Human Reproduction Archives
Human Reproduction Archives
SYSTEMATIC REVIEW Reproductive Health

Copy number variations as a risk factor for couples with idiopathic recurrent miscarriage: A systematic review

Sheila Janaina Sestari, Bruno Faulin Gamba, Francis Patrício França Ferreira, Roberta Machado de Oliveira Frota Curado, Eduardo Camelo de Castro, Nádia Aparecida Bérgamo, Lucilene Arilho Ribeiro-Bicudo

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Objective: It is well established that inherited chromosomal alterations such as copy number variations (CNVs) are associated to miscarriage. However, most studies focus on evaluating CNVs only in products of conception. The aim of this systematic review was to highlight the importance of investigating CNVs in couples with a history of recurrent miscarriage as well as their role in pregnancy, filling part of the gap between studies of recurrent miscarriage. Methods: A search in PubMed, Scientific Electronic Library Online (SCIELO), Latin American and Caribbean Literature in Health Sciences (LILACS), and Portal de CAPES/MEC databases for relevant published articles was conducted using the following controlled search terms: “copy number variation”, “cnv”, “miscarriage”, “recurrent miscarriage”, “spontaneous abortion”, “loss pregnancy”, “couple”, “microarray analysis”, “comparative genomic array”, and “array CGH”. The Boolean operators AND and OR were used. The search captured studies published up to October 2020. Results: A total of five studies were extracted for the present analysis. Sixteen CNVs involving the PDZD2, GOLPH3, TIMP2, CTNNA3, STS, EGFL6, STX6, CETN2, CTDSPL, GSTT1, HLA, MSR1, NIPA1, NIPA2, CYFIP1 and TUBGCP5 genes on ten different chromosomes were considered at potential risk for pregnancy maintenance. Conclusion: The findings of the present study affirm the importance of investigating the role of CNVs in couples with recurrent miscarriage and not just products of conception, in addition contributing to more accurate medical diagnoses.


copy number variations, recurrent miscarriage, chromosomal rearrangement, abortions, pregnancy maintenance


1. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368(9535):601-11.

2. Christiansen OB, Steffensen R, Nielsen HS, Varming K. Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecol Obstet Invest. 2008;66(4):257-67. PMid:18679035.

3. Alijotas-Reig J, Garrido-Gimenez C. Current concepts and new trends in the diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv. 2013;68(6):445-66. PMid:23942472.

4. van den Berg MMJ, van Maarle MC, van Wely M, Goddijn M. Genetics of early miscarriage. Biochim Biophys Acta. 2012;1822(12):1951-9. PMid:22796359.

5. Barini R, Couto E, Mota MM, Santos CTM, Leiber SR, Batista SC. Fatores associados ao aborto espontâneo recorrente. Rev BrasGinecol Obstet. 2000;22(4):217-23.

6. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril. 2000;73(2):300-4. PMid:10685533.

7. Sugiura-Ogasawara M, Ozaki Y, Suzumori N. Management of recurrent miscarriage. J Obstet Gynaecol Res. 2014;40(5):1174-9. PMid:24754846.

8. Royal College of Obstetricians & Gynaecologists. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage [Internet]. RCOG: London; 2011 [cited 2020 Nov 23]. (Green-Top Guideline; No. 17). Available from:

9. Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004. PMid:31486805.

10. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103-11. PMid:22835448.

11. Christiansen OB, editor. Recurrent pregnancy loss. Oxford: John Wiley & Sons; 2013.

12. Hassold TJ, Jacobs PA. Trisomy in man. Annu Rev Genet. 1984;18(1):69-97. PMid:6241455.

13. Kalousek DK, Langlois S, Barrett I, Yam I, Wilson DR, Howard-Peebles PN, et al. Uniparental disomy for chromosome 16 in humans. Am J Hum Genet. 1993;52(1):8-16. PMid:8434609.

14. Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, et al. Origins and functional impact of copy number variation in the human genome. Nature. 2010;464(7289):704-12. PMid:19812545.

15. McCarroll SA, Kuruvilla FG, Korn JM, Cawley S, Nemesh J, Wysoker A, et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008;40(10):1166-74. PMid:18776908.

16. Nagirnaja L, Palta P, Kasak L, Rull K, Christiansen OB, Nielsen HS, et al. Structural genomic variation as risk factor for idiopathic recurrent miscarriage. Hum Mutat. 2014;35(8):972-82. PMid:24827138.

17. Zhang Y-X, Zhang Y-P, Gu Y, Guan F-J, Li S-L, Xie J-S, et al. Genetic analysis of first-trimester miscarriages with a combination of cytogenetic karyotyping, microsatellite genotyping and arrayCGH. Clin Genet. 2009;75(2):133-40. PMid:19215247.

18. Feuk L, Carson AR, Scherer SW. Structural variation in the human genome. Nat Rev Genet. 2006;7(2):85-97. PMid:16418744.

19. Freeman JL, Perry GH, Feuk L, Redon R, McCarroll SA, Altshuler DM, et al. Copy number variation: new insights in genome diversity. Genome Res. 2006;16(8):949-61. PMid:16809666.

20. Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH, et al. Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genet. 2011;7(11):e1002334. PMid:22102821.

21. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, et al. Global variation in copy number in the human genome. Nature. 2006;444(7118):444-54. PMid:17122850.

22. Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science. 2007;315(5813):848-53. PMid:17289997.

23. Sato T, Migita O, Hata H, Okamoto A, Hata K. Analysis of chromosome microstructures in products of conception associated with recurrent miscarriage. Reprod Biomed Online. 2019;38(5):787-95. PMid:30926177.

24. Tekcan A, Elbistan M, Tural S, Çetinkaya MB. Effects of subtelomeric copy number variations in miscarriages. Gynecol Endocrinol. 2015;31(9):708-14. PMid:26291815.

25. Viaggi CD, Cavani S, Malacarne M, Floriddia F, Zerega G, Baldo C, et al. First-trimester euploid miscarriages analysed by array-CGH. J Appl Genet. 2013;54(3):353-9. PMid:23780398.

26. Wang H, Yuan D, Wang S, Luo L, Zhang Y, Ye J, et al. Cytogenetic and genetic investigation of miscarriage cases in Eastern China. J Matern Neonatal Med. 2020;33(20):3385-90. PMid:30741046.

27. Wang Y, Li Y, Chen Y, Zhou R, Sang Z, Meng L, et al. Systematic analysis of copy‐number variations associated with early pregnancy loss. Ultrasound Obstet Gynecol. 2020;55(1):96-104. PMid:31364215.

28. Wen J, Hanna CW, Martell S, Leung P, Lewis S, Robinson WP, et al. Functional consequences of copy number variants in miscarriage. Mol Cytogenet. 2015;8(1):6. PMid:25674159.

29. Lee C, Iafrate AJ, Brothman AR. Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet. 2007;39(7, Suppl):S48-54. PMid:17597782.

30. Kasak L, Rull K, Sõber S, Laan M. Copy number variation profile in the placental and parental genomes of recurrent pregnancy loss families. Sci Rep. 2016;2017(7):1-12. PMid:28345611.

31. Rajcan-Separovic E, Diego-Alvarez D, Robinson WP, Tyson C, Qiao Y, Harvard C, et al. Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss. Hum Reprod. 2010;25(11):2913-22. PMid:20847186.

32. van Dijk M, van Bezu J, van Abel D, Dunk C, Blankenstein MA, Oudejans CBM, et al. The STOX1 genotype associated with preeclampsia leads to a reduction of trophoblast invasion by α-T-catenin upregulation. Hum Mol Genet. 2010;19(13):2658-67. PMid:20400461.

33. Zhu Y, Lu Y, Zhang Q, Liu J-J, Li T-J, Yang J-R, et al. MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. Nucleic Acids Res. 2012;40(10):4615-25. PMid:22210897.

34. Seval Y, Akkoyunlu G, Demir R, Asar M. Distribution patterns of matrix metalloproteinase (MMP)-2 and -9 and their inhibitors (TIMP-1 and TIMP-2) in the human decidua during early pregnancy. Acta Histochem. 2004;106(5):353-62. PMid:15530550.

35. Okamoto T, Niu R, Yamada S, Osawa M. Reduced expression of tissue inhibitor of metalloproteinase (TIMP)-2 in gestational trophoblastic diseases. Mol Hum Reprod. 2002;8(4):392-8. PMid:11912288.

36. Anumba DO, El Gelany S, Elliott SL, Li TC. Circulating levels of matrix proteases and their inhibitors in pregnant women with and without a history of recurrent pregnancy loss. Reprod Biol Endocrinol. 2010;8(1):62. PMid:20565712.

37. Bowen JA, Hunt JS. The role of integrins in reproduction. Proc Soc Exp Biol Med. 2000;223(4):331-43. PMid:10721002.

38. Leon L, Bacallao K, Gabler F, Romero C, Valladares L, Vega M. Activities of steroid metabolic enzymes in secretory endometria from untreated women with Polycystic Ovary Syndrome. Steroids. 2008;73(1):88-95.

39. Yeung G, Mulero JJ, Berntsen RP, Loeb DB, Drmanac R, Ford JE. Cloning of a novel epidermal growth factor repeat containing gene egfl6: expressed in tumor and fetal tissues. Genomics. 1999;62(2):304-7. PMid:10610727.

40. Henrichsen CN, Chaignat E, Reymond A. Copy number variants, diseases and gene expression. Hum Mol Genet. 2009;18(R1):R1-8. PMid:19297395.

41. Henrichsen CN, Vinckenbosch N, Zöllner S, Chaignat E, Pradervand S, Schütz F, et al. Segmental copy number variation shapes tissue transcriptomes. Nat Genet. 2009;41(4):424-9. PMid:19270705.

42. Zhao L, Bracken MB, DeWan AT. Genome-wide association study of pre-eclampsia detects novel maternal single nucleotide polymorphisms and copy-number variants in subsets of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study cohort. Ann Hum Genet. 2013;77(4):277-87. PMid:23551011.

43. Tanwar PS, Kaneko-Tarui T, Zhang L, Teixeira JM. Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis. Hum Mol Genet. 2012;21(20):4394-405. PMid:22791749.

44. Vatin M, Burgio G, Renault G, Laissue P, Firlej V, Mondon F, et al. Refined mapping of a quantitative trait locus on chromosome 1 responsible for mouse embryonic death. PLoS One. 2012;7(8):e43356. PMid:22916247.

45. Roos S, Jansson N, Palmberg I, Säljö K, Powell TL, Jansson T. Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J Physiol. 2007;582(1):449-59.

46. Leconte M, Nicco C, Ngô C, Chéreau C, Chouzenoux S, Marut W, et al. The mTOR/AKT inhibitor temsirolimus prevents deep infiltrating endometriosis in mice. Am J Pathol. 2011;179(2):880-9. PMid:21718677.

47. Hirota Y, Cha J, Yoshie M, Daikoku T, Dey SK. Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice. Proc Natl Acad Sci USA. 2011;108(44):18073-8. PMid:22025690.

48. Adhikari D, Zheng W, Shen Y, Gorre N, Hämäläinen T, Cooney AJ, et al. Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet. 2010;19(3):397-410. PMid:19843540.

49. Karim S, Jamal HS, Rouzi A, Ardawi MSM, Schulten HJ, Mirza Z, et al. Genomic answers for recurrent spontaneous abortion in Saudi Arabia: an array comparative genomic hybridization approach. Reprod Biol. 2017;17(2):133-43. repbio.2017.03.003. PMid:28431992.

50. Nair RR, Khanna A, Singh K. Association of GSTT1 and GSTM1 polymorphisms with early pregnancy loss in an Indian population and a meta-analysis. Reprod Biomed Online. 2013;26(4):313-22. PMid:23433732.

51. Moldenhauer LM, Keenihan SN, Hayball JD, Robertson SA. GM-CSF is an essential regulator of t cell activation competence in uterine dendritic cells during early pregnancy in mice. J Immunol. 2010;185(11):7085-96. PMid:20974989.

52. Wu Y, Evers BM, Zhou BP. Small C-terminal domain phosphatase enhances snail activity through dephosphorylation. J Biol Chem. 2009;284(1):640-8. PMid:19004823.

53. Sapkota G, Knockaert M, Alarcón C, Montalvo E, Brivanlou AH, Massagué J. Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-β pathways. J Biol Chem. 2006;281(52):40412-9. PMid:17085434.

54. Krieg SA, Fan X, Hong Y, Sang QX, Giaccia A, Westphal LM, et al. Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss. Mol Hum Reprod. 2012;18(9):442-50. PMid:22505054.

55. Mallia JV, Das DK, Maitra A. Role of HLA in human pregnancy. Int J Hum Genet. 2012;12(1):33-6.

56. Faridi RM, Agrawal S. Killer immunoglobulin-like receptors (KIRs) and HLA-C allorecognition patterns implicative of dominant activation of natural killer cells contribute to recurrent miscarriages. Hum Reprod. 2011;26(2):491-7. v PMid:21159685.

57. Pinkel D, Albertson DG. Comparative genomic hybridization. Annu Rev Genomics Hum Genet. 2005;6(1):331-54. PMid:16124865.

58. Su M-T, Lin S-H, Chen Y-C, Kuo P-L. Gene-gene interactions and gene polymorphisms of VEGFA and EG-VEGF gene systems in recurrent pregnancy loss. J Assist Reprod Genet. 2014;31(6):699-705. PMid:24671265.

59. Rajcan-Separovic E, Qiao Y, Tyson C, Harvard C, Fawcett C, Kalousek D, et al. Genomic changes detected by array CGH in human embryos with developmental defects. Mol Hum Reprod. 2010;16(2):125-34. PMid:19778950.

60. Teng FYH, Wang Y, Tang BL. The syntaxins. Genome Biol. 2001;2(11):S3012. PMid:11737951.

61. Zhang Y, Shu L, Chen X. Syntaxin 6, a regulator of the protein trafficking machinery and a target of the p53 family, is required for cell adhesion and survival. J Biol Chem. 2008;283(45):30689-98. PMid:18779328.

62. Higginbotham H, Bielas S, Tanaka T, Gleeson JG. Transgenic mouse line with green-fluorescent protein-labeled centrin 2 allows visualization of the centrosome in living cells. Transgenic Res. 2004;13(2):155-64. PMid:15198203.

63. Gil Villa AM, Cardona-Maya WD, Cadavid Jaramillo ÁP. Muerte embrionaria temprana: ¿Tiene influencia el factor masculino? Arch Esp Urol. 2007;60(9):057-068. PMid:18077859.

64. Rawe VY, Terada Y, Nakamura S, Chillik C, Olmedo S, Chemes H. A pathology of the sperm centriole responsible for defective sperm aster formation, syngamy and cleavage. Hum Reprod. 2002;17(9):2344-9. PMid:12202423.

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