Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence

Abstract

Several genes are implicated in spermatogenesis and fertility regulation, and these genes are presently being analysed in clinical practice due to their involvement in male factor infertility (MFI). However, there are still few genetic analyses that are currently recommended for use in clinical practice. In this manuscript, we reviewed the genetic causes of qualitative sperm defects. We distinguished between alterations causing reduced sperm motility (asthenozoospermia) and alterations causing changes in the typical morphology of sperm (teratozoospermia). In detail, the genetic causes of reduced sperm motility may be found in the alteration of genes associated with sperm mitochondrial DNA, mitochondrial proteins, ion transport and channels, and flagellar proteins. On the other hand, the genetic causes of changes in typical sperm morphology are related to conditions with a strong genetic basis, such as macrozoospermia, globozoospermia, and acephalic spermatozoa syndrome. We tried to distinguish alterations approved for routine clinical application from those still unsupported by adequate clinical studies. The most important aspect of the study was related to the correct identification of subjects to be tested and the correct application of genetic tests based on clear clinical data. The correct application of available genetic tests in a scenario where reduced sperm motility and changes in sperm morphology have been observed enables the delivery of a defined diagnosis and plays an important role in clinical decision-making. Finally, clarifying the genetic causes of MFI might, in future, contribute to reducing the proportion of so-called idiopathic MFI, which might indeed be defined as a subtype of MFI whose cause has not yet been revealed.

Keywords: asthenozoospermia; idiopathic infertility; male factor infertility; sperm morphology; sperm motility; teratozoospermia.

Figure 1

Genetic causes of reduced sperm motility.

Figure 2

Clinical and diagnostic flowchart to patients with MFI, in particular to patients with isolated/reduced sperm motility or reduced typical sperm morphology. I-level tests: anamnesis, physical examination, scrotal and prostatic ultrasound evaluation, semen analysis, semen microbiological evaluation with HPV. II-level tests: evaluation of oxidative stress and spermatic aneuploidy. III-level tests: genetic analysis. Abbreviations: ROS—reactive oxygen species.