MECHANISMS IN ENDOCRINOLOGY: Aberrations of the X chromosome as cause of male infertility

Abstract

Male infertility is most commonly caused by spermatogenetic failure, clinically noted as oligo-or a-zoospermia. Today, in approximately 20% of azoospermic patients, a causal genetic defect can be identified. The most frequent genetic causes of azoospermia (or severe oligozoospermia) are Klinefelter syndrome (47,XXY), structural chromosomal abnormalities and Y-chromosomal microdeletions. Consistent with Ohno's law, the human X chromosome is the most stable of all the chromosomes, but contrary to Ohno's law, the X chromosome is loaded with regions of acquired, rapidly evolving genes, which are of special interest because they are predominantly expressed in the testis. Therefore, it is not surprising that the X chromosome, considered as the female counterpart of the maleassociated Y chromosome, may actually play an essential role in male infertility and sperm production. This is supported by the recent description of a significantly increased copy number variation (CNV) burden on both sex chromosomes in infertile men and point mutations in X-chromosomal genes responsible for male infertility. Thus, the X chromosome seems to be frequently affected in infertile male patients. Four principal X-chromosomal aberrations have been identified so far: (1) aneuploidy of the X chromosome as found in Klinefelter syndrome (47,XXY or mosaicism for additional X chromosomes). (2) Translocations involving the X chromosome, e.g. nonsyndromic 46,XX testicular disorders of sex development (XX-male syndrome) or X-autosome translocations. (3) CNVs affecting the X chromosome. (4) Point mutations disrupting X-chromosomal genes. All these are reviewed herein and assessed concerning their importance for the clinical routine diagnostic workup of the infertile male as well as their potential to shape research on spermatogenic failure in the next years.

Multiscale analysis of SRY‐positive 46,XX testicular disorder of sex development: Presentation of nine cases

“…The incidence is estimated to be one in 20,000 male newborns. Patients with sex‐determining region Y (SRY)‐positive 46,XX TDSD are usually asymptomatic males diagnosed in puberty or adulthood because of hypergonadotropic hypogonadism, microorchidism, and infertility due to azoospermia and Sertoli cells only (Delot & Vilain, 1993; Ropke & Tuttelmann, 2017; Zenteno‐Ruiz, Kofman‐Alfaro, & Mendez, 2001). Until the early stages of puberty, Sertoli and Leydig cells are functional in these patients.…”

Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives

“…The estimated prevalence of 1 case per 660 newborns, increasing to 3-4% among infertile men and 10-12% in azoospermic men, makes KS the most common abnormality of sex chromosomes [2][3][4]. Clinical features of the syndrome vary broadly [5][6][7][8][9], but the hallmark of KS remains infertility [5] with most of cases remaining undiagnosed until the attempt to conceive [10]. While about 85% of KS is due to one single additional X chromosome (47,XXY), the remaining 15% displays multiple aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY) causing development of a much more complex phenotype [11].…”

“…For this reason, aneuploidies with more than 47 chromosomes should be considered a distinct condition [5,11].…”

Impaired Spermatogenesis due to Small Supernumerary Marker Chromosomes: The Reason for Infertility Is Only Reliably Ascertainable by Cytogenetics

“…There may be mutations in specific genes, like azoospermia factor ( AZF ) or cystic fibrosis transmembrane conductance regulator ( CFTR ) [Manvelyan et al, 2008;Wosnitzer et al, 2014;Röpke and Tüttelmann, 2017;Colaco and Modi, 2018;Vander Borght and Wyns, 2018]. Still, fertility may be impaired as well by (a) numerical chromosomal alterations, like (mosaic) trisomy or monosomy of (one of) the gonosomes [Mau-Holzmann, 2005;Manvelyan et al, 2007;Wosnitzer et al, 2014;Neto et al, 2016], (b) structural chromosomal abnormalities, like balanced rearrangements (translocations, insertions, inversions or even complex chromosomal rearrangements) [Liehr and Weise, 2007], or (c) a combination of numerical and structural chromosomal alterations, i.e., the presence of a small supernumerary marker chromosome (sSMC) [Manvelyan et al, 2008;Liehr, 2014;Armanet et al, 2015].…”