Abstract
Infertility is a common condition estimated to affect 10–15% of couples. The clinical causes are attributed in equal parts to the male and female partners. Diagnosing male infertility mostly relies on semen (and hormone) analysis, which results in classification into the two major phenotypes of oligo- and azoospermia. The clinical routine analyses have not changed over the last 20 years and comprise screening for chromosomal aberrations and Y‑chromosomal azoospermia factor deletions. These tests establish a causal genetic diagnosis in about 4% of unselected men in infertile couples and 20% of azoospermic men. Gene sequencing is currently only performed in very rare cases of hypogonadotropic hypogonadism and the CFTR gene is routinely analysed in men with obstructive azoospermia. Still, a large number of genes have been proposed to be associated with male infertility by, for example, knock-out mouse models. In particular, those that are exclusively expressed in the testes are potential candidates for further analyses. However, the genome-wide analyses (a few array-CGH, six GWAS, and some small exome sequencing studies) performed so far have not lead to improved clinical diagnostic testing. In 2017, we started to routinely analyse the three validated male infertility genes: NR5A1, DMRT1, and TEX11. Preliminary analyses demonstrated highly likely pathogenic mutations in these genes as a cause of azoospermia in 4 men, equalling 5% of the 80 patients analysed so far, and increasing the diagnostic yield in this group to 25%. Over the past few years, we have observed a steep increase in publications on novel candidate genes for male infertility, especially in men with azoospermia. In addition, concerted efforts to achieve progress in elucidating genetic causes of male infertility and to introduce novel testing strategies into clinical routine have been made recently. Thus, we are confident that major breakthroughs concerning the genetics of male infertility will be achieved in the near future and will translate into clinical routine to improve patient/couple care.
Highlights
Infertility, which has been defined by the WHO as inability to conceive after 1 year of unprotected intercourse, is a common condition estimated to affect 10–15% of couples in developed and developing countries [56]
Lower reference ranges for these and other semen parameters have been determined in recent years from a “normal” population of men that induced a pregnancy within 1 year (
No genetic causes relevant to the clinical diagnostic work-up, treatment decisions or counselling with regard to the reproductive health of offspring have been identified in over 20 years [11, 29, 30, 48] when AZF deletions were described as a common cause of spermatogenic failure [54]
Summary
Infertility, which has been defined by the WHO as inability to conceive after 1 year of unprotected intercourse, is a common condition estimated to affect 10–15% of couples in developed and developing countries [56]. No genetic causes relevant to the clinical diagnostic work-up, treatment decisions or counselling with regard to the reproductive health of offspring have been identified in over 20 years [11, 29, 30, 48] when AZF deletions were described as a common cause of spermatogenic failure [54] This is especially surprising because it was estimated long ago that overall about 30% of cases of male infertility are caused by chromosomal abnormalities or mutations of genes involved in germ cell production and function [53] and familial clustering of male infertility was shown in some case–control studies [16, 17, 25]. Perspectives for novel genetic diagnostics after 20 years of unchanged routine
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