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

Abstract

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.

Keywords: PCOS; extracellular matrix; genetics; whole-exome sequencing.