancy and had a favorable prognosis, while nine (75%) pregnant women with fetuses with pathogenic CNVs chose to terminate the pregnancy.

Conclusions

High-resolution SNP arrays are valuable tools for identifying submicroscopic chromosomal abnormalities in the prenatal diagnosis of VSDs. An excellent outcome can be expected for VSD fetuses that are negative for chromosomal anomalies and other severe anatomic abnormalities.

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References

  1. Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39:1890–1900

    Article  PubMed  Google Scholar 

  2. Paladini D, Volpe P (2007) Ultrasound of congenital fetal anomalies. Informa Healthcare, London

    Book  Google Scholar 

  3. Mosimann B, Zidere V, Simpson JM, Allan LD (2014) Outcome and requirement for surgical repair following prenatal diagnosis of ventricular septal defect. Ultrasound Obstet Gynecol 44:76–81

    Article  CAS  PubMed  Google Scholar 

  4. Axt-Fliedner R, Schwarze A, Smrcek J, Germer U, Krapp M, Gembruch U (2006) Isolated ventricular septal defects detected by color Doppler imaging: evolution during fetal and first year of postnatal life. Ultrasound Obstet Gynecol 27:266–273

    Article  CAS  PubMed  Google Scholar 

  5. Paladini D, Russo M, Teodoro A, Pacileo G, Capozzi G, Martinelli P, Nappi C, Calabro R (2002) Prenatal diagnosis of congenital heart disease in the Naples area during the years 1994–1999—the experience of a joint fetal-pediatric cardiology unit. Prenat Diagn 22:545–552

    Article  PubMed  Google Scholar 

  6. Paladini D, Palmieri S, Lamberti A, Teodoro A, Martinelli P, Nappi C (2000) Characterization and natural history of ventricular septal defects in the fetus. Ultrasound Obstet Gynecol 16:118–122

    Article  CAS  PubMed  Google Scholar 

  7. Goldmuntz E (2005) DiGeorge syndrome: new insights. Clin Perinatol 32:963–978

    Article  PubMed  Google Scholar 

  8. Newman TB (1985) Etiology of ventricular septal defects: an epidemiologic approach. Pediatrics 76:741–749

    CAS  PubMed  Google Scholar 

  9. Thienpont B, Mertens L, de Ravel T, Eyskens B, Boshoff D, Maas N, Fryns JP, Gewillig M, Vermeesch JR, Devriendt K (2007) Submicroscopic chromosomal imbalances detected by array-CGH are a frequent cause of congenital heart defects in selected patients. Eur Heart J 28:2778–2784

    Article  CAS  PubMed  Google Scholar 

  10. Richards AA, Santos LJ, Nichols HA, Crider BP, Elder FF, Hauser NS, Zinn AR, Garg V (2008) Cryptic chromosomal abnormalities identified in children with congenital heart disease. Pediatr Res 64:358–363

    Article  PubMed  Google Scholar 

  11. Southard AE, Edelmann LJ, Gelb BD (2012) Role of copy number variants in structural birth defects. Pediatrics 129:755–763

    Article  PubMed  Google Scholar 

  12. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST (2011) American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 13:680–685

    Article  PubMed  Google Scholar 

  13. South ST, Lee C, Lamb AN, Higgins AW, Kearney HM (2013) ACMG standards and guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med 15:901–909

    Article  CAS  PubMed  Google Scholar 

  14. Committee on Genetics and the Society for Maternal-Fetal Medicine (2016) Committee Opinion No. 682: microarrays and next-generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstet Gynecol 128:e262–e268

    Article  Google Scholar 

  15. Shaffer LG, Rosenfeld JA, Dabell MP, Coppinger J, Bandholz AM, Ellison JW, Ravnan JB, Torchia BS, Ballif BC, Fisher AJ (2012) Detection rates of clinically significant genomic alterations by microarray analysis for specific anomalies detected by ultrasound. Prenat Diagn 32:986–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. An Y, Duan W, Huang G, Chen X, Li L, Nie C, Hou J, Gui Y, Wu Y, Zhang F, Shen Y, Wu B, Wang H (2016) Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population. BMC Med Genom 9:2

    Article  Google Scholar 

  17. Du L, Xie HN, Huang LH, Xie YJ, Wu LH (2016) Prenatal diagnosis of submicroscopic chromosomal aberrations in fetuses with ventricular septal defects by chromosomal microarray-based analysis. Prenat Diagn 36:1178–1184

    Article  CAS  PubMed  Google Scholar 

  18. Jansen FA, Blumenfeld YJ, Fisher A, Cobben JM, Odibo AO, Borrell A, Haak MC (2015) Array comparative genomic hybridization and fetal congenital heart defects: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 45:27–35

    Article  CAS  PubMed  Google Scholar 

  19. Liao C, Li R, Fu F, Xie G, Zhang Y, Pan M, Li J, Li D (2014) Prenatal diagnosis of congenital heart defect by genome-wide high-resolution SNP array. Prenat Diagn 34:858–863

    Article  CAS  PubMed  Google Scholar 

  20. Yan Y, Wu Q, Zhang L, Wang X, Dan S, Deng D, Sun L, Yao L, Ma Y, Wang L (2014) Detection of submicroscopic chromosomal aberrations by array-based comparative genomic hybridization in fetuses with congenital heart disease. Ultrasound Obstet Gynecol 43:404–412

    Article  CAS  PubMed  Google Scholar 

  21. 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 (2012) Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls. Hum Mol Genet 21:1513–1520

    Article  CAS  PubMed  Google Scholar 

  22. Gu H, Smith FC, Taffet SM, Delmar M (2003) High incidence of cardiac malformations in connexin40-deficient mice. Circ Res 93:201–206

    Article  CAS  PubMed  Google Scholar 

  23. Ewart JL, Cohen MF, Meyer RA, Huang GY, Wessels A, Gourdie RG, Chin AJ, Park SM, Lazatin BO, Villabon S, Lo CW (1997) Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene. Development 124:1281–1292

    CAS  PubMed  Google Scholar 

  24. Kirchhoff S, Kim JS, Hagendorff A, Thonnissen E, Kruger O, Lamers WH, Willecke K (2000) Abnormal cardiac conduction and morphogenesis in connexin40 and connexin43 double-deficient mice. Circ Res 87:399–405

    Article  CAS  PubMed  Google Scholar 

  25. Vona B, Nanda I, Neuner C, Schroder J, Kalscheuer VM, Shehata-Dieler W, Haaf T (2014) Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature. BMC Med Genet 15:72

    Article  PubMed  PubMed Central  Google Scholar 

  26. Youngs EL, Henkhaus RS, Hellings JA, Butler MG (2012) 12-year-old boy with a 4q35.2 microdeletion and involvement of MTNR1A, FAT1, and F11 genes. Clin Dysmorphol 21:93–96

    Article  PubMed  PubMed Central  Google Scholar 

  27. Abou JR, Becker T, Georgi A, Feulner T, Schumacher J, Stromaier J, Schirmbeck F, Schulze TG, Propping P, Rietschel M, Nothen MM, Cichon S (2008) Genetic variation of the FAT gene at 4q35 is associated with bipolar affective disorder. Mol Psychiatry 13:277–284

    Article  Google Scholar 

  28. Roberts JL, Hovanes K, Dasouki M, Manzardo AM, Butler MG (2014) Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services. Gene 535:70–78

    Article  CAS  PubMed  Google Scholar 

  29. Bruder-Nascimento T, Chinnasamy P, Riascos-Bernal DF, Cau SB, Callera GE, Touyz RM, Tostes RC, Sibinga NE (2014) Angiotensin II induces Fat1 expression/activation and vascular smooth muscle cell migration via Nox1-dependent reactive oxygen species generation. J Mol Cell Cardiol 66:18–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stewart DR, Kleefstra T (2007) The chromosome 9q subtelomere deletion syndrome. Am J Med Genet C Semin Med Genet 145C:383–392

    Article  CAS  PubMed  Google Scholar 

  31. Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, van Dooren M, Willemsen MH, Pfundt R, Turner A, Wilson M, McGaughran J, Rauch A, Zenker M, Adam MP, Innes M, Davies C, Lopez AG, Casalone R, Weber A, Brueton LA, Navarro AD, Bralo MP, Venselaar H, Stegmann SP, Yntema HG, van Bokhoven H, Brunner HG (2009) Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 46:598–606

    Article  CAS  PubMed  Google Scholar 

  32. Kleefstra T, Smidt M, Banning MJ, Oudakker AR, Van Esch H, de Brouwer AP, Nillesen W, Sistermans EA, Hamel BC, de Bruijn D, Fryns JP, Yntema HG, Brunner HG, de Vries BB, van Bokhoven H (2005) Disruption of the gene euchromatin histone methyl transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. J Med Genet 42:299–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Genevieve D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H (2006) Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 79:370–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D, Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14:1343–1352

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437:270–274

    Article  CAS  PubMed  Google Scholar 

  36. Kuroyanagi H, Yan J, Seki N, Yamanouchi Y, Suzuki Y, Takano T, Muramatsu M, Shirasawa T (1998) Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment. Genomics 51:76–85

    Article  CAS  PubMed  Google Scholar 

  37. Costain G, Lionel AC, Ogura L, Marshall CR, Scherer SW, Silversides CK, Bassett AS (2016) Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries. Int J Cardiol 204:115–121

    Article  PubMed  Google Scholar 

  38. Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, Trujillo JP, Minguillon J, Ramirez MJ, Pujol R, Casado JA, Banos R, Rio P, Knies K, Zuniga S, Benitez J, Bueren JA, Jaspers NG, Scharer OD, de Winter JP, Schindler D, Surralles J (2013) Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet 92:800–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, Fawcett H, Wing JF, Lewin SO, Carr L, Li TS, Yoshiura K, Utani A, Hirano A, Yamashita S, Greenblatt D, Nardo T, Stefanini M, McGibbon D, Sarkany R, Fassihi H, Takahashi Y, Nagayama Y, Mitsutake N, Lehmann AR, Ogi T (2013) Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am J Hum Genet 92:807–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tuffery-Giraud S, Beroud C, Leturcq F, Yaou RB, Hamroun D, Michel-Calemard L, Moizard MP, Bernard R, Cossee M, Boisseau P, Blayau M, Creveaux I, Guiochon-Mantel A, de Martinville B, Philippe C, Monnier N, Bieth E, Khau VKP, Desmet FO, Humbertclaude V, Kaplan JC, Chelly J, Claustres M (2009) Genotype-phenotype analysis in 2405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase. Hum Mutat 30:934–945

    Article  CAS  PubMed  Google Scholar 

  41. Gomez O, Martinez JM, Olivella A, Bennasar M, Crispi F, Masoller N, Bartrons J, Puerto B, Gratacos E (2014) Isolated ventricular septal defects in the era of advanced fetal echocardiography: risk of chromosomal anomalies and spontaneous closure rate from diagnosis to age of 1 year. Ultrasound Obstet Gynecol 43:65–71

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the patients for participating in this study.

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Author notes

  1. Fang Fu and Qiong Deng contributed equally to this work.

Authors and Affiliations

  1. Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, No. 9 of Jinsui Road, Guangzhou, 510623, Guangdong, China

    Fang Fu, Qiong Deng, Ting-ying Lei, Ru Li, Xiang-yi Jing, Xin Yang & Can Liao

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  1. Fang Fu
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  2. Qiong Deng
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  4. Ru Li
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  7. Can Liao
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Contributions

FF: project development, data collection, manuscript writing. QD: project development, data collection, manuscript writing. TL: data collection, manuscript writing. RL: methodology, data collection. XJ: methodology, data collection. XY: data collection. CL: conceptualization, project administration, funding acquisition

Corresponding author

Correspondence to Can Liao.

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Funding

This study was supported by funding from the National Natural Science Foundation of China (81671474); the National Natural Science Foundation of China (81501267); the general program of the Science and Technology Innovation Committee in Guangzhou (201604020012); the key program of the Science and Technology Department in Guangdong province (2014B020213001); the key program of the Science and Technology Bureau in Guangzhou (201400000004-4); and the key program of the Science and Technology Department in Guangdong Province (2013B022000005).

Conflict of interest

The authors declare that they have no conflict or interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Fu, F., Deng, Q., Lei, Ty. et al. Clinical application of SNP array analysis in fetuses with ventricular septal defects and normal karyotypes. Arch Gynecol Obstet 296, 929–940 (2017). https://doi.org/10.1007/s00404-017-4518-2

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  • DOI: https://doi.org/10.1007/s00404-017-4518-2

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