A common 1.6 Mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans

Male infertility is a prevalent condition, concerning 5-10% of men. So far, only some recurrent genetic factors have been described as confident contributors to spermatogenic failure. Here, we report the first re-sequencing study of the Y-chromosomalAzoospermia Factor c(AZFc) region combined with gene dosage and Y-haplogroup determination. In analysing 2,324 Estonian men, we uncovered a novel structural variant as a high-penetrant risk factor to male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ∼1.6 Mb longr2/r3inversion destabilizing theAZFcregion and predisposing to recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carriervsnon-carrier risk to spermatogenic failure was increased 8.6-fold (p= 6.0 × 10⁻⁴). The finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification in young age will facilitate timely counselling and reproductive decision-making.