FMR1 inherited from women with premature ovarian failure: case series

Cover Page

Cite item

Full Text

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

Abstract

Background: In recent years, the potential of transmission of an abnormal number of CGG triplet repeats in the FMR1 gene to the next generation as a biomarker for inheritance of early ovarian ageing has been of particular clinical interest.

Objective: Analysis of health characteristics in children born to mothers with premature ovarian failure (POF), who had an abnormal number of trinucleotide CGG repeats in the FMR1 gene.

Materials and methods: A prospective, single-center, non-consecutive case series study included 90 women aged 18 to 39 years (the mean age was 33,5 years) with POF who underwent FMR1 gene testing to identify CGG repeats in FMR1 gene. The second stage of the study was quantitative assessment of the number of CGG trinucleotide repeats in 27 children born to the carriers of an abnormal number of triplet CGG repeats in the FMR1 gene.

Results: In 66.7% of cases, various FMR1 disorders were detected in offspring. In 7.4% of cases (2/27), adverse outcomes of inheritance of trinucleotide repeat expansion from premutation allele carriers were observed resulting in formation of Martin–Bell syndrome in sons. Stable inheritance of the FMR1 premutation was observed in 22.2% of cases (6/27), while severe phenotype of POF with early onset of the disease was observed in girls versus their mothers.

Conclusion: It is advisable that FMR1 premutation allele carriers should get genetic counseling that could help them to make decision about the use of assisted reproductive techniques (ART) to achieve pregnancy with donor oocytes or embryos.

Full Text

Restricted Access

About the authors

Sandra D. Rshtuni

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation

Author for correspondence.
Email: rshtunisandra@gmail.com

Postgraduate Student, Department of Endocrinological Gynecology

Russian Federation, Moscow

Nadezhda V. Zaretskaya

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation

Email: znadezda@yandex.ru

PhD, Head of the Laboratory of Clinical Genetics

Russian Federation, Moscow

Maria V. Kuznetsova

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation

Email: mkarja@mail.ru

PhD (Bio), Senior Researcher at the Laboratory of Molecular Genetic Methods of the Institute of Reproductive Genetics

Russian Federation, Moscow

Larisa A. Marchenko

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of the Russian Federation

Email: l_marchenko@yandex.ru

Dr. Med. Sci., Professor, Department of Endocrinological Gynecology

Russian Federation, Moscow

References

  1. Qin Y., Jiao X., Simpson J.L., Chen Z.-J. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum. Reprod. Update. 2015; 21(6): 787-808. https://dx.doi.org/10.1093/humupd/ dmv036
  2. França M.M., Mendonca B.B. Genetics of ovarian insufficiency and defects of folliculogenesis. Best Pract. Res. Clin. Endocrinol. Metab. 2022; 36(1): 101594. https://dx.doi.org/10.1016/j.beem.2021.101594
  3. Bouilly J., Beau I., Barraud S., Bernard V., Azibi K., Fagart J. et al. Identification of multiple gene mutations accounts for a new genetic architecture of primary ovarian insufficiency. J. Clin. Endocr. Metab. 2016; 101(12): 4541-50. https://dx.doi.org/10.1210/jc.2016-2152
  4. Tabolacci E., Nobile V., Pucci C., Chiurazzi P. Mechanisms of the FMR1 repeat instability: how does the CGG sequence expand? Int. J. Mol. Sci. 2022; 23(10): 5425. https://dx.doi.org/10.3390/ijms23105425
  5. Eichler E.E., Richards S., Gibbs R.A., Nelson D.L. Fine structure of the human FMR1 gene. Hum. Mol. Genet. 1993; 2(8): 1147-53. https://dx.doi.org/10.1093/hmg/2.8.1147
  6. Chen L.S., Tassone F., Sahota P., Hagerman P.J. The (CGG)n repeat element within the 5' untranslated region of the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter. Hum. Mol. Genet. 2003; 12(23): 3067-74. https://dx.doi.org/10.1093/hmg/ddg331
  7. Webber L., Davies M., Anderson R., Bartlett J., Braat D., Cartwright B. et al.; European Society for Human Reproduction and Embryology (ESHRE) Guideline Group. ESHRE guideline: management of women with premature ovarian insufficiency. Hum. Reprod. 2016; 31(5): 926-37. https://dx.doi.org/10.1093/humrep/dew027
  8. Министерство здравоохранения Российской Федерации. Клинические рекомендации. Аменорея и олигоменорея. М.; 2021. [Ministry of Health of the Russian Federation. Clinical guidelines. Amenorrhea and oligomenorrhea. Moscow; 2021. (in Russian)].
  9. Шамилова Н.Н., Марченко Л.А., Долгушина Н.В., Кузнецова Е.Б., Залетаев Д.В. Роль генетических и аутоиммунных нарушений в развитии преждевременной недостаточности яичников. Акушерство и гинекология. 2012; 4-2: 67-72. [Shamilova N.N., Marchenko L.A., Dolgushina N.V., Kuznetsova E.B., Zaletayev D.V. Role of genetic and autoimmune disorders in the development of premature ovarian failure. Obstetrics and Gynecology. 2012;( 4-2): 67-72. (in Russian)].
  10. Spector E., Behlmann A., Kronquist K., Rose N.C., Lyon E., Reddi H.V.; ACMG Laboratory Quality Assurance Committee. Laboratory testing for fragile X, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 2021; 23(5): 799-812. https://dx.doi.org/10.1038/s41436-021-01115-y
  11. Gleicher N., Barad D.H. The FMR1 gene as regulator of ovarian recruitment and ovarian reserve. Obstet. Gynecol. Surv. 2010; 65(8): 523-30. https://dx.doi.org/10.1097/OGX.0b013e3181f8bdda
  12. Dombrowski C., Lévesque S., Morel M.L., Rouillard P., Morgan K., Rousseau F. Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum. Mol. Genet. 2002; 11(4): 371-8. https://dx.doi.org/10.1093/hmg/11.4.371
  13. Bussani C., Papi L., Sestini R., Baldinotti F., Bucciantini S., Bruni V., Scarselli G. Premature ovarian failure and fragile X premutation: a study on 45 women. Eur. J. Obstet. Gynecol. Reprod. Biol. 2004; 11(2): 189-91. https://dx.doi.org/10.1016/j.ejogrb.2003.06.003
  14. Schwartz C.E., Dean J., Howard-Peebles P.N., Bugge M., Mikkelsen M., Tommerup N. et al. Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am. J. Med. Genet. 1994; 51(4): 400-2. https://dx.doi.org/10.1002/ajmg.1320510419
  15. Welt C.K., Smith P. C., Taylor A.E. Evidence of early ovarian aging in fragile X premutation carriers. J. Clin. Endocrinol. Metab. 2004; 89(9): 4569-74. https://dx.doi.org/10.1210/jc.2004-0347
  16. Nolin S.L., Brown W.T., Glicksman A., Houck G.E. Jr, Gargano A.D., Sullivan A. et al. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am. J. Hum. Genet. 2003; 72(2): 454-64. https://dx.doi.org/10.1086/367713
  17. Beke A., Piko H., Haltrich I., Karcagi V., Rigo J. Jr, Molnar M.J., Fekete G. Study of patterns of inheritance of premature ovarian failure syndrome carrying maternal and paternal premutations. BMC Med. Genet. 2018; 19(1): 113. https://dx.doi.org/10.1186/s12881-018-0634-5
  18. Eichler E.E., Holden J.J., Popovich B.W., Reiss A.L., Snow K., Thibodeau S.N. et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat. Genet. 1994; 8(1): 88-94. https://dx.doi.org/10.1038/ng0994-88
  19. Табеева Г.И., Шамилова Н.Н., Жахур Н.А., Позднякова А.А., Марченко Л.А. Преждевременная недостаточность яичников – загадка XXI века. Акушерство и гинекология. 2013; 12: 16-21. [Tabeeva G.I., Shamilova N.N., Zhakhur N.A., Pozdnyakova A.A. Marchenko L.A. Premature ovarian failure is a mystery of the 21st century. Obstetrics and Gynecology. 2013; (12): 16-21. (in Russian)].
  20. Mailick M.R., Hong J., Rathouz P., Baker M.W., Greenberg J.S., Smith L., Maenner M. Low - normal FMR1 CGG repeat length: phenotypic associations. Front. Genet. 2014; 5: 309. https://dx.doi.org/10.3389/ fgene.2014.00309
  21. Fernandez-Carvajal I., Lopez Posadas B., Pan R., Raske C., Hagerman P.J., Tassone F. Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J. Mol. Diagn. 2009; 11(4): 306-10. https://dx.doi.org/10.2353/jmoldx.2009.080174
  22. Terracciano A., Pomponi M.G., Marino G.M., Chiurazzi P., Rinaldi M.M., Dobosz M., Neri G. Expansion to full mutation ofa FMR1 intermediate allele over two generations. Eur. J. Hum. Genet. 2004; 12(4): 333-6. https://dx.doi.org/10.1038/sj.ejhg.5201154
  23. Rajan-Babu I.-S., Lian M., Cheah F.S.H., Chen M., Tan A.S.C., Prasath E.B., Loh S.F., Chong S.S. FMR1 CGG repeat expansion mutation detection and linked haplotype analysis for reliable and accurate preimplantation genetic diagnosis of fragile X syndrome. Expert Rev. Mol. Med. 2017; 19: e10. https://dx.doi.org/10.1017/erm.2017.10
  24. Ardui S., Race V., de Ravel T., Van Esch H., Devriendt K., Matthijs G., Vermeesch J.R. Detecting AGG interruptions in females with a FMR1 premutation by long-read single-molecule sequencing: A 1 year clinical experience. Front. Genet. 2018; 9: 150. https://dx.doi.org/10.3389/ fgene.2018.00150

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Figure

Download (85KB)
Indexing metadata

This website uses cookies

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

About Cookies