The number of genotype-phenotype associations validated in male infertility continues to grow

Published 07 December 2021

A new systematic review of the validated monogenic causes of male infertility strengthens the evidence base for emerging gene-disease relationships; the review hopes to encourage more routine genetic testing in clinics and identify gaps in our knowledge of male infertility genetics.

In less than two years, the number of genes revealed in the literature as ‘causative’ of male infertility phenotypes has increased from 78 (in 2019) to 104, an increase of 33%. All are supported by evidence of a direct gene-disease relationship and, say the authors of a new report, ‘will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics’.(1)

This latest report is an update on the first standardised clinical validity assessment of monogenic causes of male infertility published in 2019, and like that one this latest literature evaluation has been conducted with the International Male Infertility Genomics Consortium (IMIGC). The increase in the number of ‘high-probability’ male infertility genes is not just a reflection of extended gene discovery but a function too of the recent rapid uptake of next generation sequencing in male infertility (with whole-exome sequencing described as ‘the default sequencing approach’) and research on clinical cohorts. The validation of these emerging genes will, say the authors, help give direction to which individual genes may be screened for and how they are relevant to certain types of infertility.

All 104 genes and their links to male infertility phenotypes are listed in a table, with organ effects noted in hypothalamic function, pituitary and adrenal gland dysfunction, vas deferens, reproductive organ development, Leydig cell, Sertoli-cell only syndrome, meiotic arrest, spermatogenesis and fertilisation.

As illustrated in a Campus meeting on the genetics of male infertility held online a few weeks ago, a wide range of phenotypes now appears to be largely genetic in origin.(2) Already, the genetic components of Klinefelter syndrome, Y-chromosome microdeletions and some monogenic causes of azoospermia are well recognised, but there remains a majority of male infertility cases (60-70%) without any clear diagnosis. Only 4% are actually diagnosed with a defined genetic cause. This updated systematic evaluation of all available evidence for published monogenic causes of isolated or syndrome male infertility will hopefully extend the limits for genetic testing and the diagnostic power for identifying the causes of male infertility; however, while NGS is now a cornerstone test in male infertility research, it is not, say the authors, ‘extensively employed’ in clinical diagnosis.

The report notes that the diagnostic rate of genetic tests for all types of isolated male infertility currently lies between 4 and 9%. These are rates considerably behind those seen in other heterogeneous disorders with a large genetic contribution – such as cardiomyopathies or developmental delay, where whole-exome and whole-genome sequencing are ‘routinely’ applied. However, with reduced costs of NGS and better accessibility, the authors hope that the increased number of validated genes implicated in male infertility will lead to greater diagnostic implementation.

And this in turn will help in evaluating future health risks in which male infertility may be linked to other comorbidities in later life; for example, a number of multiple DNA repair genes linked to infertility are known to be involved in some cancers. There are also implications from genetic testing in male infertility for sons of men with Y-chromosome variants conceived by ART, who presumably will inherit the same infertility phenotype as their affected fathers - and thus may in turn require ART if wanting their own biological child.

1. Houston BJ, Riera-Escamilla A, Wyrwoll MJ, et al. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene–disease relationships, Hum Reprod Update 2021; doi:10.1093/humupd/dmab030
2. See

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