Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to male infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing. Genetic screening is relevant for its diagnostic value, clinical decision making, and appropriate genetic counselling. Anomalies in sex chromosomes have major roles in severe spermatogenic impairment. Autosome-linked gene mutations are mainly involved in central hypogonadism, monomorphic teratozoospermia or asthenozoospermia, congenital obstructive azoospermia, and familial cases of quantitative spermatogenic disturbances. Results from whole-genome association studies suggest a marginal role for common variants as causative factors; however, some of these variants can be important for pharmacogenetic purposes. Results of studies on copy number variations (CNVs) demonstrate a considerably higher CNV load in infertile patients than in normozoospermic men, whereas whole-exome analysis has proved to be a highly successful diagnostic tool in familial cases of male infertility. Despite such efforts, the aetiology of infertility remains unknown in about 40% of patients, and the discovery of novel genetic factors in idiopathic infertility is a major challenge for the field of androgenetics. Large, international, and consortium-based whole-exome and whole-genome studies are the most promising approach for the discovery of the missing genetic aetiology of idiopathic male infertility.
Male infertility is a complex multifactorial pathological condition in which genetic factors have roles. Men with azoospermia are at the highest risk of being carriers of genetic anomalies (25%), whereas this risk progressively decreases with increasing sperm output.
Karyotype analysis, screening for azoospermia factor (AZF) microdeletions, and screening for mutations in candidate genes are part of the diagnostic work-up of male infertility.
Genetic testing has three objectives: diagnosis, prognosis before testicular sperm extraction (TESE), and personalizing therapy.
AZF deletion testing must be performed before TESE, as complete deletions of the AZFa and AZFb regions cause azoospermia with virtually zero chance of sperm recovery using testis biopsy.
Genetic anomalies involved in male infertility can also affect general health; thus, long-term follow-up monitoring of patients should be conducted. Furthermore, a possible link exists between infertility and the higher morbidity and lower life expectancy that is observed in infertile men than in the general population.
The aetiology of primary testicular failure is unknown in about 40% of men (idiopathic infertility), and genetic factors that have not yet been identified are likely to contribute to a large proportion of these instances. Whole-exome or whole-genome analyses are promising tools for the discovery of the missing genetic aetiology.
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This work was funded by the Spanish Ministry of Health-Instituto Carlos III to C.K. (grant number: FIS/FEDER PI14/01250) and by the European Commission - Reproductive Biology Early Research Training (REPROTRAIN, Project Number: 289880) to C.K and A.R-E. The authors thank E. Martí, President of the Fundació Puigvert, for her constant support. They also thank O. Shaeer (University of Cairo) for his constructive comments on the manuscript.
The authors declare no competing interests.
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The Androgen Receptor Gene Mutations Database: http://androgendb.mcgill.ca
Cystic Fibrosis Mutation Database: www.genet.sickkids.on.ca
Genetics Home Reference 46,XX testicular disorder of sex development: https://ghr.nlm.nih.gov/condition/46xx-testicular-disorder-of-sex-development#statistics
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Krausz, C., Riera-Escamilla, A. Genetics of male infertility. Nat Rev Urol 15, 369–384 (2018). https://doi.org/10.1038/s41585-018-0003-3
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