Abstract

INTRODUCTION

Male factor infertility concerns 7-10% of men and among these 40-60% remain unexplained.

SOURCES OF DATA

This review is based on recent published literature regarding the genetic causes of male infertility.

AREAS OF AGREEMENT

Screening for karyotype abnormalities, biallelic pathogenic variants in the CFTR gene and Y-chromosomal microdeletions have been routine in andrology practice for >20 years, explaining ~10% of infertility cases. Rare specific conditions, such as congenital hypogonadotropic hypogonadism, disorders of sex development and defects of sperm morphology and motility, are caused by pathogenic variants in recurrently affected genes, which facilitate high diagnostic yield (40-60%) of targeted gene panel-based testing.

AREAS OF CONTROVERSY

Progress in mapping monogenic causes of quantitative spermatogenic failure, the major form of male infertility, has been slower. No 'recurrently' mutated key gene has been identified and worldwide, a few hundred patients in total have been assigned a possible monogenic cause.

GROWING POINTS

Given the high genetic heterogeneity, an optimal approach to screen for heterogenous genetic causes of spermatogenic failure is sequencing exomes or in perspective, genomes. Clinical guidelines developed by multidisciplinary experts are needed for smooth integration of expanded molecular diagnostics in the routine management of infertile men.

AREAS TIMELY FOR DEVELOPING RESEARCH

Di-/oligogenic causes, structural and common variants implicated in multifactorial inheritance may explain the 'hidden' genetic factors. It is also critical to understand how the recently identified diverse genetic factors of infertility link to general male health concerns across lifespan and how the clinical assessment could benefit from this knowledge.

MeSH

Genes, Disorders Of Sex Development, Chronic Disease, Azoospermia, Genetics, Translational Research, Biomedical, Multifactorial Inheritance, Infertility, Teratozoospermia, Exome, Infertility, Male, Spermatozoa

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• Microdeletions and microduplications linked to severe congenital disorders in infertile men. Sci Rep, 2023
• An essential role of the E3 ubiquitin ligase RNF126 in ensuring meiosis I completion during spermatogenesis. J Adv Res, 2025
• Toward clinical exomes in diagnostics and management of male infertility. Am J Hum Genet, 2024
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• Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. Hum Reprod, 2022
• LIN 28B expression is downregulated in mature spermatozoa of oligozoospermic men and associates with genetic variants previously linked to pubertal onset. Endocr Connect, 2025