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Background: The human leukocyte antigen (HLA) locus includes several genes with key roles in antigen presentation and immune response, some of them inclusively found to be associated with non‐obstructive azoospermia. Still, HLA connections to other infertility phenotypes such as semen hyperviscosity (SHV), asthenozoospermia (AST), and oligozoospermia (OLI) have been often neglected. Objectives: In this work, we aimed to evaluate the association of HLA class I and II genes with SHV, AST, and OLI phenotypes while exploring a possible role in an adaptive immune response to sexually transmitted diseases (STD). Materials and methods: Whole‐exome sequencing was performed in a Portuguese cohort of 71 infertility cases and 68 controls, followed by HLA typing using a specific software—HLA*PRG:LA tool. Molecular screenings of seven STD were carried out in a subset of 72 samples (30 cases and 42 controls). Results: Statistical tests uncovered three protective alleles: HLA‐A*11:01, associated with all forms of male infertility (p = 0.0006); HLA‐DQB1*03:02 with SHV and OLI (PSHV = 0.0303, POLI = 0.0153); and HLA‐A*29:02 with OLI (p = 0.0355), which was found to interfere in sperm number together with HPV (p = 0.0313). Five risk alleles were also identified: two linked with SHV (HLA‐B*50:01, p = 0.0278; and HLA‐C*06:02, p = 0.0461), another one with both SHV and OLI (HLA‐DQA1*05:01,PSHV = 0.0444 and POLI=0.0265), and two with OLI (HLA‐C*03:03, p = 0.0480; and HLA‐DQB1*03:01, p = 0.0499). Here, HLA‐C*03:03 carriers tend to be HPV infected. Conclusions: The application of HLA*PRG:LA tool to the study of male infertility provided novel insights for an HLA correlation with semen quality, namely among SHV and OLI phenotypes. The discovery of an HLA‐A*29:02/HPV crosstalk, together with former reports of HLA alleles conferring resistance–susceptibility to diverse human pathogens, raises the hypothesis of a mechanistic link between male infertility, HLA polymorphism, and host response to STD. [ABSTRACT FROM AUTHOR]

Background: Primary spermatogenic disorders represent a severe form of male infertility whereby sperm production is impaired due to testicular dysfunction, leading to reduced quality or quantity of spermatozoa. Gene-centered research has certainly demonstrated the importance of the genetic factor in the etiology of both poor sperm morphology or motility and reduced sperm count. In the last decade, next-generation sequencing has expanded the research to whole exome which has transformed our understanding of male infertility genetics, but uncertainty persists in its diagnostic yield, especially in large unrelated populations., Objective: To evaluate the utility of exome sequencing in detecting genetic factors contributing to various traits of primary spermatogenic disorders, which is a crucial step before interpreting the diagnostic yield of the platform., Materials and Methods: We manually curated 415 manuscripts and included 19 research studies that predominantly performed whole exome sequencing in cohorts of unrelated cases with primary spermatogenic defects., Results: The detection rate, defined as the fraction of cases with an identifiable genetic cause, typically remained below 25% for quantitative defects of spermatozoa, whereas improved rates were observed for traits of abnormal sperm morphology/motility and in populations enriched with consanguineous families. Unlike the quantitative defects, the genetic architecture of the qualitative issues of spermatozoa featured a small number of recurrent genes describing a large fraction of studied cases. These observations were also in line with the lower biological complexity of the pathways affected by the reported genes., Discussion and Conclusions: This review demonstrates the variability in detection rates of exome sequencing across semen phenotypes, which may have an impact on the expectations of the diagnostic yield in the clinical setting., (© 2024 American Society of Andrology and European Academy of Andrology.)