Van Der Kelen Annelore, Uyttebroeck Sophie, Van de Voorde Stefanie, Picchetta Ludovica, Segers Ingrid, Vlaeminck Jelle, Dequeker Bart Johan H, Giron Philippe, Capalbo Antonio, Verpoest Willem, Hes Frederik J, Verdyck Pieter, Gheldof Alexander
Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Clinical Sciences, Research Group Genetics, Reproduction and Development, Centre for Medical Genetics, Laarbeeklaan 101, 1090, Brussels, Belgium.
JUNO Genetics, Reproductive Genetics, Rome, Italy.
J Assist Reprod Genet. 2025 Mar;42(3):763-771. doi: 10.1007/s10815-025-03402-y. Epub 2025 Jan 27.
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.
原发性卵巢功能不全（POI）是女性不孕的重要原因，源于卵泡功能障碍或卵母细胞过早耗竭。NOBOX、GDF9、BMP15和FSHR等基因的致病变异与POI有关。NOBOX是一种在卵母细胞和颗粒细胞中表达的转录因子，在卵泡发生中起关键作用。1%-2%的POI女性中报道有NOBOX功能丧失变异。本研究旨在描述新型NOBOX变异与不孕女性独特的卵母细胞、受精卵和胚胎成熟停滞（OZEMA）表型之间的关联。
三名经历OZEMA并接受多次体外受精（IVF）周期的无关女性存在种系NOBOX变异。将检测到的变异与一个大型基因数据库进行交叉比对，以探索它们与IVF结果的关联。
在一名卵母细胞成熟停滞的女性中检测到杂合的NM_001080413.3（NOBOX）：c.1797_1798del，p.（Cys600Phefs*27）变异。在两名经历胚胎发育停滞的女性中检测到另一种杂合变异，NM_001080413.3（NOBOX）：c.1849C>T，p.（His617Tyr）。对后两个家族中的一个进行的分离分析显示，一名受影响的姐妹存在p.（His617Tyr）变异，而两名可育姐妹未携带该变异。此外，在一个大型数据库的三名女性中发现了p.（His617Tyr）变异，其中两名出现胚胎发育停滞。
在具有OZEMA表型的女性中鉴定出两种杂合的NOBOX变异。虽然致病性NOBOX变异通常与POI有关，但我们的临床研究结果表明，NOBOX在随后的卵母细胞成熟和早期胚胎发育中起作用。
