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.
American journal of human genetics. 2024 Apr 12 [Epub ahead of print]
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 Tennisberg, Paul Korrovits, Csilla Krausz, Kenneth I Aston, Tom Lenaerts, Donald F Conrad, Margus Punab, Maris Laan
Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia., Andrology Clinic, Tartu University Hospital, 50406 Tartu, Estonia., Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA., Center of Pathology, Diagnostic Clinic, East Tallinn Central Hospital, 10138 Tallinn, Estonia., Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium; Department of Biomolecular Medicine, Faculty of Medicine and Health Science, Ghent University, 9000 Ghent, Belgium., Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; Andrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau, 08025 Barcelona, Catalonia, Spain., Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium., Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy., Department of Surgery, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia; Department of Pediatric Surgery, Clinic of Surgery, Tartu University Hospital, 51014 Tartu, Estonia., Andrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau, 08025 Barcelona, Catalonia, Spain; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy., Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT 84112, USA., Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium; Artificial Intelligence Laboratory, Vrije Universiteit Brussel, 1050 Brussels, Belgium., Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; Center for Embryonic Cell & Gene Therapy, Oregon Health & Science University, Beaverton, OR 97239, USA., Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia; Andrology Clinic, Tartu University Hospital, 50406 Tartu, Estonia; Department of Surgery, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia. Electronic address: ., Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia. Electronic address: .