Current Approach to Genetic Causes of Male Infertility and Genetic Counseling

Abstract

Generally, infertility is defined as the inability of couples who have had unprotected and regular intercourse for at least 12 months or longer to conceive naturally. When all societies in the world are examined, infertility is an important health problem affecting approximately 48 million couples, and it also has socio-cultural, economic, and psychological effects. While 8-12% of reproductive age couples have infertility problems, when gender-related reasons are examined, 20-30% of these reasons are male, 20-30% are female, and 25-40% are together with couples. While the etiology of 60% of male infertility causes has not been clarified yet, congenital urogenital anomalies are the most common causes, and genetic causes are the second most common cause among the known causes. While investigating genetic etiology in patients, chromosomal anomalies and Y microdeletions are at the forefront; however, the importance of monogenic causes has increased as some known genes have been associated with infertility because of familial segregation studies and the whole exome analyses with the development of new generation sequencing technologies. In this review, genetic causes of male infertility, diagnosis, and treatment approaches for genetic causes were examined by the current literature, and the importance of providing the proper genetic counseling to infertility patients was mentioned.

Keywords

• Genetics
• male
• infertility
• genetic counseling

Erkek İnfertilitesinin Genetik Nedenlerine Güncel Yaklaşım ve Genetik Danışmanlık

Abstract

Genel olarak infertilite, en az 12 ay veya daha uzun süre korunmasız ve düzenli cinsel ilişki yaşayan çiftlerin doğal yollarla gebe kalamaması olarak tanımlanmaktadır. Dünyadaki tüm toplumlar incelendiğinde, infertilite yaklaşık olarak 48 milyon çifti etkileyen önemli bir sağlık sorunu olmanın yanı sıra, sosyo-kültürel, ekonomik ve psikolojik etkileri de bulunmaktadır. Üreme çağındaki çiftlerin %8-12’si infertilite problemi yaşarken, cinsiyete bağlı sebepler incelendiğinde, bu nedenlerin %20-30’unu erkek cinsiyet, %20-30’unu kadın cinsiyet ve %25-40’ını çiftler beraber oluşturmaktadır. Erkek cinsiyet kaynaklı infertilite nedenlerinin %60’ının etiyolojisi henüz aydınlatılmamışken, bilinen nedenler arasında doğumsal ürogenital anomaliler en sık nedenler ve genetik nedenler ise ikinci sıklıktaki nedenlerdir. Hastalarda genetik etiyoloji araştırılırken kromozomal anomalileri ve Y mikrodelesyonları ön planda izlenmektedir, ancak, yeni nesil dizileme teknolojilerinin gelişmesiyle birlikte yapılan ailesel segregasyon çalışmaları ve tüm ekzom analizleri sonucunda bilinen bazı genlerin infertilite ile ilişkilendirilmesiyle monogenik nedenlerin önemi artmıştır. Bu derlemede, erkek infertilitesinin genetik nedenleri, genetik nedenlere yönelik tanı ve tedavi yaklaşımları güncel literatürle uyumlu bir şekilde incelenmiş ve infertilite hastalarına doğru genetik danışmanlığın sağlanmasının öneminden bahsedilmiştir.

Keywords

• Genetik
• erkek
• infertilite
• genetik danışmanlık

References

1. Parıltay E, Özkınay F. Recent advancement the genetics of isiopathic azoospermia. In: Çefle K, Öztürk Ş, editors. Infertility and genetic aspects. 1st ed. Ankara: Türkiye Klinikleri; 2019. p.32-7. Turkish.
2. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9(12):e1001356.
3. Kumar N, Singh AK. Trends of male factor infertility, an important cause of infertility: A review of literature. J Hum Reprod Sci. 2015;8(4):191-6.
4. Laan M, Kasak L, Punab M. Translational aspects of novel findings in genetics of male infertility-status quo 2021. Br Med Bull. 2021;140(1):5-22.
5. Zemrani Y, Taoufik L, Ait Zirri K, Ghoundale O, El Mezouari E, Moutaj R. Spermogram and male fertility: hospital experience in military Avicenna of Marrakech. Am J Med Case Rep. 2019;7(6):104-8.
6. Ceylaner G, Ceylaner S. Single gene disorders associated with male infertility. In: Çefle K, Öztürk Ş, editors. Infertility and genetic aspects. 1st ed. Ankara: Türkiye Klinikleri; 2019. p.57-64. Turkish.
7. Cioppi F, Rosta V, Krausz C. Genetics of azoospermia. Int J Mol Sci. 2021;22(6):3264.
8. Houston BJ, Riera-Escamilla A, Wyrwoll MJ, Salas-Huetos A, Xavier MJ, Nagirnaja L, et al. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships. Hum Reprod Update. 2021;28(1):15-29.

9. Krausz C, Riera-Escamilla A. Genetics of male infertility. Nat Rev Urol. 2018;15(6):369-84.
10. Wosnitzer M, Goldstein M, Hardy MP. Review of azoospermia. Spermatogenesis. 2014;4:e28218.
11. Lee JY, Dada R, Sabanegh E, Carpi A, Agarwal A. Role of genetics in azoospermia. Urology. 2011;77(3):598-601.
12. Kasak L, Laan M. Monogenic causes of non-obstructive azoospermia: challenges, established knowledge, limitations and perspectives. Hum Genet. 2021;140(1):135-54.
13. Nieschlag E. Klinefelter syndrome: the commonest form of hypogonadism, but often overlooked or untreated. Dtsch Arztebl Int. 2013;110(20):347-53.
14. Öztürk Ş. Male infertility: chromosomal causes. In: Çefle K, Öztürk Ş, editors. Infertility and genetic aspects. 1st ed. Ankara: Türkiye Klinikleri; 2019. p.12-9. Turkish.
15. Gürkan H. Y chromosome microdeletion and Y chromosome genes affecting fertility. In: Çefle K, Öztürk Ş, editors. Infertility and genetic aspects. 1st ed. Ankara: Türkiye Klinikleri; 2019. p.25-31. Turkish.
16. Deng J, Zhang H, Li C, Huang H, Liu S, Yang H, et al. 46,XX testicular disorders of sex development with DMD gene mutation: first case report identified prenatally by integrated analyses in China. Front Genet. 2020;10:1350.
17. Behre HM, Bergmann M, Simoni M, Tüttelmann F. Primary testicular failure. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000.
18. Berglund A, Viuff MH, Skakkebæk A, Chang S, Stochholm K, Gravholt CH. Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet J Rare Dis. 2019;14(1):16.
19. Berglund A, Stochholm K, Gravholt CH. The epidemiology of sex chromosome abnormalities. Am J Med Genet C Semin Med Genet. 2020;184(2):202-15.
20. Re L, Birkhoff JM. The 47,XYY syndrome, 50 years of certainties and doubts: A systematic review. Aggress Violent Behav. 2015;22:9-17.
21. Parizot E, Dard R, Janel N, Vialard F. Down syndrome and infertility: what support should we provide? J Assist Reprod Genet. 2019;36(6):1063-7.
22. Ray PF, Toure A, Metzler-Guillemain C, Mitchell MJ, Arnoult C, Coutton C. Genetic abnormalities leading to qualitative defects of sperm morphology or function. Clin Genet. 2017;91(2):217-32.
23. Fesahat F, Henkel R, Agarwal A. Globozoospermia syndrome: An update. Andrologia. 2020;52(2):e13459.
24. Yatsenko AN, O'Neil DS, Roy A, Arias-Mendoza PA, Chen R, Murthy LJ, et al. Association of mutations in the zona pellucida binding protein 1 (ZPBP1) gene with abnormal sperm head morphology in infertile men. Mol Hum Reprod. 2012;18(1):14-21.
25. Jiao SY, Yang YH, Chen SR. Molecular genetics of infertility: loss-of-function mutations in humans and corresponding knockout/mutated mice. Hum Reprod Update. 2021;27(1):154-89.
26. Ghédir H, Gribaa M, Mamaî O, Ben Charfeddine I, Braham A, Amara A, et al. Macrozoospermia: screening for the homozygous c.144delC mutation in AURKC gene in infertile men and estimation of its heterozygosity frequency in the Tunisian population. J Assist Reprod Genet. 2015;32(11):1651-8.
27. Ortega V, Oyanedel J, Fleck-Lavergne D, Horta F, Mercado A, Palma-Ceppi C. Macrozoospermia associated with mutations of AURKC gene: First case report in Latin America and literature review. Rev Int Androl. 2020;18(4):159-63.
28. Chemes HE. Phenotypic varieties of sperm pathology: Genetic abnormalities or environmental influences can result in different patterns of abnormal spermatozoa. Anim Reprod Sci. 2018;194:41-56.
29. Chemes HE, Puigdomenech ET, Carizza C, Olmedo SB, Zanchetti F, Hermes R. Acephalic spermatozoa and abnormal development of the head–neck attachment: a human syndrome of genetic origin. Hum Reprod. 1999;14(7):1811-8.
30. Chemes HE, Carizza C, Scarinci F, Brugo S, Neuspiller N, Schwarsztein L. Lack of a head in human spermatozoa from sterile patients: a syndrome associated with impaired fertilization. Fertil Steril. 1987;47(2):310-6.
31. Perotti ME, Giarola A, Gioria M. Ultrastructural study of the decapitated sperm defect in an infertile man. J Reprod Fertil. 1981;63(2):543-9.
32. Sha Y, Liu W, Li L, Serafimovski M, Isachenko V, Li Y, et al. Pathogenic variants in ACTRT1 cause acephalic spermatozoa syndrome. Front Cell Dev Biol. 2021;9:676246.
33. Mazaheri Moghaddam M, Mazaheri Moghaddam M, Hamzeiy H, Baghbanzadeh A, Pashazadeh F, Sakhinia E. Genetic basis of acephalic spermatozoa syndrome, and intracytoplasmic sperm injection outcomes in infertile men: a systematic scoping review. J Assist Reprod Genet. 2021;38(3):573-86.
34. Wang WL, Tu CF, Tan YQ. Insight on multiple morphological abnormalities of sperm flagella in male infertility: what is new? Asian J Androl. 2020;22(3):236-45.
35. Touré A, Martinez G, Kherraf ZE, Cazin C, Beurois J, Arnoult C, et al. The genetic architecture of morphological abnormalities of the sperm tail. Hum Genet. 2021;140(1):21-42.
36. Ben Khelifa M, Coutton C, Zouari R, Karaouzène T, Rendu J, Bidart M, et al. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94(1):95-104.
37. Kherraf ZE, Cazin C, Coutton C, Amiri-Yekta A, Martinez G, Boguenet M, et al. Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations. Clin Genet. 2019;96(5):394-401.
38. Millar AC, Faghfoury H, Bieniek JM. Genetics of hypogonadotropic hypogonadism. Transl Androl Urol. 2021;10(3):1401-9.
39. Krausz C, Riera-Escamilla A. Monogenic forms of male infertility. Exp Suppl. 2019;111:341-66.
40. Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A. Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. Front Endocrinol (Lausanne). 2014;5:109.
41. Topaloğlu AK. Update on the genetics of idiopathic hypogonadotropic hypogonadism. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):113-22.
42. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, et al. European consensus statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547-64.
43. Lima Amato LG, Latronico AC, Gontijo Silveira LF. Molecular and genetic aspects of congenital isolated hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am. 2017;46(2):283-303.
44. Liu Y, Zhi X. Advances in genetic diagnosis of Kallmann syndrome and genetic interruption. Reprod Sci. 2022;29(6):1697-709.
45. Hsu P, Ma A, Wilson M, Williams G, Curotta J, Munns CF, et al. CHARGE syndrome: a review. J Paediatr Child Health. 2014;50(7):504-11.
46. Huang S, Song J, He C, Cai X, Yuan K, Mei L, et al. Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome. Gene Ther. 2021;[Epub ahead of print]. doi: 10.1038/s41434-021-00240-2.
47. Mehmood S, Hoggard N, Hadjivassiliou M. Gordon Holmes syndrome: finally genotype meets phenotype. Pract Neurol. 2017;17(6):476-8.