Monogenic Contributions to Familial Endometriosis: A Scoping Review

Introduction: Endometriosis is a chronic gynecological disorder characterized by the ectopic growth of endometrial-like tissue, with emerging evidence highlighting a significant genetic contribution to its etiology. While genome-wide association studies have identified multiple common variants associated with sporadic endometriosis, the contribution of rare variants in familial endometriosis remains understudied. This scoping review aims to collate the published literature on familial endometriosis and systematically curate the genetic findings reported for familial endometriosis, including details of genetic variants, gene functions, and their associated biological pathways, to explore the monogenic inheritance of this disorder.

This scoping review adhered to the PRISMA guidelines for Scoping Reviews and was registered on the Open Science Framework (OSF). A comprehensive search was conducted across four major literature databases: PubMed, Web of Science, Scopus, and Embase. The Population, Concept, Context (PCC) framework of Joanna Briggs Institute (JBI) guidance was utilized for eligibility, where the population included participants with a familial history of endometriosis. The concept comprised studies focusing on the identification of genes and genetic variants for familial endometriosis. Context included English language and peer-reviewed primary research articles involving research on the genetics of familial endometriosis from all over the world. Data were extracted on the study design, phenotypic and genotypic characteristics of patients, family history, identified genes/variants, their location, detection methods, and other details. Further investigation into the biological relevance of the identified genes in terms of their functions and pathways was done using various bioinformatic tools, including Gene Ontology, Pathway Enrichment, and Gene-Pathway Network.

Eight studies comprising 16 families with familial endometriosis met the inclusion criteria, which identified variants within 18 genes, including CYP1A1, GSTM1, GSTT1, CDKN2BAS, FN1, WNT4, UGT2B28, USP17L2, TNFRSF1B, CIITA, NPSR1, CRABP1, GEN1, ADGRG7, TFG, FGFR4, NALCN, and NAV2. The identified variants spanned coding as well as non-coding regions. The identified genes were implicated in key biological roles in endometriosis-relevant pathways such as estrogen metabolism, inflammation, immune regulation, epithelial-to-mesenchymal transition, and neurogenic signaling.

This scoping review collated 18 genes implicated in familial endometriosis from across the literature, suggesting monogenic causes with rare, potentially deleterious genetic variants underlying the origin of the disease in families. Further research and functional validation on these potential candidate genes is necessary to understand the genetics of familial endometriosis, which could potentially pave the way for personalized risk prediction and targeted therapeutic strategies.