PDF herunterladen
CC BY 4.0 · Glob Med Genet 2024; 11(01): 123-131
DOI: 10.1055/s-0044-1785227
Original Article

Patterns of Cytogenomic Findings from a Case Series of Recurrent Pregnancy Loss Provide Insight into the Extent of Genetic Defects Causing Miscarriages

Autumn DiAdamo
1   Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
,
Hongyan Chai
1   Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
,
Mei Ling Chong
1   Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
,
Guilin Wang
1   Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
2   Yale Center for Genome Analysis, New Haven, Connecticut, United States
,
Jiadi Wen
1   Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
,
Yong-Hui Jiang
1   Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
3   Yale Center for Genomic Health, Yale University School of Medicine, New Haven, Connecticut, United States
,
Peining Li 
1   Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
3   Yale Center for Genomic Health, Yale University School of Medicine, New Haven, Connecticut, United States
› Institutsangaben Funding This study was partly supported by NIH grant R01 HD105267-01 to Y.-H. J.
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints

Abstract

Background A retrospective study was performed to evaluate the patterns of cytogenomic findings detected from a case series of products of conception (POC) in recurrent pregnancy loss (RPL) over a 16-year period from 2007 to 2023.

Results This case series of RPL was divided into a single analysis (SA) group of 266 women and a consecutive analysis (CA) group of 225 women with two to three miscarriages analyzed. Of the 269 POC from the SA group and the 469 POC from the CA group, a spectrum of cytogenomic abnormalities of simple aneuploidies, compound aneuploidies, polyploidies, and structural rearrangements/pathogenic copy number variants (pCNVs) were detected in 109 (41%) and 160 cases (34%), five (2%) and 11 cases (2%), 35 (13%) and 36 cases (8%), and 10 (4%) and 19 cases (4%), respectively. Patterns with recurrent normal karyotypes, alternating normal and abnormal karyotypes, and recurrent abnormal karyotypes were detected in 74 (33%), 71 (32%), and 80 (35%) of consecutive miscarriages, respectively. Repeat aneuploidies of monosomy X and trisomy 16, triploidy, and tetraploidy were detected in nine women.

Conclusions A comparable spectrum of cytogenomic abnormalities was noted in the SA and CA groups of RPL. A skewed likelihood of 2/3 for recurrent normal and abnormal karyotypes and 1/3 for alternating normal and abnormal karyotypes in consecutive miscarriages was observed. Routine cytogenetic analysis should be performed for consecutive miscarriages. Further genomic sequencing to search for detrimental and embryonic lethal variants causing miscarriages and pathogenic variants inducing aneuploidies and polyploidies should be considered for RPL with recurrent normal and abnormal karyotypes.

Keywords

recurrent pregnancy loss - products of conception - chromosomal abnormalities - pathogenic copy number variants

Ethics Approval and Informed Consent Statement

This project was categorized as a chart review retrospective case study and deemed exempt from Institutional Review Board (IRB) approval and granted waiver of consent based on the policy of the Yale University IRB.


Data Availability Statement

Data and materials are available from the corresponding author upon request.


Authors' Contribution

P.L. organized this retrospective study and wrote the manuscript. A. D. A. compiled cases from the laboratory database. H.C., M.C., and G.W. performed CMA on POC specimens and reviewed cytogenomic results. J.W. and Y.-H.J. provided scientific insight and reviewed the manuscript.




Publikationsverlauf

Artikel online veröffentlicht:
29. März 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Warburton D, Fraser FC. Spontaneous abortion risks in man: data from reproductive histories collected in a medical genetics unit. Am J Hum Genet 1964; 16 (01) 1-25
    PubMedGoogle Scholar
  • 2 Tise CG, Byers HM. Genetics of recurrent pregnancy loss: a review. Curr Opin Obstet Gynecol 2021; 33 (02) 106-111
    CrossrefPubMedGoogle Scholar
  • 3 Sankaranarayanan K. The role of non-disjunction in aneuploidy in man. An overview. Mutat Res 1979; 61 (01) 1-28
    CrossrefPubMedGoogle Scholar
  • 4 van den Berg MM, van Maarle MC, van Wely M, Goddijn M. Genetics of early miscarriage. Biochim Biophys Acta 2012; 1822 (12) 1951-1959
    CrossrefPubMedGoogle Scholar
  • 5 Zhou Q, Wu S-Y, Amato K, DiAdamo A, Li P. Spectrum of cytogenomic abnormalities revealed by array comparative genomic hybridization in products of conception culture failure and normal karyotype samples. J Genet Genomics 2016; 43 (03) 121-131
    CrossrefPubMedGoogle Scholar
  • 6 Schaeffer AJ, Chung J, Heretis K, Wong A, Ledbetter DH, Lese Martin C. Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submicroscopic imbalances in spontaneous miscarriages. Am J Hum Genet 2004; 74 (06) 1168-1174
    CrossrefPubMedGoogle Scholar
  • 7 Shimokawa O, Harada N, Miyake N. et al. Array comparative genomic hybridization analysis in first-trimester spontaneous abortions with ‘normal’ karyotypes. Am J Med Genet A 2006; 140 (18) 1931-1935
    CrossrefPubMedGoogle Scholar
  • 8 Xiang B, Li A, Valentin D, Nowak NJ, Zhao H, Li P. Analytical and clinical validity of whole-genome oligonucleotide array comparative genomic hybridization for pediatric patients with mental retardation and developmental delay. Am J Med Genet A 2008; 146A (15) 1942-1954
    CrossrefPubMedGoogle Scholar
  • 9 Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98 (05) 1103-1111
    CrossrefPubMedGoogle Scholar
  • 10 Bender Atik R, Christiansen OB, Elson J. et al; ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018 (02) hoy004
    CrossrefPubMedGoogle Scholar
  • 11 Nikitina TV, Sazhenova EA, Zhigalina DI, Tolmacheva EN, Sukhanova NN, Lebedev IN. Karyotype evaluation of repeated abortions in primary and secondary recurrent pregnancy loss. J Assist Reprod Genet 2020; 37 (03) 517-525
    CrossrefPubMedGoogle Scholar
  • 12 Yatsenko SA, Quesada-Candela C, Saller DN. et al. Cytogenetic signatures of recurrent pregnancy losses. Prenat Diagn 2021; 41 (01) 70-78
    CrossrefPubMedGoogle Scholar
  • 13 van Dijk MM, Kolte AM, Limpens J. et al. Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis. Hum Reprod Update 2020; 26 (03) 356-367
    CrossrefPubMedGoogle Scholar
  • 14 Lei D, Zhang XY, Zheng PS. Recurrent pregnancy loss: fewer chromosomal abnormalities in products of conception? A meta-analysis. J Assist Reprod Genet 2022; 39 (03) 559-572
    CrossrefPubMedGoogle Scholar
  • 15 Xiang B, Li P, Hemingway SS, Qumsiyeh M. CytoAccess, a relational laboratory information management system for a clinical cytogenetics laboratory. J Assoc Genet Technol 2006; 32 (04) 168-170
    PubMedGoogle Scholar
  • 16 Chai H, Grommisch B, DiAdamo A, Wen J, Hui P, Li P. Inverted duplication, triplication and quintuplication through sequential breakage-fusion-bridge events induced by a terminal deletion at 5p in a case of spontaneous abortion. Mol Genet Genomic Med 2019; 7 (10) e00965
    CrossrefPubMedGoogle Scholar
  • 17 Wen J, Grommisch B, DiAdamo A. et al. Detection of cytogenomic abnormalities by OncoScan microarray assay for products of conception from formalin-fixed paraffin-embedded and fresh fetal tissues. Mol Cytogenet 2021; 14 (01) 21
    CrossrefPubMedGoogle Scholar
  • 18 Peng G, Zhou Q, Chai H. et al. Estimation on risk of spontaneous abortions by genomic disorders from a meta-analysis of microarray results on large case series of pregnancy losses. Mol Genet Genomic Med 2023; 11 (08) e2181
    CrossrefPubMedGoogle Scholar
  • 19 Zhao C, Chai H, Zhou Q. et al. Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss. Genet Med 2021; 23 (03) 435-442
    CrossrefPubMedGoogle Scholar
  • 20 Kline J, Vardarajan B, Abhyankar A. et al. Embryonic lethal genetic variants and chromosomally normal pregnancy loss. Fertil Steril 2021; 116 (05) 1351-1358
    CrossrefPubMedGoogle Scholar
  • 21 Buonaiuto S, Biase ID, Aleotti V. et al. Prioritization of putatively detrimental variants in euploid miscarriages. Sci Rep 2022; 12 (01) 1997
    CrossrefPubMedGoogle Scholar
  • 22 Xiang H, Wang C, Pan H. et al. Exome-sequencing identifies novel genes associated with recurrent pregnancy loss in a Chinese cohort. Front Genet 2021; 12: 746082
    CrossrefPubMedGoogle Scholar
  • 23 Wang X, Shi W, Zhao S. et al. Whole exome sequencing in unexplained recurrent miscarriage families identified novel pathogenic genetic causes of euploid miscarriage. Hum Reprod 2023; 38 (05) 1003-1018
    CrossrefPubMedGoogle Scholar
  • 24 Berkay EG, Şoroğlu CV, Kalaycı T, Uyguner ZO, Akçapınar GB, Başaran S. A new enrichment approach for candidate gene detection in unexplained recurrent pregnancy loss and implantation failure. Mol Genet Genomics 2023; 298 (01) 253-272
    CrossrefPubMedGoogle Scholar
  • 25 Burada F, Sosoi S, Iliescu D, Ioana M, Cernea D, Tudorache S. A rare occurrence of three consecutive autosomal trisomic pregnancies in a couple without offspring. Clin Exp Obstet Gynecol 2016; 43 (02) 287-290
    CrossrefPubMedGoogle Scholar
  • 26 Filges I, Manokhina I, Peñaherrera MS. et al. Recurrent triploidy due to a failure to complete maternal meiosis II: whole-exome sequencing reveals candidate variants. Mol Hum Reprod 2015; 21 (04) 339-346
    CrossrefPubMedGoogle Scholar
  • 27 Cook S, Wilcox K, Grommisch B. et al. Prenatal diagnosis of Xq26.1-q26.3 duplication in two fetuses of a woman with gonadal mosaicism. N Am J Med Sci 2014; 7 (04) 176-179
    Google Scholar
  • 28 Alibakhshi R, Nejati P, Hamani S, Mir-Ahadi N, Jalilian N. Cytogenetic analysis of 570 couples with recurrent pregnancy loss: reporting 11 years of experience. J Hum Reprod Sci 2020; 13 (03) 216-220
    CrossrefPubMedGoogle Scholar
  • 29 Elhady GM, Kholeif S, Nazmy N. Chromosomal aberrations in 224 couples with recurrent pregnancy loss. J Hum Reprod Sci 2020; 13 (04) 340-348
    CrossrefPubMedGoogle Scholar
  • 30 Martínez-Glez V, Tenorio J, Nevado J. et al. A six-attribute classification of genetic mosaicism. Genet Med 2020; 22 (11) 1743-1757
    CrossrefPubMedGoogle Scholar
  • 31 Wei Y, Xu F, Li P. Technology-driven and evidence-based genomic analysis for integrated pediatric and prenatal genetics evaluation. J Genet Genomics 2013; 40 (01) 1-14
    CrossrefPubMedGoogle Scholar