Novel variants in YTHDC2 cause non-obstructive azoospermia by disrupting the mitotic-to-meiotic transition in humans and mice

Biallelic missense variants in YTHDC2 (m6A RNA helicase reader), disrupted mitotic-to-meiotic transition

Biallelic missense variants in YTHDC2, an RNA helicase specifically expressed in male germ cells, are identified in men with non-obstructive azoospermia or severe oligozoospermia. YTHDC2 is essential for meiotic progression; its loss causes arrest at early prophase I of meiosis I, confirmed by murine models and human testicular biopsies. This study establishes YTHDC2 as a new gene for meiotic-origin male infertility, with robust functional evidence in two species.

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Monogenic male infertility remains largely underdiagnosed, with a genetic basis identified in only 20–30% of non-obstructive azoospermia. YTHDC2 is a relevant addition to male infertility genetic panels, particularly for forms with meiotic arrest on biopsy. The dual human + murine validation strengthens the robustness of the association.

Clinical impact: 2/3 · Evidence strength: 3/3 · Novelty: 2/2 · Sample size: 0/1 · Publication status: 1/1 → Total: 8/10