Oocyte/zygote/embryo maturation arrest: a clinical study expanding the phenotype of NOBOX variants

Primary ovarian insufficiency (POI) is an important cause of female infertility, stemming from follicle dysfunction or premature oocyte depletion. Pathogenic variants in genes such as NOBOX, GDF9, BMP15, and FSHR have been linked to POI. NOBOX, a transcription factor expressed in oocytes and granulosa cells, plays a pivotal role in folliculogenesis. Loss-of-function variants in NOBOX are reported in 1-2% of POI women. This study aims to describe the association of novel NOBOX variants with a distinct oocyte, zygote, and embryo maturation arrest (OZEMA) phenotype in infertile women.

Three unrelated women experiencing OZEMA and undergoing multiple in vitro fertilization (IVF) cycles present with a germline NOBOX variant. The detected variants were cross-referenced with a large genetic database to explore their association with IVF outcomes.

A heterozygous NM_001080413.3 (NOBOX): c.1797_1798del, p.(Cys600Phefs*27) variant was detected in a woman with oocyte maturation arrest. Another heterozygous variant, NM_001080413.3 (NOBOX): c.1849C > T, p.(His617Tyr), was detected in two women experiencing embryonic developmental arrest. Segregation analysis in one of the two latter families revealed the presence of the p.(His617Tyr) variant in an affected sister, while the two fertile sisters did not carry this variant. Furthermore, the p.(His617Tyr) variant was found in three women in a large database of whom two presented with an embryonic developmental arrest.

Two heterozygous NOBOX variants were identified in women with an OZEMA phenotype. Where pathogenic NOBOX variants are typically linked to POI, our clinical findings suggest that NOBOX plays a role in subsequent oocyte maturation and early embryo development.