Gene panel analysis for oocyte/zygote/embryo maturation arrest in female infertility: a multicenter study in Japan

Abstract

Abstract Oocyte/zygote/embryo maturation arrest (OZEMA) causes recurrent failure of oocyte maturation, fertilization, or early embryonic development, but its genetic basis and clinically useful testing indicators remain unclear in Japanese patients. We performed a multicenter retrospective cohort study of 50 Japanese women with primary infertility who repeatedly exhibited OZEMA across multiple retrieval cycles. Whole-exome sequencing was used to analyze 24 OZEMA-associated genes, and pathogenic or likely pathogenic variants were classified according to ACMG/AMP guidelines. Pathogenic or likely pathogenic variants were identified in 10 patients (20%), most frequently in TUBB8 ( n  = 6), followed by PATL2 , ZP2 , ZP3 , and CHEK1 ( n  = 1 each). Variant-positive patients had markedly fewer metaphase II oocytes, fertilized oocytes, day-3 embryos, transfer-eligible day-3 embryos, and blastocysts than variant-negative patients. No variant-positive patient achieved a day-3 embryo. Failure to achieve day-3 embryos showed 100% sensitivity and 82.5% specificity for predicting pathogenic or likely pathogenic variants, with higher specificity than failure to achieve transfer-eligible day-3 embryos or blastocysts. These findings characterized OZEMA-associated genetic variants in a Japanese multicenter cohort and suggest that failure to achieve day-3 embryos may help identify patients who require genetic testing.