Further delineation of familial polycystic ovary syndrome (PCOS) via whole-exome sequencing: PCOS-related rare FBN3 and FN1 gene variants are identified.

AIM: To identify pathogenic rare coding Mendelian/high-effect size variant(s) by whole-exome sequencing in familial polycystic ovary syndrome (PCOS) patients to elucidate PCOS-related pathways. METHODS: Twenty women and their affected available relatives diagnosed with PCOS according to Rotterdam criteria were recruited. Whole-exome sequencing on germ-line DNA from 31 PCOS probands and their affected relatives was performed. Whole-exome sequencing data were further evaluated by pathway and chemogenomics analyses. In-slico analysis of candidate variants were done by VarCards for functional predictions and VarSite for impact on three-dimensional (3D) structures in the candidate proteins. RESULTS: Two heterozygous rare FBN3 missense variants in three patients, and one FN1 missense variant in one patient from three different PCOS families were identified. CONCLUSION: We identified three novel FBN3 and FN1 variants for the first time in the literature and linked with PCOS. Further functional studies may identify causality of these newly discovered PCOS-related variants, and their role yet remains to be investigated. Our findings may improve our understanding of the biological pathways affected and identify new drug targets.

The control of oocyte survival by intrinsic and extrinsic factors.

CAPSULE: Mechanisms that control the survival of oocytes and, by extension, the duration of ovarian function have been identified. However, it is still not clear whether oocyte "quality" is related to survival, nor is the role of the granulosa cells of follicles in follicle survival entirely understood. Here, we consider oocyte-intrinsic and oocyte-extrinsic mechanisms of oocyte loss and argue that developing a better understanding of such physiological events is needed to protect fertility, fecundity, and ovarian function in women.The duration that ovaries function is, as is intuitive, controlled by the number of remaining oocytes within follicles. Once the number of follicles drops beneath a threshold number, ovarian function ceases. Thus, understanding mechanisms that control oocyte survival is paramount as we consider strategies to protect or prolong ovarian function in women. It is often assumed that physiological oocyte survival is entirely controlled by "oocyte- intrinsic" factors, such as poor genetic quality or accumulated damage to the oocyte itself. Oocytes that have poor genetic quality due to development or accumulated damage would then die sooner than those of higher "quality." Indeed, new data suggest that oocyte-intrinsic genetic quality as determined by the ability to repair double-stranded DNA breaks is a significant contributor to oocyte survival and the duration of ovarian function. However, the nature of the follicle, where the oocyte and surrounding granulosa cells exist in intimate contact and rely upon each other for survival signals and metabolic function, makes it unlikely that oocyte-intrinsic factors entirely control oocyte survival. We and others are assessing the role of adjacent somatic (granulosa) cells in follicle survival, determining the relative importance of "oocyte-extrinsic" factors.