Spermatogenic failure

The clinical spectrum extends from severe oligozoospermia through cryptozoospermia to complete azoospermia, with marked variability across the underlying genetic forms. Where testicular biopsy is performed, histology ranges from hypospermatogenesis to meiotic arrest or a Sertoli cell-only pattern. Beyond reduced sperm count, monogenic defects can also impair sperm motility and morphology, producing asthenoteratozoospermia or isolated structural abnormalities of the sperm flagellum, head or acrosome.

Infertility affects approximately 15% of couples of reproductive age worldwide, with male factors contributing to roughly 50% of cases. A molecular diagnosis is reached in only a minority of affected men with standard work-up, although targeted sequencing increases the yield in selected phenotypes.

This panel targets genes whose pathogenic variants have been associated with spermatogenic failure. Validated monogenic causes span a large and growing set of genes across several phenotypes.

• Quantitative spermatogenic failure, e.g., non-obstructive azoospermia (NOA) caused by meiotic or maturation arrest, severe oligozoospermia oroligoasthenoteratozoospermia (OAT)
• Sperm flagellar morphology (multiple morphological abnormalities of the sperm flagella, MMAF, presenting as asthenoteratozoospermia)
• Sperm head and acrosome morphology, e.g., globozoospermia or macrozoospermia
• Related andrological entities within scope, e.g., or

Inheritance varies by gene and condition; for any individual gene, the mode of inheritance (autosomal dominant or recessive, X-linked, or Y-linked) should be confirmed against current gene-specific evidence before counselling. Since identified variants are the underlying cause of subfertility or infertility transmission to offspring has to be carefully considered before starting the process of assisted reproduction (ART).

Work-up combines repeated semen analysis ( criteria), physical examination, endocrine profiling and imaging. A dedicated differential work-up separates spermatogenic failure due to monogenic causes from mechanistically distinct conditions such as obstructive azoospermia, sex-chromosome aneuploidy, Y-chromosome microdeletion and (see Differential diagnosis). Genetic testing of the panel genes targets monogenic forms once acquired and obstructive causes other than have been considered.

Main differential diagnoses include:

• Klinefelter syndrome (47,XXY): commonest sex-chromosome aneuploidy underlying NOA, with primary testicular failure; detected by karyotype rather than by this sequencing panel; typically arises de novo.
• region, detected by a separate Y-deletion assay.
• : hypogonadotropic, with absent or arrested puberty and (in Kallmann) hyposmia; caused by a different, genetically heterogeneous gene set.
• Obstructive azoospermia of other causes: preserved spermatogenesis with mechanical obstruction; distinguished from CBAVD by clinical and imaging findings.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports reproductive planning options, including assessment of the likelihood of sperm retrieval, which the treating physicians decide together with the affected individual.
• A known familial variant can support predictive testing of at-risk relatives, so they can clarify their personal risk and access counselling and reproductive options where indicated.

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