The role of comprehensive genetic testing in patients of early reproductive age with genital malformations: A retrospective study

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Abstract

Background. Congenital malformations of the genital organs exhibit numerous anatomical variants and are characterized by impaired function due to complete or partial obstruction of the organs. Uterine and/or vaginal abnormalities significantly impair reproductive outcomes and are often associated with abnormalities in other organs and systems. To date, the etiology of congenital malformations of the uterus and/or vagina remains controversial; the possible role of genetic predisposition and molecular genetic predictors for these conditions has not been clarified.

Aim. To assess the occurrence of various reproductive system malformations among patients admitted at the federal center, to characterize the known genetic causes of congenital malformations of the female genital organs according to the literature, and to propose an algorithm for genetic testing of adolescent girls diagnosed with malformations of the uterus and/or vagina.

Materials and methods. Retrospective analysis of data from 2160 medical records and discharge reports of patients with reproductive system malformations, admitted for examination and treatment to the Department of Gynecology of Children and Adolescents of the Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology from 2013 to 2023. During the analysis, special attention was paid to clinical, history, and instrumental data, as well as the results of genetic counseling and molecular genetic testing.

Results. An in-depth genetic testing showed that of the 749 examined patients, 516 (68.9%) had uterine and vaginal aplasia, 107 (14.3%) had partial or total vaginal aplasia with a functioning uterus, and 126 (16.8%) had obstruction of one of the hemivaginas with doubling of the uterus. In all cases, the patients' karyotypes were normal female (46,XX).

Conclusion. According to the study results, the main groups of anomalies of the internal reproductive organs (aplasia of the uterus and vagina – Mayer–Rokitansky–Küster–Hauser syndrome; vaginal aplasia with a functioning uterus; anomalies of Müllerian duct fusion – uterine doubling and OHVIRA syndrome) were identified, data on the known genetic mechanisms of the development of these malformations were described, the approach for molecular genetic search for genetic etiology in these groups of patients was proposed.

About the authors

Zalina K. Batyrova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Author for correspondence.
Email: linadoctor@mail.ru
ORCID iD: 0000-0003-4997-6090

Cand. Sci. (Med.)

Russian Federation, Moscow

Polina N. Tsabai

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0001-5110-0827

Geneticist

Russian Federation, Moscow

Zaira H. Kymykova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0001-7511-1432

Cand. Sci. (Med.)

Russian Federation, Moscow

Elena V. Uvarova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Sechenov First Moscow State Medical University (Sechenov University)

Email: linadoctor@mail.ru
ORCID iD: 0000-0002-3105-5640

D. Sci. (Med.), Prof., Corr. Memb. RAS

Russian Federation, Moscow; Moscow

Andrey A. Bystritskiy

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0002-0436-9951
SPIN-code: 1281-7670
Scopus Author ID: 6601980173

Leading Res. Officer

Russian Federation, Moscow

Vladimir D. Chuprynin

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0009-0003-7856-2863

Cand. Sci. (Med.)

Russian Federation, Moscow

Anna S. Bolshakova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0002-7508-0899

Geneticist

Russian Federation, Moscow

Nadezhda V. Zaretskaia

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0001-6754-3833

Cand. Sci. (Med.)

Russian Federation, Moscow

Nadezhda S. Pavlova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0001-5619-2695

Biologist

Russian Federation, Moscow

Jekaterina S. Shubina

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0003-4383-7428

Cand. Sci. (Biol.)

Russian Federation, Moscow

Dmitry Y. Trofimov

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: linadoctor@mail.ru
ORCID iD: 0000-0002-1569-8486

D. Sci. (Biol.), Corr. Memb. RAS

Russian Federation, Moscow

References

  1. Аракелян А.С., Попрядухин А.Ю., Карапетян Э.А. Сочетанные пороки развития в гинекологии. Анализ 1530 клинических наблюдений. (Собственный материал). Российский вестник акушера-гинеколога. 2021;21(4):88-93 [Arakelyan AS, Popryadukhin AYu, Karapetyan EA. Concomitant malformations in gynecology. Analysis of 1530 clinical observations. (Own material). Rossiiskii Vestnik Akushera-Ginekologa. 2021;21(4):88-93 (in Russian)]. doi: 10.17116/rosakush20212104188
  2. Аракелян А.С. Пороки развития матки и влагалища: современные методы диагностики, хирургического лечения и реабилитации. Дисс… д-ра мед. наук. 2021 [Arakelian AS. Poroki razvitiia matki i vlagalishcha: sovremennye metody diagnostiki, khirurgicheskogo lecheniia i reabilitatsii. Diss… d-ra med. nauk. 2021 (in Russian)].
  3. Saravelos SH, Cocksedge KA, Li TC. Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal. Hum Reprod Update. 2008;14(5):415-29. doi: 10.1093/humupd/dmn018
  4. Chan YY, Jayaprakasan K, Tan A, et al. Reproductive outcomes in women with congenital uterine anomalies: a systematic review. Ultrasound Obstet Gynecol. 2011;38(4):371-82. doi: 10.1002/uog.10056
  5. Tong J, Zhu L, Chen N, Lang J. Endometriosis in association with Herlyn-Werner-Wunderlich syndrome. Fertil Steril. 2014;102(3):790-4. doi: 10.1016/j.fertnstert.2014.05.025
  6. Казанцева Е.В., Траль Т.Г., Толибова Г.Х. Клинико-анамнестические данные и морфофункциональные особенности эндометрия у женщин с аномалиями развития матки. Журнал акушерства и женских болезней. 2021;70(2):5-12 [Kazantseva EV, Tral TG, Tolibova GKh. Сlinical and anamnestic data and morphofunctional characteristics of the endometrium in women with uterine developmental anomalies. Zhurnal Akusherstva i Zhenskikh Boleznei. 2021;70(2):5-12 (in Russian)]. doi: 10.17816/JOWD54605
  7. Herlin MK. Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications. Front Endocrinol (Lausanne). 2024;15:1368990. doi: 10.3389/fendo.2024.1368990
  8. Marcus S, Al-Shawaf T, Brinsden P. The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation. Am J Obstet Gynecol. 1996;175(1):85-9. doi: 10.1016/s0002-9378(96)70255-7
  9. Kapczuk K, Kedzia W. Primary Amenorrhea Due to Anatomical Abnormalities of the Reproductive Tract: Molecular Insight. Int J Mol Sci. 2021;22(21):11495. doi: 10.3390/ijms222111495
  10. Батырова З.К., Уварова Е.В., Кумыкова З.Х., и др. Современные молекулярно-генетические представления о синдроме Майера–Рокитанского–Кюстера–Хаузера. Репродуктивное здоровье детей и подростков. 2022;18(2):25-30 [Batyrova ZK, Uvarova EV, Kumykova ZKh. Modern molecular genetic concepts in Mayer–Rokytansky–Kuster-Hauser syndrome. Reproduktivnoe Zdorove Detei i Podrostkov. 2022;18(2):25-30 (in Russian)]. doi: 10.33029/1816-2134-2022-18-2-25-30
  11. Ахапкина Е.С., Батырова З.К., Уварова Е.В., Наджарян А.Г. Клинико-анамнестические и эндокринологические особенности девочек с синдромом Майера–Рокитанского–Кюстера–Хаузера. Репродуктивное здоровье детей и подростков. 2019;15(4):33-40 [Akhapkina ES, Batyrova ZK, Uvarova EV, Nadzharyan AG. Clinical-anamnestic and endocrinological features of girls with Mayer–Rokitansky–Kuester–Hauser syndrome. Reproduktivnoe Zdorove Detei i Podrostkov. 2019;15(4):33-40 (in Russian)]. doi: 10.24411/1816-2134-2019-14004
  12. Аракелян А.С., Фархат К.Н., Адамян Л.В., Попрядухин А.Ю. Редкое сочетание врожденной аномалии развития яичников и матки. Акушерство и гинекология. 2021;5:191-8 [Arakelyan AS, Farkhat KN, Adamyan LV, Popryadukhin AYu. A rare concurrence of congenital ovarian and uterine malformations. Akusherstvo i Ginekologiia. 2021;5:191-8 (in Russian)]. doi: 10.18565/aig.2021.5.191-198
  13. Адамян Л.В., Алясова А.В., Степанян А.А. Эндометриоз и пороки развития половых органов у детей и подростков. Что общего? Проблемы репродукции. 2024;30(3):14-22 [Adamyan LV, Alyasova AV, Stepanian AA. Endometriosis and genital malformations in children and adolescents. What do they have in common? Russ J Hum Reprod. 2024;30(3):14-22 (in Russian)]. doi: 10.17116/repro20243003114
  14. Cospain A, Dion L, Bidet M, et al. Optimizing care for MRKH patients: From malformation screening to uterus transplantation eligibility. Acta Obstet Gynecol Scand. 2025;104(3):514-21. doi: 10.1111/aogs.14985
  15. Kisu I, Yamada M, Ikenoue S, Yamagami W. Pregnancy and Delivery After Solid Organ and Uterus Transplantation: A Review. J Clin Med. 2025;14(14):5138. doi: 10.3390/jcm14145138
  16. Бобкова М.В., Баранова Е.Е., Кузнецова М.В., и др. Семейный случай синдрома Мейера–Рокитанского–Кюстера–Хаузера и обзор литературы. Проблемы репродукции. 2015;21(4):17-22 [Bobkova MV, Baranova EE, Kuznetsova MV. Family case of Mayer–Rokitansky–Kuster–Hauser syndrome and literature review. Russ J Hum Reprod. 2015;21(4):17-22 (in Russian)]. EDN:UKSHNB
  17. Herlin M, Hojland AT, Petersen MB. Familial occurrence of Mayer–Rokitansky–Küster–Hauser syndrome: A case report and review of the literature. Am J Med Genet. 2014;164(9):2276-86. doi: 10.1002/ajmg.a.36652
  18. Daum H, Kremer E, Frumkin A, et al. A case report of familial Mayer-Rokitansky-Küster-Hauser syndrome as part of the phenotypic spectrum of the 2q37 deletion. J Pediatr Adolesc Gynecol. 2024;37(1):95-7. doi: 10.1016/j.jpag.2023.09.006
  19. Аракелян А.С., Попрядухин А.Ю., Карапетян Э.А. Генетические факторы развития синдрома Майера–Рокитанского–Кюстера–Хаузера (аплазии матки и влагалища). Проблемы репродукции. 2020;26(5):43-50 [Arakelyan AS, Popryadukhin AYu, Karapetyan EA. Genetic factors in the development of the Mayer-Rokitansky-Küster-Hauser syndrome (aplasia of the uterus and vagina). Russ J Hum Reprod. 2020;26(5):43-50 (in Russian)]. doi: 10.17116/repro20202605143
  20. Ma C, Chen N, Jolly A, et al; Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) Study Group. Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome. Genet Med. 2022;24(11):2262-73. doi: 10.1016/j.gim.2022.08.012
  21. Tewes AC, Hucke J, Romer T, et al. Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update. Sex Dev. 2019;13(1):35-40. doi: 10.1159/000496819
  22. Biason-Lauber A, De Filippo G, Konrad D, et al. WNT4 deficiency – a clinical phenotype distinct from the classic Mayer–Rokitansky–Kuster–Hauser syndrome: a case report. Human Reprod. 2007;22(1):224-9. doi: 10.1093/humrep/del360
  23. Philibert P, Biason-Lauber A, Rouzier R, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities: a French collaborative study. Journal Clin Endocrinol Metab. 2008;93(3):895-900. doi: 10.1210/jc.2007-2023
  24. Wang M, Li Y, Ma W, et al. Analysis of WNT9B mutations in Chinese women with Mayer–Rokitansky–Küster–Hauser syndrome. Reprod Biomed Online. 2014;28(1):80-5. doi: 10.1016/j.rbmo.2013.09.022
  25. Chen N, Zhao S, Jolly A, et al. Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome. Am J Hum Genet. 2021;108(2):337-45. doi: 10.1016/j.ajhg.2020.12.014
  26. Ravel C, Lorenço D, Dessolle L, et al. Mutational analysis of the WNT gene family in women with Mayer–Rokitansky–Kuster–Hauser syndrome. Fertil Steril. 2009;91(4):1604-7. doi: 10.1016/j.fertnstert.2008.12.006
  27. Herlin MK, Le VQ, Hojland AT, et al. Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. A case report. Hum Reprod. 2019;34(9):1838-46. doi: 10.1093/humrep/dez126
  28. De Tomasi L, David P, Humbert C, et al. Mutations in GREB1L cause bilateral kidney agenesis in humans and mice. Am J Hum Genet. 2017;101(5):803-14. doi: 10.1016/j.ajhg.2017.09.026
  29. Jolly A, Du H, Borel C, et al. Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome. HGG Adv. 2023;4(3):100188. doi: 10.1016/j.xhgg.2023.100188
  30. Tian W, Chen N, Ye Y, et al. A genotype-first analysis in a cohort of Mullerian anomaly. J Hum Genet. 2022;67(6):347-52. doi: 10.1038/s10038-021-00996-w
  31. Mikhael S, Dugar S, Morton M, et al. Genetics of agenesis/hypoplasia of the uterus and vagina: narrowing down the number of candidate genes for Mayer–Rokitansky–Küster–Hauser Syndrome. Hum Genet. 2021;140(4):667-80. doi: 10.1007/s00439-020-02239-y
  32. Ding L, Tian Q. Identification of a novel variant in MYRF gene in a patient with 46, XX disorders of sex development. Gynecol Endocrinol. 2025;41(1):2546985. doi: 10.1080/09513590.2025.2546985
  33. Eggermann T, Ledig S, Begemann M, et al. Search for altered imprinting marks in Mayer–Rokitansky–Küster–Hauser patients. Mol Genet Genomic Med. 2018;6(6):1225-8. doi: 10.1002/mgg3.426
  34. Chu C, Li L, Lu D, et al. Whole-Exome Sequencing Identified a TBX6 Loss of Function Mutation in a Patient with Distal Vaginal Atresia. J Pediatr Adolesc Gynecol. 2019;32(5):550-4. doi: 10.1016/j.jpag.2019.06.006
  35. Kang J, Zhou Q, Chen N, et al. Clinical and Genetic Characteristics of a Cohort with Distal Vaginal Atresia. Int J Mol Sci. 2022;23(21):12853. doi: 10.3390/ijms232112853
  36. Marquez J, O'Sullivan L, Squire AE, et al. Case Report: a novel variant in WT1 leads to focal segmental glomerulosclerosis and uterovaginal anomalies through exon skipping. Front Nephrol. 2025;5:1542475. doi: 10.3389/fneph.2025.1542475
  37. Bonetti E, Anderson G, Duranti S, et al. Clinical features and surgical options of obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome: A systematic review and a meta-analysis of prevalence. Int J Gynecol Obstet. 2025;171(1):152-64. doi: 10.1002/ijgo.70164
  38. Макиян З.Н., Адамян Л.В., Асатурова А.В., Ярыгина Н.К. Маточные рудименты: клинико-морфологические варианты и оптимизация хирургического лечения. Акушерство и гинекология. 2019;12:126-32 [Makiyan ZN, Adamyan LV, Asaturova AV, Yarygina NK. Uterine rudiments: clinical and morphological options of surgical treatment and its optimization. Akusherstvo i Ginekologiia. 2019;12:126-32 (in Russian)]. doi: 10.18565/aig.2019.12.126-132
  39. Dietrich JE. Diagnosis and Management of Mullerian Anomalies Across Differing Resource Settings: Worldwide Adaptations. J Pediatr Adolesc Gynecol. 2022;35(5):536-40. doi: 10.1016/j.jpag.2022.04.007
  40. Luo LJ, Feng F, Li SH, et al. Sequence variant in the CDC42BPB gene is potentially associated with Mullerian duct anomalies. J Obstet Gynaecol Res. 2020;46(5):684-93. doi: 10.1111/jog.14211
  41. Saygili S, Atayar E, Canpolat N, et al. A homozygous HOXA11 variation as a potential novel cause of autosomal recessive congenital anomalies of the kidney and urinary tract. Clin Genet. 2020;98(4):390-5. doi: 10.1111/cge.13813
  42. Zhu Y, Cheng Z, Wang J, et al. A novel mutation of HOXA11 in a patient with septate uterus. Orphanet J Rare Dis. 2017;12(1):178. doi: 10.1186/s13023-017-0727-9
  43. Liu S, Gao X, Qin Y, et al. Nonsense mutation of EMX2 is potential causative for uterus didelphysis: first molecular explanation for isolated incomplete müllerian fusion. Fertil Steril. 2015;103(3):769-74.e2. doi: 10.1016/j.fertnstert.2014.11.030
  44. Ledig S, Tewes AC, Hucke J, et al. Array-comparative genomic hybridization analysis in patients with Müllerian fusion anomalies. Clin Genet. 2018;93(3):640-6. doi: 10.1111/cge.13160
  45. Li L, Chu C, Li S, et al. Renal agenesis-related genes are associated with Herlyn-Werner-Wunderlich syndrome. Fertil Steril. 2021;116(5):1360-9. doi: 10.1016/j.fertnstert.2021.06.033
  46. Rhodes HL, Bownass L, Smithson SF, Woodward MN. CRKL Gene Deletion in Familial Zinner (OSVIRA) and OHVIRA Syndromes. Pediatrics. 2025;155(1):e2024068135. doi: 10.1542/peds.2024-068135
  47. Utsch B, Becker K, Brock D, et al. A novel stable polyalanine [poly (A)] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly (A)-harbouring transcription factors depends on a critical repeat length? Hum Genet. 2002;110(5):488-94. doi: 10.1007/s00439-002-0712-8
  48. Geng W, Li F, Zhang R, et al. Hand-foot-genital syndrome due to a duplication variant in the GC-rich region of HOXA13. Eur J Med Genet. 2023;66(3):104711. doi: 10.1016/j.ejmg.2023.104711
  49. Innis JW. Hand-foot-genital syndrome. 2019. In: GeneReviews. Available at: https://europepmc.org/article/NBK/nbk1423. Accessed:15.03.2025.

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