Uterus didelphys, longitudinal vaginal septum and diminished ovarian reserve in a patient with MYRF-associated disease
Tsabai P.N., Batyrova Z.K., Kumykova Z.Kh., Kovalskaya V.A., Sidorchuk M.A., Goltsov A.Yu., Sadelov I.O., Tolmacheva E.R., Uvarova E.V., Sukhikh G.T., Trofimov D.Yu.
Background: Congenital abnormalities of female reproductive organs result from the abnormal formation, fusion or resorption of Müllerian ducts during the intrauterine period and can lead to adverse reproductive outcomes. A number of studies have identified a higher incidence of ovarian dysfunction in patients with uterine abnormalities; however, other studies do not support this correlation. Uterine defects are frequently associated with syndromic pathologies; yet the etiology of the most prevalent Müllerian anomalies remains unclear or multifactorial.
Case report: This paper presents a clinical observation of a patient with uterus didelphys, longitudinal vaginal septum and diminished ovarian reserve as part of cardiac-urogenital syndrome caused by a likely pathogenic variant p.Ala440ThrfsTer2 in the MYRF gene. The patient was recommended to consider assisted reproductive technologies with preimplantation genetic testing to prevent the birth of an affected child.
Conclusion: This case illustrates the pleiotropic effect of the MYRF transcription factor. Pathogenic variants in the MYRF gene can impair the development of both Müllerian derivatives and ovaries, and lead to diminished ovarian reserve, which is also accompanied by dysfunction of other organs and systems. MYRF should be considered as a candidate gene for a variety of uterine abnormalities, diminished ovarian reserve and premature ovarian insufficiency in female patients in the presence or absence of extragenital manifestations.
Authors’ contributions: Sukhikh G.T., Uvarova E.V., Trofimov D.Yu. – developing the concept and design of the study; Tsabai P.N., Batyrova Z.K., Kumykova Z.Kh., Kovalskaya V.A. – consulting patients, collecting and processing material; Goltsov A.Yu. – performing laboratory studies; Sadelov I.O., Tolmacheva E.R. – conducting bioinformatics analysis; Tsabai P.N., Sidorchuk M.A., Tolmacheva E.R. – writing the text; Batyrova Z.K., Kumykova Z.Kh. – editing the article.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: This study was supported by a grant from the Russian Science Foundation [Grant No. 24-14-00460].
Ethical Approval: The study was approved by the Ethical Review Board of the Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia.
Patient Consent for Publication: The patient and her parents provided the written informed consent that all information (including photographs) could be used for research purposes.
For citation: Tsabai P.N., Batyrova Z.K., Kumykova Z.Kh., Kovalskaya V.A., Sidorchuk M.A., Goltsov A.Yu., Sadelov I.O., Tolmacheva E.R., Uvarova E.V., Sukhikh G.T., Trofimov D.Yu. Uterus didelphys, longitudinal vaginal septum and diminished ovarian reserve in a patient with MYRF-associated disease.
Akusherstvo i Ginekologiya/ bstetrics and Gynecology. 2025; (4): 171-177 (in Russian)
https://dx.doi.org/10.18565/aig.2024.321
Keywords
case report
cardiac-urogenital syndrome
MYRF
uterus didelphys
diminished ovarian reserve
vaginal septum
Müllerian anomaly
whole exome sequencing
References
- Chan Y.Y., Jayaprakasan K., Zamora J., Thornton J.G., Raine-Fenning N., Coomarasamy A. The prevalence of congenital uterine anomalies in unselected and high-risk populations: a systematic review. Hum. Reprod. Update. 2011; 17(6): 761-71. https://dx.doi.org/10.1093/humupd/dmr028.
- Cospain A., Dion L., Bidet M., Nyangoh Timoh K., Quelin C., Carton I. et al. Optimizing care for MRKH patients: From malformation screening to uterus transplantation eligibility. Acta Obstet. Gynecol. Scand. 2025; 104(3): 514-21. https://dx.doi.org/10.1111/aogs.14985.
- Chan Y.Y., Jayaprakasan K., Tan A., Thornton J.G., Coomarasamy A., Raine-Fenning N.J. Reproductive outcomes in women with congenital uterine anomalies: a systematic review. Ultrasound Obstet. Gynecol. 2011; 38(4): 371-82. https://dx.doi.org/10.1002/uog.10056.
- Wang Y., He Y.L., Yuan L., Yu J.C., Xue H.D., Jin Z.Y. Typical and atypical pelvic MRI characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a comprehensive analysis of 201 patients. Eur. Radiol. 2020; 30(7): 4014-22. https://dx.doi.org/10.1007/s00330-020-06681-4.
- Allen J.W., Cardall S., Kittijarukhajorn M., Siegel C.L. Incidence of ovarian maldescent in women with mullerian duct anomalies: evaluation by MRI. AJR Am. J. Roentgenol. 2012; 198(4): W381-5. https://dx.doi.org/10.2214/AJR.11.6595.
- Chen H.A., Grimshaw A.A., Taylor-Giorlando M., Vijayakumar P., Li D, Margetts M., Pelosi E. et al. Ovarian absence: a systematic literature review and case series report. J. Ovarian Res. 2023; 16(1): 13. https://dx.doi.org/10.1186/s13048-022-01090-1.
- 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 A.S., Popryadukhin A.Yu., Karapetyan E.A. Concomitant malformations in gynecology. Analysis of 1530 clinical observations. (Own material). Russian Bulletin of Obstetrician-Gynecologist. 2021; 21(4): 88-93. (in Russian)]. https://dx.doi.org/10.17116/rosakush20212104188.
- Connell M., Owen C., Segars J. Genetic syndromes and genes involved in the development of the female reproductive tract: a possible role for gene therapy. J. Genet. Syndr. Gene Ther. 2013; 4: 127. https://dx.doi.org/10.4172/2157-7412.1000127.
- Touraine P., Chabbert-Buffet N., Plu-Bureau G., Duranteau L., Sinclair A.H., Tucker E.J. Premature ovarian insufficiency. Nat. Rev. Dis. Primers. 2024; 10(1): 63. https://dx.doi.org/10.1038/s41572-024-00547-5.
- Reyes A.P., León N.Y., Frost E.R., Harley V.R. Genetic control of typical and atypical sex development. Nat. Rev. Urol. 2023; 20(7): 434-51. https://dx.doi.org/10.1038/s41585-023-00754-x.
- Liu S., Gao X., Qin Y., Liu W., Huang T., Ma J. 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. https://dx.doi.org/10.1016/j.fertnstert.2014.11.030.
- Wang X., Zhang X., Liu S., Li G., Cui L., Qin Y. et al. Novel mutations in the TP63 gene are potentially associated with Müllerian duct anomalies. Hum. Reprod. 2016; 31(12): 2865-71. https://dx.doi.org/10.1093/humrep/dew259.
- Li R., Wu S.P., Zhou L., Nicol B., Lydon J.P., Yao H.H. et al. Increased FOXL2 expression alters uterine structures and functions. Biol. Reprod. 2020; 103(5): 951-65. https://dx.doi.org/10.1093/biolre/ioaa143.
- Shubina J., Tolmacheva E., Maslennikov D., Kochetkova T., Mukosey I., Sadelov I. et al. WES-based screening of 7,000 newborns: A pilot study in Russia. HGG Adv. 2024; 5(4): 100334. https://dx.doi.org/10.1016/j.xhgg.2024.100334.
- Chen S., Francioli L.C., Goodrich J.K., Collins R.L., Kanai M., Wang Q. et al.; Genome Aggregation Database Consortium. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024; 625(7993): 92-100. https://dx.doi.org/10.1038/s41586-023-06045-0.
- Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J. et al.; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015; 17(5): 405-24. https://dx.doi.org/10.1038/gim.2015.30.
- Favier M., Brischoux-Boucher E., Pyle L.C., Mottet N., Auber-Lenoir M., Cattin J. et al. Fetal presentation of MYRF-related cardiac urogenital syndrome: an emerging and challenging prenatal diagnosis. Prenat. Diagn. 2024; 44(13):1647-58. https://dx.doi.org/10.1002/pd.6700.
- Hamanaka K., Takata A., Uchiyama Y., Miyatake S., Miyake N., Mitsuhashi S. et al. MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration. Hum. Mol. Genet. 2019; 28(14): 2319-29. https://dx.doi.org/10.1093/hmg/ddz066.
- Kurahashi H., Azuma Y., Masuda A., Okuno T., Nakahara E., Imamura T. et al. MYRF is associated with encephalopathy with reversible myelin vacuolization. Ann. Neurol. 2018; 83(1): 98-106. https://dx.doi.org/10.1002/ana.25125.
- Calonga-Solís V., Fabbri-Scallet H., Ott F., Al-Sharkawi M., Künstner A., Wünsch L. et al. MYRF: A new regulator of cardiac and early gonadal development-insights from single cell RNA sequencing analysis. J. Clin. Med. 2022; 11(16): 4858. https://dx.doi.org/10.3390/jcm11164858.
- Qi H., Yu L., Zhou X., Wynn J., Zhao H., Guo Y. et al. De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet. 2018; 14(12): e1007822. https://dx.doi.org/10.1371/journal.pgen.1007822.
- Slaba K., Jezova M., Pokorna P., Palova H., Tuckova J., Papez J. et al. Two sisters with cardiac-urogenital syndrome secondary to pathogenic splicing variant in the MYRF gene with unaffected parents: A case of gonadal mosaicism? Mol. Genet. Genomic Med. 2023; 11(5): e2139. https://dx.doi.org/10.1002/mgg3.2139.
- Gupta N., Endrakanti M., Gupta N., Dadhwal V., Naini K., Manchanda S. et al. Diverse clinical manifestations and intrafamilial variability due to an inherited recurrent MYRF variant. Am. J. Med. Genet. A. 2022; 188(7): 2187-91. https://dx.doi.org/10.1002/ajmg.a.62744.
Received 16.12.2024
Accepted 03.04.2025
About the Authors
Polina N. Tsabai, geneticist, M.D., Department of Clinical Genetics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, polinatsabai@gmail.com, https://orcid.org/0000-0001-5110-0827Zalina K. Batyrova, gynecologist, M.D., PhD., Department of Pediatric and Adolescent Gynecology, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, linadoctor@mail.ru, https://orcid.org/0000-0003-4997-6090
Zaira Kh. Kumykova, gynecologist, M.D., PhD., Department of Pediatric and Adolescent Gynecology, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, zai-kumykova@yandex.ru,
https://orcid.org/0000-0001-7511-1432
Valeria A. Kovalskaia, geneticist, M.D., Department of Clinical Genetics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, mikhailova.v.a@mail.ru, https://orcid.org/0000-0002-8728-8574
Mariia A. Sidorchuk, geneticist, M.D., Department of Clinical Genetics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, sidorchuk.mariia.98@gmail.com, https://orcid.org/0009-0008-1373-7905
Andrey Yu. Goltsov, researcher, Laboratory of Molecular Genetic Methods, Institute of Reproductive Genetics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, andrey.goltsov@gmail.com,
https://orcid.org/0000-0002-4004-4214
Igor O. Sadelov, geneticist at the Laboratory for the Genomic Data Analysis, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, sadelovigor@gmail.com, https://orcid.org/0000-0001-5916-0672
Ekaterina R. Tolmacheva, researcher at the Laboratory for the Genomic Data Analysis, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, +7(903)135-95-48, tetisae@gmail.com,
https://orcid.org/0000-0003-2901-0539
Elena V. Uvarova, Dr. Med. Sci., Professor, Corresponding Member of RAS, Head of Department of Pediatric and Adolescent Gynecology, Academician V.I. Kulakov
National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997,
elena-uvarova@yandex.ru, https://orcid.org/0000-0002-3105-5640
Gennady T. Sukhikh, Dr. Med. Sci., Professor, Academician of RAS, Director, Academician V.I. Kulakov National Medical Research Center for Obstetrics,
Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, https://orcid.org/0000-0002-7712-1260
Dmitry Yu. Trofimov, Dr. Med. Sci., Professor of the RAS, Corresponding Member of RAS, Director of the Institute of Reproductive Genetics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 4, Acad. Oparin str., Moscow, Russia, 117997, molgen@bk.ru, https://orcid.org/0000-0002-1569-8486
Corresponding author: Polina N. Tsabai, polinatsabai@gmail.com
Similar Articles
