1. A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans.
- Author
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Hallast P, Kibena L, Punab M, Arciero E, Rootsi S, Grigorova M, Flores R, Jobling MA, Poolamets O, Pomm K, Korrovits P, Rull K, Xue Y, Tyler-Smith C, and Laan M
- Subjects
- Adolescent, Adult, Azoospermia epidemiology, Estonia, Humans, Male, Middle Aged, Young Adult, Azoospermia genetics, Chromosome Inversion genetics, Gene Deletion, Spermatogenesis genetics
- Abstract
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 CDY genes 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., Competing Interests: PH, LK, MP, EA, SR, MG, RF, MJ, OP, KP, PK, KR, YX, CT, ML No competing interests declared, (© 2021, Hallast et al.)- Published
- 2021
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