P-550 Monoallelic CCNB2 variants may cause oocyte maturation defects and embryo developmental arrest

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Abstract Study question Have all the genes that may cause embryo development arrest and oocyte maturation defects been identified in female patients? Summary answer We identified a variant in CCNB2 in our patient. To our knowledge, this is first time that meiotic arrest can be caused by mutated-CCNB2. What is known already Successful reproduction involves the maturation of gametes, fertilization, and early development of the embryo. Oocyte maturation involves a sequence of both morphological and molecular transformations, progressing from germinal vesicle oocytes to metaphase I oocytes and ultimately to metaphase II oocytes. Any disruption in the process of oocyte maturation can result in infertility. With the widespread use of whole exome sequencing (WES), several genes that influence oocyte maturation at different stages have been recently identified. Study design, size, duration We here report the case of repeated ART failure due to oocyte maturation defect and embryo developmental arrest. Participants/materials, setting, methods A 30-year-old female and 38-year-old male applied to our clinic due to unexplained infertility for 4 years. The first ART attempt resulted in 2 of 13 oocytes with late MII. During ART performed in our center, germinal vesicle and meiotic arrest were observed in all oocytes. No mature oocytes were obtained. Her grandfather’s sister was also infertile. WES and Sanger analysis were performed to detect any mutation in known/candidate genes and show familial segregation Main results and the role of chance WES analysis revealed no mutation in genes that were previously reported as a cause of oocyte maturation defect or early embryo development in human. We do a further analysis of genes highly or specifically expressed in oocytes or expressed at low levels yet previous studies have suggested its role in embryo development. We identified a c.787C>T, p.Arg263* heterozygous nonsense variant in the CCNB2 gene that was extremely rare in both multiple databases and our in-house database. Multiple lines of computational evidence support the deleterious effect of the variant on the gene product. This variant was transmitted from her healthy father. CCNNB2 is not expressed in any cells other than oocytes in human. The activity of the M phase-promoting factor (MPF) is crucial for advancing through both mitosis and meiosis. CCNB2 plays a vital role by contributing to the activity of pre-MPF during prophase, necessary for generating enough MPF to proceed through maturation. Furthermore, CCNB2 is significantly involved in mouse oocyte meiosis, playing a key role in both the G2/M and MI/anaphase I transitions. Limitations, reasons for caution New disease-causing variants in this gene should be demonstrated in larger cohorts with female infertility. In addition, further functional studies should be carried out both in CCNB2-mutated human and animals. Wider implications of the findings This study may provide a better understanding background of female infertility and the failure of the ART process. CCNB2 may have a crucial role in the oocyte maturation process and can be utilized as a female infertility genetic marker. Trial registration number NA