Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom
Laura Kibena
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
Margus Punab
Andrology Unit, Tartu University Hospital, Tartu, Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
Elena Arciero
Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom
Siiri Rootsi
Institute of Genomics, Estonian Biocentre, University of Tartu, Tartu, Estonia
Marina Grigorova
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
Rodrigo Flores
Institute of Genomics, Estonian Biocentre, University of Tartu, Tartu, Estonia
Mark A Jobling
Department of Genetics & Genome Biology, University of Leicester, Leicester, United Kingdom
Olev Poolamets
Andrology Unit, Tartu University Hospital, Tartu, Estonia
Kristjan Pomm
Andrology Unit, Tartu University Hospital, Tartu, Estonia
Paul Korrovits
Andrology Unit, Tartu University Hospital, Tartu, Estonia
Kristiina Rull
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Women’s Clinic, Tartu University Hospital, Tartu, Estonia
Yali Xue
Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom
Chris Tyler-Smith
Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom
Male infertility is a prevalent condition, affecting 5–10% of men. So far, few genetic factors have been described as contributors to spermatogenic failure. Here, we report the first re-sequencing study of the Y-chromosomal Azoospermia Factor c (AZFc) region, combined with gene dosage analysis of the multicopy DAZ, BPY2, and CDYgenes and Y-haplogroup determination. In analysing 2324 Estonian men, we uncovered a novel structural variant as a high-penetrance risk factor for male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ~1.6 Mb r2/r3 inversion, destabilizing the AZFc region and predisposing to large recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk for spermatogenic failure was increased 8.6-fold (p=6.0×10−4). This finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification at young age will facilitate timely counselling and reproductive decision-making.