Toward clinical exomes in diagnostics and management of male infertility

Kristiina Lillepea, Anna Grete Juchnewitsch, Laura Kasak, Anu Valkna, Avirup Dutta, Kristjan Pomm, Olev Poolamets, Liina Nagirnaja, Erik Tamp, Eisa Mahyari, Vladimir Vihljajev, Stanislav Tjagur, Sofia Papadimitriou, Antoni Riera-Escamilla, Nassim Versbraegen, Ginevra Farnetani, Helen Castillo-Madeen, Mailis Sütt, Viljo Kübarsepp, Sven TennisbergPaul Korrovits, Csilla Krausz, Kenneth I. Aston, Tom Lenaerts, Donald F. Conrad, Margus Punab, Maris Laan

Onderzoeksoutput: Articlepeer review


Infertility, affecting ∼10% of men, is predominantly caused by primary spermatogenic failure (SPGF). We screened likely pathogenic and pathogenic (LP/P) variants in 638 candidate genes for male infertility in 521 individuals presenting idiopathic SPGF and 323 normozoospermic men in the ESTAND cohort. Molecular diagnosis was reached for 64 men with SPGF (12%), with findings in 39 genes (6%). The yield did not differ significantly between the subgroups with azoospermia (20/185, 11%), oligozoospermia (18/181, 10%), and primary cryptorchidism with SPGF (26/155, 17%). Notably, 19 of 64 LP/P variants (30%) identified in 28 subjects represented recurrent findings in this study and/or with other male infertility cohorts. NR5A1 was the most frequently affected gene, with seven LP/P variants in six SPGF-affected men and two normozoospermic men. The link to SPGF was validated for recently proposed candidate genes ACTRT1, ASZ1, GLUD2, GREB1L, LEO1, RBM5, ROS1, and TGIF2LY. Heterozygous truncating variants in BNC1, reported in female infertility, emerged as plausible causes of severe oligozoospermia. Data suggested that several infertile men may present congenital conditions with less pronounced or pleiotropic phenotypes affecting the development and function of the reproductive system. Genes regulating the hypothalamic-pituitary-gonadal axis were affected in >30% of subjects with LP/P variants. Six individuals had more than one LP/P variant, including five with two findings from the gene panel. A 4-fold increased prevalence of cancer was observed in men with genetic infertility compared to the general male population (8% vs. 2%; p = 4.4 × 10−3). Expanding genetic testing in andrology will contribute to the multidisciplinary management of SPGF.

Originele taal-2English
Pagina's (van-tot)877-895
Aantal pagina's19
TijdschriftAmerican Journal of Human Genetics
Nummer van het tijdschrift5
StatusPublished - 2 mei 2024

Bibliografische nota

Publisher Copyright:
© 2024 American Society of Human Genetics


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