Genetics of Azoospermia

Abstract

Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients.

Keywords: CBAVD; Klinefelter syndrome; NGS; NOA; Y chromosome microdeletions; azoospermia; congenital hypogonadotropic hypogonadism; exome; genetics; infertility.

Figure 1

Diagnostic yield of genetic testing in azoospermia with different etiology: (a) Congenital Hypogonadotropic Hypogonadism; (b) Non-Obstructive Azoospermia due to primary testicular failure, after the exclusion of all know acquired causes; (c) Congenital Bilateral Absence of Vas Deferens. Abbreviations: AZF—Azoospermia Factor Region; CBAVD—Congenital Bilateral Absence of Vas Deferens; CHH—Congenital Hypogonadotropic Hypogonadism; NOA—Non-Obstructive Azoospermia; * See Reviews [7,8]; ** 47,XXY Klinefelter syndrome, 46,XX male syndrome, Yq’-‘; *** See articles [9,10,11].

Figure 2

Semen phenotype and TESE outcomes of the different types of AZF microdeletion. Abbreviations: AZF—Azoospermia Factor Region; Cen—centromere; PAR1—Pseudoautosomal Region 1; PAR2—Pseudoautosomal Region 2; SRY—Sex-determining Region Y gene; TESE—Testicular Sperm Extraction.