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http://dx.doi.org/10.5653/cerm.2021.04476

Update on genetic screening and treatment for infertile men with genetic disorders in the era of assisted reproductive technology  

Lee, Seung Ryeol (Department of Urology, CHA Bundang Medical Center, CHA University)
Lee, Tae Ho (Department of Urology, Fertility Center, CHA Gangnam Medical Center, CHA University)
Song, Seung-Hun (Department of Urology, Fertility Center, CHA Gangnam Medical Center, CHA University)
Kim, Dong Suk (Department of Urology, Fertility Center, CHA Gangnam Medical Center, CHA University)
Choi, Kyung Hwa (Department of Urology, CHA Bundang Medical Center, CHA University)
Lee, Jae Ho (Department of Biomedical Science, College of Life Science, CHA University)
Kim, Dae Keun (Department of Urology, CHA Fertility Center Seoul Station, CHA University School of Medicine)
Publication Information
Clinical and Experimental Reproductive Medicine / v.48, no.4, 2021 , pp. 283-294 More about this Journal
Abstract
A genetic etiology of male infertility is identified in fewer than 25% of infertile men, while 30% of infertile men lack a clear etiology, resulting in a diagnosis of idiopathic male infertility. Advances in reproductive genetics have provided insights into the mechanisms of male infertility, and a characterization of the genetic basis of male infertility may have broad implications for understanding the causes of infertility and determining the prognosis, optimal treatment, and management of couples. In a substantial proportion of patients with azoospermia, known genetic factors contribute to male infertility. Additionally, the number of identified genetic anomalies in other etiologies of male infertility is growing through advances in whole-genome amplification and next-generation sequencing. In this review, we present an up-to-date overview of the indications for appropriate genetic tests, summarize the characteristics of chromosomal and genetic diseases, and discuss the treatment of couples with genetic infertility by microdissection-testicular sperm extraction, personalized hormone therapy, and in vitro fertilization with pre-implantation genetic testing.
Keywords
Azoospermia; Genetics; Infertility; Spermatozoa;
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1 Knowles MR, Zariwala M, Leigh M. Primary ciliary dyskinesia. Clin Chest Med 2016;37:449-61.   DOI
2 Ben Khelifa M, Coutton C, Zouari R, Karaouzene 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;94:95-104.   DOI
3 Hussein A, Ozgok Y, Ross L, Rao P, Niederberger C. Optimization of spermatogenesis-regulating hormones in patients with non-obstructive azoospermia and its impact on sperm retrieval: a multicentre study. BJU Int 2013;111(3 Pt B):E110-4.   DOI
4 Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, Schlegel PN. Successful fertility treatment for Klinefelter's syndrome. J Urol 2009;182:1108-13.   DOI
5 Snoek R, Stokman MF, Lichtenbelt KD, van Tilborg TC, Simcox CE, Paulussen AD, et al. Preimplantation genetic testing for monogenic kidney disease. Clin J Am Soc Nephrol 2020;15:1279-86.   DOI
6 Agarwal A, Majzoub A, Baskaran S, Panner Selvam MK, Cho CL, Henkel R, et al. Sperm DNA fragmentation: a new guideline for clinicians. World J Mens Health 2020;38:412-71.   DOI
7 Asero P, Calogero AE, Condorelli RA, Mongioi L, Vicari E, Lanzafame F, et al. Relevance of genetic investigation in male infertility. J Endocrinol Invest 2014;37:415-27.   DOI
8 Tuttelmann F, Ruckert C, Ropke A. Disorders of spermatogenesis: perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med Genet 2018;30:12-20.   DOI
9 Yamauchi Y, Riel JM, Ruthig V, Ward MA. Mouse Y-encoded transcription factor Zfy2 is essential for sperm formation and function in assisted fertilization. PLoS Genet 2015;11:e1005476.   DOI
10 Elliott DJ. The role of potential splicing factors including RBMY, RBMX, hnRNPG-T and STAR proteins in spermatogenesis. Int J Androl 2004;27:328-34.   DOI
11 Cimadomo D, Craciunas L, Vermeulen N, Vomstein K, Toth B. Definition, diagnostic and therapeutic options in recurrent implantation failure: an international survey of clinicians and embryologists. Hum Reprod 2021;36:305-17.   DOI
12 Kleiman SE, Yogev L, Lehavi O, Hauser R, Botchan A, Paz G, et al. The likelihood of finding mature sperm cells in men with AZFb or AZFb-c deletions: six new cases and a review of the literature (1994-2010). Fertil Steril 2011;95:2005-12.   DOI
13 Kotov AA, Olenkina OM, Godneeva BK, Adashev VE, Olenina LV. Progress in understanding the molecular functions of DDX3Y (DBY) in male germ cell development and maintenance. Biosci Trends 2017;11:46-53.   DOI
14 Amiri-Yekta A, Coutton C, Kherraf ZE, Karaouzene T, Le Tanno P, Sanati MH, et al. Whole-exome sequencing of familial cases of multiple morphological abnormalities of the sperm flagella (MMAF) reveals new DNAH1 mutations. Hum Reprod 2016;31:2872-80.   DOI
15 Lee HS, Kim MJ, Ko DS, Jeon EJ, Kim JY, Kang IS. Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease. Clin Exp Reprod Med 2013;40:163-8.   DOI
16 Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. Fertil Steril 2021;115:54-61.   DOI
17 Thirumavalavan N, Gabrielsen JS, Lamb DJ. Where are we going with gene screening for male infertility? Fertil Steril 2019;111:842-50.   DOI
18 Ramirez-Velazco A, Aguayo-Orozco TA, Figuera L, Rivera H, Jave-Suarez L, Aguilar-Lemarroy A, et al. Williams-Beuren syndrome in Mexican patients confirmed by FISH and assessed by aCGH. J Genet 2019;98:34.   DOI
19 Simoni M, Gromoll J, Dworniczak B, Rolf C, Abshagen K, Kamischke A, et al. Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia. Fertil Steril 1997;67:542-7.   DOI
20 Kamp C, Huellen K, Fernandes S, Sousa M, Schlegel PN, Mielnik A, et al. High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome. Mol Hum Reprod 2001;7:987-94.   DOI
21 Kohn TP, Kohn JR, Owen RC, Coward RM. The prevalence of Y-chromosome microdeletions in oligozoospermic men: a systematic review and meta-analysis of European and North American studies. Eur Urol 2019;76:626-36.   DOI
22 Song SH, Park SH, Shin E, Jung JH, Shim SH, Kim DS. Male infertility associated with a supernumerary marker chromosome. World J Mens Health 2017;35:205-8.   DOI
23 Lee I, Alur-Gupta S, Gallop R, Dokras A. Utilization of preimplantation genetic testing for monogenic disorders. Fertil Steril 2020;114:854-60.   DOI
24 Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, et al. European Association of Urology guidelines on male infertility: the 2012 update. Eur Urol 2012;62:324-32.   DOI
25 Rohayem J, Fricke R, Czeloth K, Mallidis C, Wistuba J, Krallmann C, et al. Age and markers of Leydig cell function, but not of Sertoli cell function predict the success of sperm retrieval in adolescents and adults with Klinefelter's syndrome. Andrology 2015;3:868-75.   DOI
26 Colaco S, Modi D. Genetics of the human Y chromosome and its association with male infertility. Reprod Biol Endocrinol 2018;16:14.   DOI
27 Collodel G, Moretti E. Sperm morphology and aneuploidies: defects of supposed genetic origin. Andrologia 2006;38:208-15.   DOI
28 Okutman O, Rhouma MB, Benkhalifa M, Muller J, Viville S. Genetic evaluation of patients with non-syndromic male infertility. J Assist Reprod Genet 2018;35:1939-51.   DOI
29 Vogt PH. Azoospermia factor (AZF) in Yq11: towards a molecular understanding of its function for human male fertility and spermatogenesis. Reprod Biomed Online 2005;10:81-93.   DOI
30 Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 2003;423:825-37.   DOI
31 Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod 2002;17:2813-24.   DOI
32 Gatta V, Stuppia L, Calabrese G, Morizio E, Guanciali-Franchi P, Palka G. A new case of Yq microdeletion transmitted from a normal father to two infertile sons. J Med Genet 2002;39:E27.   DOI
33 Krausz C, Forti G. Sperm cryopreservation in male infertility due to genetic disorders. Cell Tissue Bank 2006;7:105-12.   DOI
34 Saxena R, de Vries JW, Repping S, Alagappan RK, Skaletsky H, Brown LG, et al. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics 2000;67:256-67.   DOI
35 Dul EC, van Ravenswaaij-Arts CM, Groen H, van Echten-Arends J, Land JA. Who should be screened for chromosomal abnormalities before ICSI treatment? Hum Reprod 2010;25:2673-7.   DOI
36 Raven G, de Jong FH, Kaufman JM, de Ronde W. In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocrinol Metab 2006;91:3324-8.   DOI
37 Fisher K, Keng J, Ziegler J. Nutrition assessment and intervention in a pediatric patient with angelman syndrome: a case presentation highlighting clinical challenges and evidence-based solutions. Lifestyle Genom 2020;13:43-52.   DOI
38 de la Chapelle A. Analytic review: nature and origin of males with XX sex chromosomes. Am J Hum Genet 1972;24:71-105.
39 Dong Y, Du RC, Jiang YT, Wu J, Li LL, Liu RZ. Impact of chromosomal translocations on male infertility, semen quality, testicular volume and reproductive hormone levels. J Int Med Res 2012;40:2274-83.   DOI
40 Anton E, Blanco J, Egozcue J, Vidal F. Sperm studies in heterozygote inversion carriers: a review. Cytogenet Genome Res 2005;111:297-304.   DOI
41 Del Giudice F, Busetto GM, De Berardinis E, Sperduti I, Ferro M, Maggi M, et al. A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility. Asian J Androl 2020;22:360-7.   DOI
42 Harbuz R, Zouari R, Pierre V, Ben Khelifa M, Kharouf M, Coutton C, et al. A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation. Am J Hum Genet 2011;88:351-61.   DOI
43 Ring JD, Lwin AA, Kohler TS. Current medical management of endocrine-related male infertility. Asian J Androl 2016;18:357-63.   DOI
44 Schlegel PN. Aromatase inhibitors for male infertility. Fertil Steril 2012;98:1359-62.   DOI
45 Shiraishi K, Ohmi C, Shimabukuro T, Matsuyama H. Human chorionic gonadotrophin treatment prior to microdissection testicular sperm extraction in non-obstructive azoospermia. Hum Reprod 2012;27:331-9.   DOI
46 Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990;344:768-70.   DOI
47 Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril 2017;108:393-406.   DOI
48 Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003;18:1660-5.   DOI
49 Boroujeni PB, Sabbaghian M, Totonchi M, Sodeifi N, Sarkardeh H, Samadian A, et al. Expression analysis of genes encoding TEX11, TEX12, TEX14 and TEX15 in testis tissues of men with non-obstructive azoospermia. JBRA Assist Reprod 2018;22:185-92.
50 Obradors A, Fernandez E, Rius M, Oliver-Bonet M, Martinez-Fresno M, Benet J, et al. Outcome of twin babies free of Von Hippel-Lindau disease after a double-factor preimplantation genetic diagnosis: monogenetic mutation analysis and comprehensive aneuploidy screening. Fertil Steril 2009;91:933.
51 Chang LJ, Chen SU, Tsai YY, Hung CC, Fang MY, Su YN, et al. An update of preimplantation genetic diagnosis in gene diseases, chromosomal translocation, and aneuploidy screening. Clin Exp Reprod Med 2011;38:126-34.   DOI
52 Fruhmesser A, Kotzot D. Chromosomal variants in Klinefelter syndrome. Sex Dev 2011;5:109-23.   DOI
53 Martin RH. Cytogenetic determinants of male fertility. Hum Reprod Update 2008;14:379-90.   DOI
54 Krausz C, Casamonti E. Spermatogenic failure and the Y chromosome. Hum Genet 2017;136:637-55.   DOI
55 Belling K, Russo F, Jensen AB, Dalgaard MD, Westergaard D, Rajpert-De Meyts E, et al. Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity. Hum Mol Genet 2017;26:1219-29.   DOI
56 Wong EC, Ferguson KA, Chow V, Ma S. Sperm aneuploidy and meiotic sex chromosome configurations in an infertile XYY male. Hum Reprod 2008;23:374-8.   DOI
57 Speed RM, Faed MJ, Batstone PJ, Baxby K, Barnetson W. Persistence of two Y chromosomes through meiotic prophase and metaphase I in an XYY man. Hum Genet 1991;87:416-20.   DOI
58 Vorona E, Zitzmann M, Gromoll J, Schuring AN, Nieschlag E. Clinical, endocrinological, and epigenetic features of the 46,XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab 2007;92:3458-65.   DOI
59 Wu QY, Li N, Li WW, Li TF, Zhang C, Cui YX, et al. Clinical, molecular and cytogenetic analysis of 46, XX testicular disorder of sex development with SRY-positive. BMC Urol 2014;14:70.   DOI
60 Antonelli A, Gandini L, Petrinelli P, Marcucci L, Elli R, Lombardo F, et al. Chromosomal alterations and male infertility. J Endocrinol Invest 2000;23:677-83.   DOI
61 Anton E, Vidal F, Egozcue J, Blanco J. Genetic reproductive risk in inversion carriers. Fertil Steril 2006;85:661-6.   DOI
62 Dagdeviren Cakir A, Bas F, Akin O, Siklar Z, Ozcabi B, Berberoglu M, et al. Clinical characteristics and growth hormone treatment in patients with Prader-Willi syndrome. J Clin Res Pediatr Endocrinol 2021;13:308-19.   DOI
63 Yatsenko AN, Georgiadis AP, Ropke A, Berman AJ, Jaffe T, Olszewska M, et al. X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med 2015;372:2097-107.   DOI
64 Del Giudice F, Kasman AM, Ferro M, Sciarra A, De Berardinis E, Belladelli F, et al. Clinical correlation among male infertility and overall male health: a systematic review of the literature. Investig Clin Urol 2020;61:355-71.   DOI
65 Song SH, Chiba K, Ramasamy R, Lamb DJ. Recent advances in the genetics of testicular failure. Asian J Androl 2016;18:350-5.   DOI
66 Frydman N, Romana S, Le Lorc'h M, Vekemans M, Frydman R, Tachdjian G. Assisting reproduction of infertile men carrying a Robertsonian translocation. Hum Reprod 2001;16:2274-7.   DOI
67 Foresta C, Ferlin A, Moro E. Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum Mol Genet 2000;9:1161-9.   DOI
68 Vinci G, Chantot-Bastaraud S, El Houate B, Lortat-Jacob S, Brauner R, McElreavey K. Association of deletion 9p, 46,XY gonadal dysgenesis and autistic spectrum disorder. Mol Hum Reprod 2007;13:685-9.   DOI
69 Kuroda S, Usui K, Sanjo H, Takeshima T, Kawahara T, Uemura H, et al. Genetic disorders and male infertility. Reprod Med Biol 2020;19:314-22.   DOI
70 Vernet N, Mahadevaiah SK, Yamauchi Y, Decarpentrie F, Mitchell MJ, Ward MA, et al. Mouse Y-linked Zfy1 and Zfy2 are expressed during the male-specific interphase between meiosis I and meiosis II and promote the 2nd meiotic division. PLoS Genet 2014;10:e1004444.   DOI
71 Yang F, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ. Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis. J Cell Biol 2008;180:673-9.   DOI
72 Bashamboo A, Ferraz-de-Souza B, Lourenco D, Lin L, Sebire NJ, Montjean D, et al. Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet 2010;87:505-12.   DOI
73 Li Y, Zhang DJ, Qiu Y, Kido T, Lau YC. The Y-located proto-oncogene TSPY exacerbates and its X-homologue TSPX inhibits transactivation functions of androgen receptor and its constitutively active variants. Hum Mol Genet 2017;26:901-12.   DOI
74 Mou L, Wang Y, Li H, Huang Y, Jiang T, Huang W, et al. A dominant-negative mutation of HSF2 associated with idiopathic azoospermia. Hum Genet 2013;132:159-65.   DOI
75 Lopes AM, Aston KI, Thompson E, Carvalho F, Goncalves J, Huang N, et al. Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1. PLoS Genet 2013;9:e1003349.   DOI
76 Coutton C, Escoffier J, Martinez G, Arnoult C, Ray PF. Teratozoospermia: spotlight on the main genetic actors in the human. Hum Reprod Update 2015;21:455-85.   DOI
77 Guttenbach M, Engel W, Schmid M. Analysis of structural and numerical chromosome abnormalities in sperm of normal men and carriers of constitutional chromosome aberrations: a review. Hum Genet 1997;100:1-21.   DOI