Spontaneous natural conception and live birth in three patients with likely pathogenic variants in TUBB8, ZP2, and ZP3 associated with female subfertility

Three patients with genetically confirmed female subfertility due to heterozygous likely pathogenic variants in TUBB8 (c.613G > A), ZP2 (c.1421T > C), or ZP3 (c.518 C > G), respectively, had histories of recurrent adverse assisted reproductive technology (ART) outcomes, including zona pellucida (ZP) abnormalities or oocyte degeneration, reduced fertilization, poor embryo development or limited viable embryo availability, and implantation failure. Notably, all three patients eventually achieved successful live births. Patient 1, after two failed ART cycles, delivered a male infant following a third ICSI attempt, and later conceived naturally, delivering a female infant. Patient 2, after five unsuccessful IVF/ICSI cycles and no implantation, conceived naturally years later and delivered a male infant. Patient 3, following two failed IVF/ICSI attempts, conceived via donor oocytes and later delivered a male infant through natural conception. These cases expand the reported reproductive outcome spectrum of women carrying likely pathogenic variants in oocyte- and ZP-related genes. The findings suggest that reproductive outcomes in selected heterozygous carriers may be more variable than previously appreciated and that residual reproductive potential may occasionally be retained. These observations may help refine reproductive genetic counseling for women with genetically associated subfertility, while further case accumulation and functional studies are required.