Graziani, A., Rocca, M. S., Vinanzi, C., Masi, G., Grande, G., De Toni, L., & Ferlin, A. (2024). Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence. Genes. https://doi.org/10.3390/genes15050600
Graziani A, Rocca MS, Vinanzi C, Masi G, Grande G, De Toni L, Ferlin A. Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence. Genes. 2024. doi:10.3390/genes15050600
Graziani, Andrea, et al. "Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence." Genes, 2024.
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Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy.
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RRM Academy Synopsis
Isolated poor sperm motility or shape has a strong genetic basis
Isolated poor sperm motility or shape has a strong genetic basis, and few genetic tests are yet recommended for clinical use, this 2024 narrative review reports. The authors separate genes recommended for testing from genes found in few patients. They rank genetic testing as a third-level test, after history, examination, semen analysis and other earlier tests.
Key Findings
Male factors are involved, alone or with a female factor, in about 50% of infertility cases. Genetic factors cause 10–15% of male factor infertility cases, alone or in combination with other factors.
Among more than 5000 infertile couples in the authors' series, about 12% of the males had total or progressive motility below the fifth WHO percentile as their only semen alteration.
Over 30 disease-causing genes are associated with multiple morphological alterations of flagella (MMAF) without other symptoms of primary ciliary dyskinesia. Mutations in DNAH1 seem to account for 25% of MMAF cases.
Macrozoospermia (oversized sperm heads) affects less than 1% of patients with male factor infertility, and globozoospermia (round-headed sperm) less than 0.1%.
SUN5 mutations or deletions cause approximately 40–50% of reported acephalic spermatozoa syndrome (headless sperm). About 80% of patients with type I globozoospermia carry a DPY19L2 mutation.
Interpretation
The paper is a narrative review of published work. The authors base testing recommendations on clinical guidelines, genetic reviews, current opinion and their own opinion. Many genes rest on case reports or small groups of patients, and mitochondrial testing is still to be evaluated for routine use. The authors rate the possibility of a genetic cause as very high when all sperm are immotile or share one identical malformation, especially as an isolated finding. Across infertile men as a group, they write that these defects are rarely caused by genetic alterations. They call for well-designed studies in defined subtypes of male infertility.
RRM Context
Restorative reproductive medicine evaluates both partners and looks for the cause of reduced fertility before choosing treatment. The review points the same way. The authors describe male factor evaluation as couple-oriented, with male and female factors considered together. They say an unexplained male factor diagnosis, reported in about 30–50% of cases, should follow a thoughtful and complete diagnostic process. The WHO manual they cite calls semen analysis the starting point of that process.
Our editorial summary of this paper, not the article's abstract.
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.
Male Fertility › Male Endocrine and Genetic Factors › Genetic Causes of Male Infertility · Clinical Guidelines and Standards › Diagnostic Criteria and Classification › Diagnostic Criteria · Genetics and Immunology › Reproductive Genetics › Single Gene Conditions
Andrea Graziani, Maria Santa Rocca, Cinzia Vinanzi, Giulia Masi, Giuseppe Grande, Luca De Toni, Alberto Ferlin
A Graziani, M Rocca, C Vinanzi, G Masi, G Grande, L Toni, A Ferlin
PMID 38790229 38790229 DOI 10.3390/genes15050600 10.3390/genes15050600 Graziani et al. 2024, Graziani 2024
