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.

Pharmaceutical Repurposing Strategies for Metabolic Disorders: Insights from Mendelian Randomization Studies

“…This study highlights several key genes with robust associations across metabolic disorder-related diseases, suggesting FN1 (fibronectin 1), ICAM1 (Intercellular Adhesion Molecule 1), and SNCA (Synuclein Alpha) as potential critical targets for these conditions. Research indicates FN1 as an adverse marker for PCOS 35,49 and T1D 34 , consistent with the observed increased prevalence of metabolic features (diabetes, hypertension, etc.) in women with PCOS 50–52 .…”

“…1 ). Among these, the FN1 gene had the most disease connections, including 5 diseases ( Table 2 ), where an increase in FN1 protein was identified as a risk factor for Type 1 Diabetes (T1D) 34 , Polycystic Ovary Syndrome (PCOS) 35 , and a protective factor for Non-Alcoholic Fatty Liver Disease (NAFLD), Hypothyroidism/Myxedema, and Hyperthyroidism. The OBSCN gene was also linked to 5 diseases, with increased protein expression posing a risk for NAFLD, Colorectal Cancer 36 , Parkinson’s Disease, and serving as a protective factor for Preeclampsia and Non-Small Cell Lung Cancer 37 .…”

Exome sequencing to explore the possibility of predicting genetic susceptibility to the joint occurrence of polycystic ovary syndrome and Hashimoto’s thyroiditis

“…Changes in ovarian ECM composition and the organization of collagen, fibronectin, and elastin play significant roles in follicle development ( 115 ). Recently, two rare missense variants in FBN3 encoding an ECM protein, a member of the fibrillin/latent TGF-β binding protein (LTBP) family, and a missense variant in FN1 , which encodes a member of the fibronectin family, were identified by WES in families with PCOS ( 48 ). In addition, the FBN3 D19S884 allele 8 variant has been identified by candidate gene analysis and its causality in PCOS susceptibility has been suggested ( 116 , 117 ).…”

Signaling pathways and targeted therapeutic strategies for polycystic ovary syndrome

“…Fibrillin 3 regulates the bioactivity of TGF-b by binding to the TGF-b superfamily ligands. Hence, some variants of the Fibrillin gene are thought to alter the normal function of TGF-b signaling and contribute to the pathogenesis of PCOS (285). Elevated follistatin levels have been detected in PCOS patients, regardless of weight.…”