Women with FSHR-inactivating mutations causing resistant ovarian syndrome benefit from oocyte in-vitro maturation.

RESEARCH QUESTION: Is in-vitro maturation (IVM) of oocytes effective for treating women with resistant ovarian syndrome (ROS) carrying biallelic FSHR-inactivating mutations?

DESIGN

Three patients with ROS were recruited for this study. Candidate pathogenic mutations were identified using whole-exome sequencing (WES). A cAMP production assay was performed to evaluate the effects of these mutations. IVM of oocytes was performed to achieve pregnancy.

RESULTS

After undergoing conventional IVF in the first cycle, WES was performed for the three patients with ROS. They were found to be carrying biallelic FHSR mutations, including four novel missense mutations (c.263C>T, c.1106T>C, c.211G>T and c.1349T>A) and one previously reported missense mutation (c.44G>A). A cAMP production assay was performed to evaluate the effects of these mutations, which revealed that they led to almost-complete inactivation of the mutated receptors upon FSH stimulation. IVM of the oocytes was performed for two patients and blastocysts were obtained successfully; these patients delivered healthy babies following frozen embryo transfer.

CONCLUSIONS

The five missense mutations in FSHR were deleterious and associated with ROS in the three patients. To the best of our knowledge, this is the first report of patients with biallelic FSHR-inactivating mutations who gave birth to genetically related children after IVM treatment. The findings show that IVM is an effective treatment for patients with ROS with FSHR-inactivating mutations.