A common 1.6 Mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans
Mark A. Jobling,
Posted 09 Dec 2020
medRxiv DOI: 10.1101/2020.12.08.20245928
Posted 09 Dec 2020
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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