Clinical Significance of Monogenic Mutations in the Euploid Embryo Genome Associated with Miscarriage

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Background. Chromosomal abnormalities of the embryo are the most common cause of miscarriage. However, at least 100 thousand cases of repeated pregnancy losses occur annually in the world, in which cytogenetic methods determine the chromosome euploid set in the abortive material. One of the causes of miscarriage is probably the loss of function of certain genes. It is assumed that the detection of genetic factors determining the etiology of pregnancy loss can help to develop personalized methods of diagnosis and preconception care in cases where the classical approach with chromosomal analysis is insufficient.

Aims — to analyze the experience of genetic testing of euploid embryos and identify the most significant genetic variants in miscarriage.

Methods. A search was conducted for sources of scientific literature in the PubMed and RSCI (elibrary) databases. The search for full-text articles was carried out on the websites of journals and using the ResearchGate database. The review included articles published in peer-reviewed scientific publications in the period from 2013 to 2023.

Results. Studies conducted on animals and analysis of human embryos during miscarriage have revealed a list of genes which loss of function may be associated with embryolethality. Analyzing the data of the scientific literature, we concluded that a number of genes potentially related to miscarriage can lead to various diseases in the postnatal period.

Conclusions. Scientific research aimed at finding monogenic causes of miscarriage is of great scientific and practical importance, since it can contribute to improving the algorithm of examination and pre-conception preparation of married couples with a history of pregnancy loss.

Full Text

Restricted Access

About the authors

Elena V. Kudryavtseva

Ural State Medical University

Author for correspondence.
Email: elenavladpopova@yandex.ru
ORCID iD: 0000-0003-2797-1926
SPIN-code: 7232-3743

MD, PhD, Assistant Professor

Russian Federation, Yekaterinburg

Olga P. Kovtun

Ural State Medical University

Email: usma@usma.ru
ORCID iD: 0000-0002-5250-7351
SPIN-code: 9919-9048

MD, PhD, Professor, Academician of the RAS

Russian Federation, Yekaterinburg

Vladislav V. Kovalev

Ural State Medical University

Email: vvkovakev55@gmail.com
ORCID iD: 0000-0001-8640-8418
SPIN-code: 2061-0704

MD, PhD, Professor

Russian Federation, Yekaterinburg

References

  1. Feichtinger M, Wallner E, Hartmann B, et al. Transcervical embryoscopic and cytogenetic findings reveal distinctive differences in primary and secondary recurrent pregnancy loss. Fertil Steril. 2017;107(1):144–149. doi: https://doi.org/10.1016/j.fertnstert.2016.09.037
  2. Peng L, Yang W, Deng X, et al. Research progress on ANXA5 in recurrent pregnancy loss. J Reprod Immunol. 2022;153:103679. doi: https://doi.org/10.1016/j.jri.2022.103679
  3. Coomarasamy A, Dhillon-Smith RK, Papadopoulou A, et al. Recurrent miscarriage: evidence to accelerate action. Lancet. 2021;397(10285):1675–1682. doi: https://doi.org/10.1016/S0140-6736(21)00681-4
  4. Quenby S, Gallos ID, Dhillon-Smith RK, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021;397(10285):1658–1667. doi: https://doi.org/10.1016/S0140-6736(21)00682-6
  5. Bender Atik R, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):hoy004. doi: https://doi.org/10.1093/hropen/hoy004
  6. Colley E, Hamilton S, Smith P, et al. Potential genetic causes of miscarriage in euploid pregnancies: a systematic review. Hum Reprod Update. 2019;25(4):452–472. doi: https://doi.org/10.1093/humupd/dmz015
  7. Zhang J, Wang S, Yang Y, et al. [Application of high-throughput whole genome sequencing and STR typing for the analysis of chorea villus tissue samples from spontaneous abortion]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019;36(12):1171–1174. doi: https://doi.org/10.3760/cma.j.issn.1003-9406.2019.12.005
  8. Кудрявцева Е.В., Ковалев В.В., Баранов И.И., и др. Роль хромосомных аберраций эмбриона в генезе привычного и спорадического невынашивания беременности // Вопросы гинекологии, акушерства и перинатологии. — 2021. — Т. 20. — № 1. — С. 34–39. [Kudryavtseva EV, Kovalev VV, Baranov II, et al. The role of fetal chromosomal aberrations in the genesis of recurrent and sporadic miscarriage. Vopr ginekol akus perinatol. (Gynecology, Obstetrics and Perinatology). 2021;20(1):34–39. (In Russ.)] doi: https://doi.org/10.20953/1726-1678-2021-1-34-39
  9. Kline J, Vardarajan B, Abhyankar A, et al. Embryonic lethal genetic variants and chromosomally normal pregnancy loss. Fertil Steril. 2021;116(5):1351–1358. doi: https://doi.org/10.1016/j.fertnstert.2021.06.039
  10. Кудрявцева Е.В., Ковалев В.В., Потапов Н.Н., и др. Сравнительный анализ цитогенетического исследования и хромосомного микроматричного анализа биологического материала при невынашивании беременности // Медицинская генетика. — 2018. — Т. 17. — № 5. — С. 23–27. [Kudryavtseva EV, Kovalev VV, Potapov NN, et al. Comparative analysis of standard karyotyping and chromosomal microarray analysis of products of conception obtained with miscarriage. Medicinskaja Genetika. 2018;17(5):23–27. (In Russ.)] doi: https://doi.org/10.25557/2073-7998.2018.05.23-27
  11. Кашеварова А.А., Скрябин Н.А., Никитина Т.В., и др. Онтогенетическая плейотропия генов, вовлеченных в CNV у спонтанных абортусов человека // Генетика. — 2019. — Т. 55. — № 10. — С. 1158–1171. [Kashevarova AA, Skryabin NA, Nikitina TV, et al. Ontogenetic pleiotropy of genes involved in CNVs in human spontaneous abortions. Russian Journal of Genetics. 2019;55(10):1158–1171. (In Russ.)] doi: https://doi.org/10.1134/S0016675819100060
  12. Kowalczyk K, Smyk M, Bartnik-Głaska M, et al. Application of array comparative genomic hybridization (aCGH) for identification of chromosomal aberrations in the recurrent pregnancy loss. J Assist Reprod Genet. 2022;39(2):357–367. doi: https://doi.org/10.1007/s10815-022-02400-8
  13. Привычный выкидыш: клинические рекомендации. — М.: Российское общество акушеров-гинекологов, 2021. — С. 46. [Recurrent miscarriage: clinical guidelines. Moscow: Russian Society of Obstetricians and Gynecologists; 2021. S. 46. (In Russ.)]
  14. Robbins SM, Thimm MA, Valle D, et al. Genetic diagnosis in first or second trimester pregnancy loss using exome sequencing: a systematic review of human essential genes. J Assist Reprod Genet. 2019;36(8):1539–1548. doi: https://doi.org/10.1007/s10815-019-01499-6
  15. Miscarriage: worldwide reform of care is needed. Lancet. 2021; 397(10285):1597. doi: https://doi.org/10.1016/S0140-6736(21)00954-5
  16. Laisk T, Soares ALG, Ferreira T, et al. The genetic architecture of sporadic and multiple consecutive miscarriage. Nat Commun. 2020;11(1):5980. doi: https://doi.org/10.1038/s41467-020-19742-5
  17. Carp HJA (ed.). Recurrent Pregnancy Loss. Causes, Controversies, and Treatment. 3rd ed. London: Taylor & F. CRC Press; 2020.
  18. Quintero-Ronderos P, Laissue P. Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches. Reprod Sci. 2020;27(8):1541–1552. doi: https://doi.org/10.1007/s43032-020-00187-6
  19. Костюнина О.В., Абдельманова А.С., Мартынова Е.У., и др. Поиск геномных областей, несущих летальные рецессивные варианты у свиней породы дюрок // Сельскохозяйственная биология. — 2020. — Т. 55. — № 2. — С. 275–284. [Kostyunina OV, Abdelmanova AS, Martynova EU, et al. Search for genomic regions carrying the lethal genetic variants in the duroc pigs. Agricultural Вiology. 2020;55(2):275–284. (In Russ.)] doi: https://doi.org/10.15389/agrobiology.2020.2.275rus
  20. Баранов В.С., Коган И.Ю., Кузнецова Т.В. Прогресс генетики эмбрионального развития человека и вспомогательные репродуктивные технологии // Генетика. — 2019. — Т. 55. — № 10. — С. 1109–1121. [Baranov VS, Kogan IY, Kuznetzova TV. Advances in developmental genetics and achievements in assisted reproductive technology. Russian Journal of Genetics. 2019;55(10):1109–1121. (In Russ.)] doi: https://doi.org/10.1134/S0016675819100023
  21. Najafi K, Mehrjoo Z, Ardalani F, et al. Identifying the causes of recurrent pregnancy loss in consanguineous couples using whole exome sequencing on the products of miscarriage with no chromosomal abnormalities. Sci Rep. 2021;11(1):6952. doi: https://doi.org/10.1038/s41598-021-86309-9
  22. Shamseldin HE, Swaid A, Alkuraya FS. Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing. Genet Med. 2013;15(4):307–309. doi: https://doi.org/10.1038/gim.2012.130
  23. Cacheiro P, Westerberg CH, Mager J, et al. Mendelian gene identification through mouse embryo viability screening. Genome Med. 2022;14(1):119. doi: https://doi.org/10.1186/s13073-022-01118-7
  24. Dawes R, Lek M, Cooper ST. Gene discovery informatics toolkit defines candidate genes for unexplained infertility and prenatal or infantile mortality. NPJ Genom Med. 2019;4:8. doi: https://doi.org/10.1038/s41525-019-0081-z
  25. Berkay EG, Şoroğlu CV, Kalaycı T, et al. A new enrichment approach for candidate gene detection in unexplained recurrent pregnancy loss and implantation failure. Mol Genet Genomics. 2023;298(1):253–272. doi: https://doi.org/10.1007/s00438-022-01972-5
  26. Wu P, Chen D, Wang K, et al. Whole-genome sequence association study identifies cyclin dependent kinase 8 as a key gene for the number of mummified piglets. Anim Biosci. 2023;36(1):29–42. doi: https://doi.org/10.5713/ab.22.0115
  27. Reich P, Falker-Gieske C, Pook T, et al. Development and validation of a horse reference panel for genotype imputation. Genet Sel Evol. 2022;54(1):49. doi: https://doi.org/10.1186/s12711-022-00740-8
  28. Cheong A, Lingutla R, Mager J. Expression analysis of mammalian mitochondrial ribosomal protein genes. Gene Expr Patterns. 2020;38:119147. doi: https://doi.org/10.1016/j.gep.2020.119147
  29. Cheng C, Cleak J, Weiss L, et al. Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice. Orphanet J Rare Dis. 2022;17(1):386. doi: https://doi.org/10.1186/s13023-022-02446-y
  30. Houston BJ, Oud MS, Aguirre DM, et al. Programmed Cell Death 2-Like (Pdcd2l) Is Required for Mouse Embryonic Development. G3 (Bethesda). 2020;10(12):4449–4457. doi: https://doi.org/10.1534/g3.120.401714
  31. Chen X, Yin W, Chen S, et al. Loss of PIGK function causes severe infantile encephalopathy and extensive neuronal apoptosis. Hum Genet. 2021;140(5):791–803. doi: https://doi.org/10.1007/s00439-020-02243-2
  32. An Online Catalog of Human Genes and Genetic Disorders. Available from: https://www.omim.org/ (accessed: 12.01.2024).
  33. Uehara T, Abe K, Oginuma M, et al. Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants. Sci Rep. 2020;10(1):17575. doi: https://doi.org/10.1038/s41598-020-74642-4
  34. Глотов О.С., Чернов А.Н., Глотов А.С., и др. Перспективы применения экзомного секвенирования для решения проблем в репродукции человека (часть II) // Акушерство и гинекология. — 2022. — № 12. — С. 40–45. [Glotov OS, Chernov AN, Glotov AS, et al. Prospects for using exome sequencing to solve problems in human reproduction (part ii). Akusherstvo i Ginekologija. 2022;12:40–45. (In Russ.)] doi: https://doi.org/10.18565/aig.2022.220
  35. Fu M, Mu S, Wen C, et al. Whole exome sequencing analysis of products of conception identifies novel mutations associated with missed abortion. Mol Med Rep. 2018;18(2):2027–2032. doi: https://doi.org/10.3892/mmr.2018.9201
  36. Weitensteiner V, Zhang R, Bungenberg J, et al. Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene. Birth Defects Res. 2018;110(7):587–597. doi: https://doi.org/10.1002/bdr2.1200
  37. Zaghlool A, Halvardson J, Zhao JJ, et al. A Role for the Chromatin-Remodeling Factor BAZ1A in Neurodevelopment. Hum Mutat. 2016;37(9):964–975. doi: https://doi.org/10.1002/humu.23034
  38. Al-Hamed MH, Sayer JA, Alsahan N, et al. Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families. Journal of Nephrology. 2021;34(3):893–900. doi: https://doi.org/10.1007/s40620-020-00795-0
  39. Dainese L, Adam N, Boudjemaa S, et al. Glycogen Storage Disease Type IV and Early Implantation Defect: Early Trophoblastic Involvement Associated with a New GBE1 Mutation. Pediatr Dev Pathol. 2016;19(6):512–515. doi: https://doi.org/10.2350/14-09-1557-CR.1
  40. Cristofoli F, De Keersmaecker B, De Catte L, et al. Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening. Mol Syndromol. 2017;8(6):282–293. doi: https://doi.org/10.1159/000479666
  41. Alves APVD, Freitas AB, Levi JE, et al. COL1A1, COL4A3, TIMP2 and TGFB1 polymorphisms in cervical insufficiency. J Perinat Med. 2021;49(5):553–558. doi: https://doi.org/10.1515/jpm-2020-0320
  42. Alegina EV, Tetruashvili NK, Agadzhanova AA, et al. Role of Collagen Gene Polymorphisms in the Structure of Early Gestation Loss. Bull Exp Biol Med. 2016;160(3):360–363. doi: https://doi.org/10.1007/s10517-016-3171-2
  43. Rajcan-Separovic E. Next generation sequencing in recurrent pregnancy loss-approaches and outcomes. Eur J Med Genet. 2020;63(2):103644. doi: https://doi.org/10.1016/j.ejmg.2019.04.001
  44. Ellard S, Kivuva E, Turnpenny P, et al. An exome sequencing strategy to diagnose lethal autosomal recessive disorders. Eur J Hum Genet. 2015;23(3):401–404. doi: https://doi.org/10.1038/ejhg.2014.120
  45. Qiao Y, Wen J, Tang F, et al. Whole exome sequencing in recurrent early pregnancy loss. Mol Hum Reprod. 2016;22(5):364–372. doi: https://doi.org/10.1093/molehr/gaw008
  46. Rae W, Gao Y, Bunyan D, et al. A novel FOXP3 mutation causing fetal akinesia and recurrent male miscarriages. Clin Immunol. 2015;161(2):284–285. doi: https://doi.org/10.1016/j.clim.2015.09.006
  47. Kasak L, Rull K, Yang T, et al. Recurrent Pregnancy Loss and Concealed Long-QT Syndrome. J Am Heart Assoc. 2021;10(17):e021236. doi: https://doi.org/10.1161/JAHA.121.021236
  48. Cuneo BF, Kaizer AM, Clur SA, et al. Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study. Am J Obstet Gynecol. 2020;222(3):263.e1–263.e11. doi: https://doi.org/10.1016/j.ajog.2019.09.004
  49. Саженова Е.А., Лебедев И.Н. Молекулярные механизмы нарушений импринтированных генов при патологии эмбрионального развития и привычном невынашивании беременности // Медицинская генетика. — 2020. — Т. 19. — №. 11. — С. 79–80. [Sazhenova EA, Lebedev IN. Molecular mechanisms of imprinted gene disturbance in the embryonic development pathology and recurrent pregnancy loss. Medical Genetics. 2020;19(11):79–80. (In Russ.)] doi: https://doi.org/10.25557/2073-7998.2020.11.79-80
  50. Sazhenova EA, Nikitina TV, Vasilyev SA, et al. NLRP7 variants in spontaneous abortions with multilocus imprinting disturbances from women with recurrent pregnancy loss. J Assist Reprod Genet. 2021;38(11):2893–2908. doi: https://doi.org/10.1007/s10815-021-02312-z
  51. Fallahi J, Razban V, Momtahan M, et al. A Novel Mutation in NLRP7 Related to Recurrent Hydatidiform Mole and Reproductive Failure. Int J Fertil Steril. 2019;13(2):135–138. doi: https://doi.org/10.22074/ijfs.2019.5657
  52. Takahashi N, Coluccio A, Thorball CW, et al. ZNF445 is a primary regulator of genomic imprinting. Genes Dev. 2019;33(1-2):49–54. doi: https://doi.org/10.1101/gad.320069.118
  53. Саженова Е.А., Лебедев И.Н. Молекулярные механизмы нарушений импринтированных генов при патологии пре- и постнатального развития // Медицинская генетика. — 2018. — Т. 17. — № 11. — С. 3–6. [Sazhenova EA, Lebedev IN. Molecular mechanisms of disturbance of imprinted genes in pathology of pre- and postnatal development. Medical Genetics. 2018;17(11):3–6. (In Russ.)] doi: https://doi.org/10.25557/2073-7998.2018.11.3-6
  54. Eggermann T, Yapici E, Bliek J, et al. Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences. Clin Epigenetics. 2022;14(1):41. doi: https://doi.org/10.1186/s13148-022-01259-x
  55. Andreasen L, Christiansen OB, Niemann I, et al. NLRP7 or KHDC3L genes and the etiology of molar pregnancies and recurrent miscarriage. Mol Hum Reprod. 2013;19(11):773–781. doi: https://doi.org/10.1093/molehr/gat056
  56. Саженова Е.А., Никитина Т.В., Лебедев И.Н. Способ профилактики привычного невынашивания беременности. Патент РФ на изобретение № RU2659152C1. 28.06.2018. [Sazhenova EA, Nikitina TV, Lebedev IN. Prevention of recurrent miscarriage. Patent RUS No. RU2659152C1. 2018.06.28. (In Russ.)]
  57. Scriven PN. Combining PGT-A with PGT-M risks trying to do too much. J Assist Reprod Genet. 2022;39(9):2015–2018. doi: https://doi.org/10.1007/s10815-022-02519-8
  58. Ребриков Д.В. Редактирование генома человека // Вестник Российского государственного медицинского университета. — 2016. — № 3. — С. 4–15. [Rebrikov DV. Human genome editing. Bulletin of Russian State Medical University. 2016;3:4–15. (In Russ.)]. doi: https://doi.org/10.24075/brsmu.2016-03-01
  59. Coomarasamy A, Gallos ID, Papadopoulou A, et al. Sporadic miscarriage: evidence to provide effective care. Lancet. 2021;397(10285):1668–1674. doi: https://doi.org/10.1016/S0140-6736(21)00683-8

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 "Paediatrician" Publishers LLC



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies