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Genetic Evaluation of Male Infertility

  • Khalid A. Fakhro
  • Amal Robay
  • Juan L. Rodriguez-Flores
  • Ronald G. CrystalEmail author
Chapter
  • 68 Downloads

Abstract

Male infertility affects 7% of all men worldwide, yet for the majority the underlying cause is not found. From the very first identified karyotyping abnormalities to the very recent discovery of point mutations disrupting spermatogenesis, it is clear that a substantial number of patients suffer from genetic abnormalities. However, the discovery of these causes has largely been limited by the resolutions of the technologies used for patient assessment. In recent years, the advent of better tools and more comprehensive databases of genetic variations has led to profound discoveries of genes and pathways underlying male infertility. This chapter reviews these technologies and the discoveries they have led to and sets the scene for the transformation of infertile patient care in the era of next-generation sequencing.

Keywords

Infertility  Genetic testing  Karyotyping  Fluorescence in situ hybridization  Chromosome  AZF region  Next-generation sequencing 

References

  1. 1.
    Brugh VM 3rd, Lipshultz LI. Male factor infertility: evaluation and management. Med Clin North Am. 2004;88:367–85.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Tournaye H, Krausz C, Oates RD. Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes Endocrinol. 2017;5:544–53.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231–45.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    White MJD. The chromosomes. 6th ed. New York: Chapman and Hall, distributed by Halsted Press; 1973.Google Scholar
  6. 6.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Lotti F, Maggi M. Ultrasound of the male genital tract in relation to male reproductive health. Hum Reprod Update. 2015;21:56–83.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    McCallum T, Milunsky J, Munarriz R, Carson R, Sadeghi-Nejad H, Oates R. Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: phenotypic findings and genetic considerations. Hum Reprod. 2001;16:282–8.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Oates RD, Amos JA. The genetic basis of congenital bilateral absence of the vas deferens and cystic fibrosis. J Androl. 1994;15:1–8.PubMedPubMedCentralGoogle Scholar
  10. 10.
    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. Hum Reprod. 2012;27:25–35.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Huang JX, Scott MB, Pu XY, Zhou-Cun A. Association between single-nucleotide polymorphisms of DNMT3L and infertility with azoospermia in Chinese men. Reprod Biomed Online. 2012;24:66–71.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Yang B, Wang J, Zhang W, Pan H, Li T, Liu B, et al. Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population. Andrology. 2017;5:954–7.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, et al. Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol Cell Biol. 2004;24:8642–8.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Patat O, Pagin A, Siegfried A, Mitchell V, Chassaing N, Faguer S, et al. Truncating mutations in the adhesion G protein-coupled receptor G2 gene ADGRG2 cause an X-linked congenital bilateral absence of Vas Deferens. Am J Hum Genet. 2016;99:437–42.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Krausz C, Hoefsloot L, Simoni M, Tuttelmann F. European Academy of A, European Molecular Genetics Quality N. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state-of-the-art 2013. Andrology. 2014;2:5–19.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1996;5:933–43.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Lo Giacco D, Chianese C, Sanchez-Curbelo J, Bassas L, Ruiz P, Rajmil O, et al. Clinical relevance of Y-linked CNV screening in male infertility: new insights based on the 8-year experience of a diagnostic genetic laboratory. Eur J Hum Genet. 2014;22:754–61.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Krausz C, Casamonti E. Spermatogenic failure and the Y chromosome. Hum Genet. 2017;136:637–55.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Krausz C, Degl’Innocenti S, Nuti F, Morelli A, Felici F, Sansone M, et al. Natural transmission of USP9Y gene mutations: a new perspective on the role of AZFa genes in male fertility. Hum Mol Genet. 2006;15:2673–81.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Tyler-Smith C, Krausz C. The will-o’-the-wisp of genetics--hunting for the azoospermia factor gene. N Engl J Med. 2009;360:925–7.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Repping S, Skaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet. 2002;71:906–22.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Nathanson KL, Kanetsky PA, Hawes R, Vaughn DJ, Letrero R, Tucker K, et al. The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum Genet. 2005;77:1034–43.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Krausz C. Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011;25:271–85.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Calogero AE, Giagulli VA, Mongioi LM, Triggiani V, Radicioni AF, Jannini EA, et al. Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J Endocrinol Investig. 2017;40:705–12.CrossRefGoogle Scholar
  26. 26.
    Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, Bouligand J, et al. GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178:R55–80.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Morin SJ, Eccles J, Iturriaga A, Zimmerman RS. Translocations, inversions and other chromosome rearrangements. Fertil Steril. 2017;107:19–26.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Therman E, Susman B, Denniston C. The nonrandom participation of human acrocentric chromosomes in Robertsonian translocations. Ann Hum Genet. 1989;53:49–65.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Elbardisi H, Majzoub A, Al Said S, Al Rumaihi K, El Ansari W, Alattar A, et al. Geographical differences in semen characteristics of 13 892 infertile men. Arab J Urol. 2018;16:3–9.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Staessen C, Tournaye H, Van Assche E, Michiels A, Van Landuyt L, Devroey P, et al. PGD in 47,XXY Klinefelter’s syndrome patients. Hum Reprod Update. 2003;9:319–30.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Yang F, Silber S, Leu NA, Oates RD, Marszalek JD, Skaletsky H, et al. TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse. EMBO Mol Med. 2015;7:1198–210.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Fakhro KA, Elbardisi H, Arafa M, Robay A, Rodriguez-Flores JL, Al-Shakaki A, et al. Point-of-care whole-exome sequencing of idiopathic male infertility. Genet Med. 2018;20:1365–73.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Adelman CA, Petrini JH. ZIP4H (TEX11) deficiency in the mouse impairs meiotic double strand break repair and the regulation of crossing over. PLoS Genet. 2008;4:e1000042.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro M. The androgen receptor gene mutations database: 2012 update. Hum Mutat. 2012;33:887–94.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Gao T, Marcelli M, McPhaul MJ. Transcriptional activation and transient expression of the human androgen receptor. J Steroid Biochem Mol Biol. 1996;59:9–20.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Davis-Dao CA, Tuazon ED, Sokol RZ, Cortessis VK. Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis. J Clin Endocrinol Metab. 2007;92:4319–26.PubMedCrossRefGoogle Scholar
  38. 38.
    Tuttelmann F, Simoni M, Kliesch S, Ledig S, Dworniczak B, Wieacker P, et al. Copy number variants in patients with severe oligozoospermia and Sertoli-cell-only syndrome. PLoS One. 2011;6:e19426.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Krausz C, Giachini C, Lo Giacco D, Daguin F, Chianese C, Ars E, et al. High resolution X chromosome-specific array-CGH detects new CNVs in infertile males. PLoS One. 2012;7:e44887.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Stouffs K, Vandermaelen D, Massart A, Menten B, Vergult S, Tournaye H, et al. Array comparative genomic hybridization in male infertility. Hum Reprod. 2012;27:921–9.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Shen Y, Xu J, Yang X, Liu Y, Ma Y, Yang D, et al. Evidence for the involvement of the proximal copy of the MAGEA9 gene in Xq28-linked CNV67 specific to spermatogenic failure. Biol Reprod. 2017;96:610–6.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Chianese C, Gunning AC, Giachini C, Daguin F, Balercia G, Ars E, et al. X chromosome-linked CNVs in male infertility: discovery of overall duplication load and recurrent, patient-specific gains with potential clinical relevance. PLoS One. 2014;9:e97746.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Krausz C, Escamilla AR, Chianese C. Genetics of male infertility: from research to clinic. Reproduction. 2015;150:R159–74.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Mitchell MJ, Metzler-Guillemain C, Toure A, Coutton C, Arnoult C, Ray PF. Single gene defects leading to sperm quantitative anomalies. Clin Genet. 2017;91:208–16.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Ayhan O, Balkan M, Guven A, Hazan R, Atar M, Tok A, et al. Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet. 2014;51:239–44.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Maor-Sagie E, Cinnamon Y, Yaacov B, Shaag A, Goldsmidt H, Zenvirt S, et al. Deleterious mutation in SYCE1 is associated with non-obstructive azoospermia. J Assist Reprod Genet. 2015;32:887–91.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Okutman O, Muller J, Baert Y, Serdarogullari M, Gultomruk M, Piton A, et al. Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family. Hum Mol Genet. 2015;24:5581–8.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Ramasamy R, Bakircioglu ME, Cengiz C, Karaca E, Scovell J, Jhangiani SN, et al. Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia. Fertil Steril. 2015;104:286–91.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Tenenbaum-Rakover Y, Weinberg-Shukron A, Renbaum P, Lobel O, Eideh H, Gulsuner S, et al. Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure. J Med Genet. 2015;52:391–9.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Arafat M, Har-Vardi I, Harlev A, Levitas E, Zeadna A, Abofoul-Azab M, et al. Mutation in TDRD9 causes non-obstructive azoospermia in infertile men. J Med Genet. 2017;54:633–9.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Gershoni M, Hauser R, Yogev L, Lehavi O, Azem F, Yavetz H, et al. A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes. Genet Med. 2017;19:998–1006.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Kherraf ZE, Christou-Kent M, Karaouzene T, Amiri-Yekta A, Martinez G, Vargas AS, et al. SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes. EMBO Mol Med. 2017;9:1132–49.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Consortium GT. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–5.CrossRefGoogle Scholar
  55. 55.
    Li L, Sha Y, Wang X, Li P, Wang J, Kee K, et al. Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa. Oncotarget. 2017;8:19914–22.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Shang Y, Zhu F, Wang L, Ouyang YC, Dong MZ, Liu C, et al. Essential role for SUN5 in anchoring sperm head to the tail. elife. 2017;6:e28199.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Sha YW, Sha YK, Ji ZY, Mei LB, Ding L, Zhang Q, et al. TSGA10 is a novel candidate gene associated with acephalic spermatozoa. Clin Genet. 2018;93:776–83.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Zhu F, Wang F, Yang X, Zhang J, Wu H, Zhang Z, et al. Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome. Am J Hum Genet. 2016;99:942–9.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    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;47:310–6.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Dieterich K, Soto Rifo R, Faure AK, Hennebicq S, Ben Amar B, Zahi M, et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet. 2007;39:661–5.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Ben Khelifa M, Coutton C, Blum MG, Abada F, Harbuz R, Zouari R, et al. Identification of a new recurrent aurora kinase C mutation in both European and African men with macrozoospermia. Hum Reprod. 2012;27:3337–46.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Adachi T, Kawamura K, Furusawa Y, Nishizaki Y, Imanishi N, Umehara S, et al. Japan’s initiative on rare and undiagnosed diseases (IRUD): towards an end to the diagnostic odyssey. Eur J Hum Genet. 2017;25:1025–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Wang X, Jin H, Han F, Cui Y, Chen J, Yang C, et al. Homozygous DNAH1 frameshift mutation causes multiple morphological anomalies of the sperm flagella in Chinese. Clin Genet. 2017;91:313–21.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Baccetti B, Collodel G, Estenoz M, Manca D, Moretti E, Piomboni P. Gene deletions in an infertile man with sperm fibrous sheath dysplasia. Hum Reprod. 2005;20:2790–4.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Tang S, Wang X, Li W, Yang X, Li Z, Liu W, et al. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2017;100:854–64.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Knowles MR, Zariwala M, Leigh M. Primary ciliary dyskinesia. Clin Chest Med. 2016;37:449–61.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Takeuchi K, Kitano M, Kiyotoshi H, Ikegami K, Ogawa S, Ikejiri M, et al. A targeted next-generation sequencing panel reveals novel mutations in Japanese patients with primary ciliary dyskinesia. Auris Nasus Larynx. 2018;45:585–91.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Avidan N, Tamary H, Dgany O, Cattan D, Pariente A, Thulliez M, et al. CATSPER2, a human autosomal nonsyndromic male infertility gene. Eur J Hum Genet. 2003;11:497–502.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Zhang Y, Malekpour M, Al-Madani N, Kahrizi K, Zanganeh M, Lohr NJ, et al. Sensorineural deafness and male infertility: a contiguous gene deletion syndrome. J Med Genet. 2007;44:233–40.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Avenarius MR, Hildebrand MS, Zhang Y, Meyer NC, Smith LL, Kahrizi K, et al. Human male infertility caused by mutations in the CATSPER1 channel protein. Am J Hum Genet. 2009;84:505–10.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet. 2010;11:31–46.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11:415–25.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Biesecker LG, Burke W, Kohane I, Plon SE, Zimmern R. Next-generation sequencing in the clinic: are we ready? Nat Rev Genet. 2012;13:818–24.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745–55.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Xi R, Kim TM, Park PJ. Detecting structural variations in the human genome using next generation sequencing. Brief Funct Genomics. 2010;9:405–15.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Koboldt DC, Larson DE, Chen K, Ding L, Wilson RK. Massively parallel sequencing approaches for characterization of structural variation. Methods Mol Biol. 2012;838:369–84.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Genomes Project C, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–73.CrossRefGoogle Scholar
  80. 80.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Rehm HL, Bale SJ, Bayrak-Toydemir P, Berg JS, Brown KK, Deignan JL, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013;15:733–47.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Koziel JA, Frana TS, Ahn H, Glanville TD, Nguyen LT, van Leeuwen JH. Efficacy of NH3 as a secondary barrier treatment for inactivation of Salmonella Typhimurium and methicillin-resistant Staphylococcus aureus in digestate of animal carcasses: Proof-of-concept. PLoS One. 2017;12:e0176825.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Lu C, Xu M, Wang R, Qin Y, Wang Y, Wu W, et al. Pathogenic variants screening in five non-obstructive azoospermia-associated genes. Mol Hum Reprod. 2014;20:178–83.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Xu M, Qin Y, Qu J, Lu C, Wang Y, Wu W, et al. Evaluation of five candidate genes from GWAS for association with oligozoospermia in a Han Chinese population. PLoS One. 2013;8:e80374.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Okutman O, Muller J, Skory V, Garnier JM, Gaucherot A, Baert Y, et al. A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family. J Assist Reprod Genet. 2017;34:683–94.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Oud MS, Ramos L, O’Bryan MK, McLachlan RI, Okutman O, Viville S, et al. Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia. Hum Mutat. 2017;38:1592.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Dong Y, Pan Y, Wang R, Zhang Z, Xi Q, Liu RZ. Copy number variations in spermatogenic failure patients with chromosomal abnormalities and unexplained azoospermia. Genet Mol Res. 2015;14:16041–9.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    van der Ven K, Fimmers R, Engels G, van der Ven H, Krebs D. Evidence for major histocompatibility complex-mediated effects on spermatogenesis in humans. Hum Reprod. 2000;15:189–96.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Alazami AM, Alshammari MJ, Baig M, Salih MA, Hassan HH, Alkuraya FS. NPHP4 mutation is linked to cerebello-oculo-renal syndrome and male infertility. Clin Genet. 2014;85:371–5.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Sha YW, Xu X, Mei LB, Li P, Su ZY, He XQ, et al. A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF). Gene. 2017;633:48–53.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Sha Y, Yang X, Mei L, Ji Z, Wang X, Ding L, et al. DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population. Fertil Steril. 2017;107:1312-8 e2.CrossRefGoogle Scholar
  93. 93.
    Xu X, Sha YW, Mei LB, Ji ZY, Qiu PP, Ji H, et al. A familial study of twins with severe asthenozoospermia identified a homozygous SPAG17 mutation by whole-exome sequencing. Clin Genet. 2017;93:345.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Espinosa JR, Ayub Q, Chen Y, Xue Y, Tyler-Smith C. Structural variation on the human Y chromosome from population-scale resequencing. Croat Med J. 2015;56:194–207.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Poznik GD, Xue Y, Mendez FL, Willems TF, Massaia A, Wilson Sayres MA, et al. Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences. Nat Genet. 2016;48:593–9.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Massaia A, Xue Y. Human Y chromosome copy number variation in the next generation sequencing era and beyond. Hum Genet. 2017;136:591–603.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Cooke HJ, Saunders PT. Mouse models of male infertility. Nat Rev Genet. 2002;3:790–801.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Yatsenko AN, Iwamori N, Iwamori T, Matzuk MM. The power of mouse genetics to study spermatogenesis. J Androl. 2010;31:34–44.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Jamsai D, O’Bryan MK. Mouse models in male fertility research. Asian J Androl. 2011;13:139–51.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med. 2008;14:1197–213.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Brebion G, Bressan RA, Pilowsky LS, David AS. Processing speed and working memory span: their differential role in superficial and deep memory processes in schizophrenia. J Int Neuropsychol Soc. 2011;17:485–93.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Lin YN, Matzuk MM. Genetics of male fertility. Methods Mol Biol. 2014;1154:25–37.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Das L, Parbin S, Pradhan N, Kausar C, Patra SK. Epigenetics of reproductive infertility. Front Biosci (Schol Ed). 2017;9:509–35.CrossRefGoogle Scholar
  104. 104.
    Sinha A, Singh V, Yadav S. Multi-omics and male infertility: status, integration and future prospects. Front Biosci (Schol Ed). 2017;9:375–94.CrossRefGoogle Scholar
  105. 105.
    Stuppia L, Franzago M, Ballerini P, Gatta V, Antonucci I. Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics. 2015;7:120.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Carrell DT, Aston KI, Oliva R, Emery BR, De Jonge CJ. The “omics” of human male infertility: integrating big data in a systems biology approach. Cell Tissue Res. 2016;363:295–312.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Hong Y, Wang C, Fu Z, Liang H, Zhang S, Lu M, et al. Systematic characterization of seminal plasma piRNAs as molecular biomarkers for male infertility. Sci Rep. 2016;6:24229.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Sha Y, Sha Y, Ji Z, Ding L, Zhang Q, Ouyang H, et al. Comprehensive genome profiling of single sperm cells by multiple annealing and looping-based amplification cycles and next-generation sequencing from carriers of Robertsonian translocation. Ann Hum Genet. 2017;81:91–7.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Du Y, Li M, Chen J, Duan Y, Wang X, Qiu Y, et al. Promoter targeted bisulfite sequencing reveals DNA methylation profiles associated with low sperm motility in asthenozoospermia. Hum Reprod. 2016;31:24–33.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Weng SL, Chiu CM, Lin FM, Huang WC, Liang C, Yang T, et al. Bacterial communities in semen from men of infertile couples: metagenomic sequencing reveals relationships of seminal microbiota to semen quality. PLoS One. 2014;9:e110152.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Jodar M, Selvaraju S, Sendler E, Diamond MP, Krawetz SA, Reproductive Medicine N. The presence, role and clinical use of spermatozoal RNAs. Hum Reprod Update. 2013;19:604–24.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Yang Q, Hua J, Wang L, Xu B, Zhang H, Ye N, et al. MicroRNA and piRNA profiles in normal human testis detected by next generation sequencing. PLoS One. 2013;8:e66809.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat. 2000;15:7–12.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Khalid A. Fakhro
    • 1
    • 2
  • Amal Robay
    • 1
  • Juan L. Rodriguez-Flores
    • 3
  • Ronald G. Crystal
    • 3
    Email author
  1. 1.Department of Genetic MedicineWeill Cornell Medicine – QatarDohaQatar
  2. 2.Human Genetics DepartmentSidra MedicineDohaQatar
  3. 3.Department of Genetic MedicineWeill Cornell Medical CollegeNew YorkUSA

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