Utility of exome sequencing in primary spermatogenic disorders: From research to diagnostics

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.

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.

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.

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.

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.