LAUSR

Abstract Objective: Premature ovarian insufficiency is a heterogeneous condition that can be caused by several factors, such as genetic, environmental, etc. and represents one of the main causes of female infertility. One of the genes implicated is GDF9, which encodes a member of the transforming growth factor-beta superfamily that participates in the coordination of somatic cell activity, female fertility, including folliculogenesis, and oocyte maturation. Damaging variants in GDF9-encoded growth factors can cause the production of inhibin, perturb oocyte granulosa cell microenvironments, and obstruct follicle development. A novel GDF9 variant is herein reported to consolidate the role of GDF9 in ovarian function and female fertility. Methods: A 38-year-old female was referred for the investigation of secondary amenorrhea. Eventually, she was referred for genetic evaluation whereby conventional karyotyping and Fragile-X molecular testing were normal. Whole Exome Sequencing was performed, followed by targeted Sanger sequencing in all family members for variant confirmation and evaluation. Results: In this study we report a patient presenting with secondary amenorrhea due to premature ovarian failure and a pituitary lesion with radiological characteristics compatible with a Rathke cyst or a macroadenoma, residing between the adenohypophysis and neurohypophysis. Whole Exome Sequencing revealed a novel heterozygous stoploss variant c.1364A>C, p.(*455Serext*8) in the GDF9 gene. Conclusions: Should the predicted elongated GDF9 protein and differentially configurated GDF9 mature protein molecule form unstable dimers, rapid proteolytic degradation may take place and inhibit homo/heterodimer formation.