Disease gene discovery in male infertility: past, present and future

Abstract

Identifying the genes causing male infertility is important to increase our biological understanding as well as the diagnostic yield and clinical relevance of genetic testing in this disorder. While significant progress has been made in some areas, mainly in our knowledge of the genes underlying rare qualitative sperm defects, the same cannot be said for the genetics of quantitative sperm defects. Technological advances and approaches in genomics are critical for the process of disease gene identification. In this review we highlight the impact of various technological developments on male infertility gene discovery as well as functional validation, going from the past to the present and the future. In particular, we draw attention to the use of unbiased genomics approaches, the development of increasingly relevant functional assays and the importance of large-scale international collaboration to advance disease gene identification in male infertility.

Fig. 1

Timeline of the discovery of key genes involved in male infertility. The development of novel molecular techniques and technological advancements introduced since 1956 have allowed for the identification of key genes responsible for the various types of male infertility in humans. Although the first male infertility genes were first identified in the late 1980s, the widespread application of microarray and NGS approaches has resulted in an increase in the detection of male infertility genes

Fig. 2

Breakdown of genetic tools used in published male infertility studies over the past decade. Based on an analysis of all published literature related to monogenic forms of male infertility, Sanger sequencing was the predominant tool used (82%) in 2010 but has since then seen a reduced usage down to 26% in 2019. In the same time period, NGS-based techniques gained ground to become currently the most common tool (61%)

Fig. 3

Mutagenesis techniques for functional validation and examples in male infertility research. Outline of the current mutagenesis techniques for functional validation, and the approximate year of application. Comparison of the main characteristics of the described techniques and some published examples of the application of these technologies in male infertility research