CFTR mutations in male infertility

CFTR mutation analysis is recommended for congenital bilateral aplasia of the vas deferens as well as for cystic fibrosis. Aside azoospermia, the association of CFTR mutations with male infertility is still unclear. A total of 2146 men from couples with reproductive problems were screened for CFTR mutation and intron 8 poly-Т polymorphism (IVS8). Semen analysis was examined for 1820 men. Molecular haplotyping to detect linked TG repeats was performed for IVS8 5T cases. Among 5T alleles only 5T-12TG and 5T-13TG were classified as mutations. Our data showed that 12 patients were compound heterozygotes (all azoospermic) and 4.2% patients were carriers of one mutation. CFTR mutation frequency was significantly higher for azoospermia group to compare with oligozoospermia, severe oligozoospermia, asthenozoospermia and normozoospermia groups. For couples in which man had compound genotype we analyzed infertility threatment accomplished in our clinic (N = 8): 13 IVF-ICSI cycles (in vitro fertilization and intracytoplasmic sperm injection) and two artificial inseminations with donor sperms. Acceptable quality testicular sperms for ICSI have been received by testicular biopsy in all cases. Pregnancy and delivery were achieved for 7 couples.

CFTR, мужское бесплодие, азооспермия, ВДОСП, аллель 5T и повторы IVS8, тестикулярные сперматозоиды, ЭКО-ИКСИ, CFTR, male infertility, azoospermia, CBAVD, IVS8 5T and TG repeats, testicular sperms, IVF-ICSI

1. Иващенко ТЭ, Баранов ВС. Биохимические и молекулярно-генетические основы патогенеза муковисцидоза. Интермедика, Санкт-Петербург. 2002:256.

2. Андрология. Мужское здоровье и дисфункция репродуктивной системы. Под ред. Нишлага Э, Бере ГМ. Медицинское информационное агентство. 2005:554.

3. Claustres M. Molecular pathology of the CFTR locus in male infertility. Reproductive BioMedicine Online. 2005;10(1):14-41.

4. Phillipson GTM, Petrucco OM, Matthews CD. Congenital bilateral aplasia of the vas deferens, cystic fibrosis mutation analysis and intracytoplasmic sperm injection. Human Reproduction. 2000; 15(2):431-435.

5. Dequeker E, Stuhrmann M, Morris M et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders - updated European recommendations. European Journal of Human Genetics. 2008:1-15.

6. Yu J, Chen Z, Ni Y, Li Z. CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis. Human Reproduction. 2012; 27(1):25-35.

7. Yu J, Chen Z, Zhang T. et al. Association of genetic variants in CFTR gene, IVS8 c.1210-12T[5_9] and c.1210-35_1210-12GT[8_12], with spermatogenetic failure: case-control study and meta-analysis. Molecular Human Reproduction. 2011; 17(9):594-603.

8. Technical Standards and Guidelines for CFTR Mutation Testing. American College of Medical Genetics. 2011. http://www.acmg.net/docs/CFTR_Mutation_Testing_2011.pdf

9. Diagnostic evaluation of the infertile male: a committee opinion. Practice Committee of the American Society for Reproductive Medicine Fertility and Sterility. 2015; 103(3):e18-e25.

10. Male Infertility. Diagnosis and Treatment. Ed. Oehninger S.C., Kruger T.F. Informa Healthcare 2007:468.

11. Mocanu E, Shattock R, Barton D et al. All azoospermic males should be screened for cystic fibrosis mutations before intracytoplasmic sperm injection. Fertility and Sterility. 2010; 94(6):2448-5240.

12. Петрова НВ, Кондратьева ЕИ, Красовский СА и др. Проект национального консенсуса «Муковисцидоз: определение, диагностические критерии и терапия». Раздел «Генетика муковисцидоза. Молекулярно-генетическая диагностика при муковисцидозе». Медицинская генетика. 2016;15(11):29-43.

13. Chen H, Ruan YC, Xu WM et al. Regulation of male fertility by CFTR and implications in male infertility. Human Reproduction Update. 2012; 18(6):703-713.

14. Маркова ЕВ, Татару ДА, Преда ОГ. Фрагментный анализ полиморфизма (TG)mTn интрона 8 гена CFTR. Медицинская генетика. 2017;16(1):11-19.

15. Руководство ВОЗ по исследованию и обработке эякулята человека. Пятое издание (2010). Капитал принт. 2012:291.

16. Josserand RN, Bey-Omar F, Rollet J et al. Cystic fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens. Human Reproduction. 2001; 16(10):2093-2097.

17. Castellani C, Cuppens H, Macek M. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. Journal of Cystic Fibrosis. 2008; 7:179-196.

18. Маркова Е.В., Татару Д.А. STR-маркеры хромосом, несущих мутации F508del и CFTRdele2,3(21kb) гена CFTR. Медицинская генетика. 2017; 16(6):9-20.

19. Elhanbly S, El-ASied A, Fawzy M et al. Relationship of paternal age with outcome of percutaneous epididymal sperm aspiration - in intracytoplasmic sperm injection, in cases of congenital bilateral aplasia of the vas deferens. Fertility and Sterility. 2015; 104(3):602-606.

20. Lu S, Cui Y, Zhang H et al. Association of cystic fibrosis transmembrane-conductance regulator gene mutation with negative outcome of intracytoplasmic sperm injection pregnancy in cases of congenital bilateral absence of vas deferens. Fertility and Sterility. 2014; 101(5):1255-1260.

21. Llabador MA, Pagin A, Lefebvre-Maunoury C et al. Congenital bilateral absence of the vas deferens: the impact of spermatogenesis quality on intracytoplasmic sperm injection outcomes in 108 men. Andrology. 2015; 3:473-480.

22. Регистр ВРТ. Отчет за 2014 год. http://www.rahr.ru/d_registr_otchet/registr_BRT_RARCH16.pdf

23. Wong LC, Alper O, Hsu A et al. The necessity of complete CFTR mutation analysis of an infertile couple before in vitro fertilization. Fertility and Sterility. 2004; 82(4):947-949.

24. Шерман ВД, Капранов НИ, Каширская НЮ, Кондратьева ЕИ. Роль неонатального скрининга в оптимизации медицинской помощи больным муковисцидозом в России. Медицинская генетика. 2013; 12(11):24-28.