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Primary infertility affects 15% of couples worldwide, yet many genetic causes remain unknown. Through whole-exome sequencing of a woman with primary infertility and repeated embryo implantation failure, we identified a novel homozygous frameshift mutation in GREB1 (c.5364delC, p.Ala1789Argfs∗42). Sanger sequencing confirmed heterozygous carrier status in both parents. Functional studies demonstrated the absence of nonsense-mediated mRNA decay but abnormal GREB1 protein expression via western blotting. Computational modeling predicted pathogenic structural alterations. This variant is absent in gnomAD/ExAC databases. Our findings establish GREB1 mutations as a novel cause of female infertility, highlighting its role in endometrial receptivity regulation.