However, the majority of these genes still lack a definitive gene–disease relationship (Oud et al. With the advent of large-scale sequencing strategies (especially exome analysis by next-generation sequencing, or NGS), more and more novel genes have been reported to be linked with male infertility. Known genetic factors are present in each of these etiological categories, and, depending on the severity of the spermatogenic impairment, they account for about 10–20% of cases. Male factors contribute to infertility in about 50% of cases and can be classified into four major etiological categories: (i) hypothalamic–pituitary axis dysfunction (ii) quantitative alterations of spermatogenesis (iii) qualitative alterations of spermatogenesis and (iv) ductal obstruction/dysfunction (Tournaye et al. Infertility is a frequent condition affecting one out of six couples in Western countries (Krausz and Riera-Escamilla 2018). Therefore, we conclude that additional methodological approaches are urgently warranted to advance our understanding of the genetics of X-linked male infertility. Furthermore, the complexity and highly repetitive structure of the X chromosome hinder the mutational analysis of X-linked genes in humans. Although genetic studies of germ cell-enriched X-chromosomal genes in mice suggest a role of certain human orthologs in infertile men, these genes in mice and humans have striking evolutionary differences. However, to date, only very few genetic causes have been identified as being definitively responsible for male infertility in humans. These features make X-linked genes particularly attractive for studying male spermatogenic failure. Furthermore, because males normally only have a single X chromosome and because X-linked genetic anomalies are generally only present in a single copy in males, any loss-of-function mutations in single-copy X-chromosomal genes cannot be compensated by a normal allele. Male infertility is most commonly caused by spermatogenic defects to which X chromosome dosage is closely linked for example, any supernumerary X chromosome as in Klinefelter syndrome will lead to male infertility. In this review, we focus on the X chromosome’s unique biology as associated with human male infertility. The X chromosome is a key player in germ cell development, as has been highlighted for males in previous studies revealing that the mammalian X chromosome is enriched in genes expressed in early spermatogenesis.
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