Biallelic BRCA2 variants induce premature ovarian insufficiency by impaired meiotic homologous recombination

The DNA damage response plays a pivotal role in ovarian aging. Breast cancer susceptibility gene 2 (BRCA2), which participates in homologous recombination (HR), is a key regulator of natural menopause. Rare BRCA2 variants have been identified in patients with premature ovarian insufficiency (POI). However, the underlying molecular mechanisms are not well understood. Using a viable mouse model, Brca2c.68-1G>C/c.4384-4394del, carrying compound heterozygous variants mirroring the ones identified in a POI pedigree, we illustrated the essential role of BRCA2 in primordial follicle pool establishment. Germline deficiency of BRCA2 did not affect primordial germ cell (PGC) proliferation but impaired the recruitment of RAD51 and DMC1 to programmed DNA double-strand breaks (DSBs) during meiotic HR, causing postnatal oocyte depletion. Moreover, Brca2c.68-1G>C/c.4384-4394del mice presented increased tumor susceptibility. These findings confirmed the pathogenicity of BRCA2 biallelic variants in POI, revealing the dual impact on germ cell development and somatic cancer risk, underscoring the necessity of tumor surveillance in POI patients with BRCA2 mutations.