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

By Pille Hallast, Laura Kibena, Margus Punab, Elena Arciero, Siiri Rootsi, Marina Grigorova, Rodrigo Flores, Mark A. Jobling, Olev Poolamets, Kristjan Pomm, Paul Korrovits, Kristiina Rull, Yali Xue, Chris Tyler-Smith, Maris Laan

Posted 09 Dec 2020
medRxiv DOI: 10.1101/2020.12.08.20245928

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-chromosomal Azoospermia 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 long r2/r3 inversion destabilizing the AZFc region and predisposing to recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk to spermatogenic failure was increased 8.6-fold (p = 6.0 x 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.

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