Puzzling Out the Genetic Architecture of Endometriosis: Whole-Exome Sequencing and Novel Candidate Gene Identification in a Deeply Clinically Characterised Cohort

Endometriosis (EM) is a common multifactorial gynaecological disorder. Although Genome-Wide Association Studies have largely been employed, the current knowledge of genetic mechanisms underlying EM far from complete, and other approaches are needed. To this purpose, whole-exome sequencing (WES) was performed on deeply characterised cohort 80 patients aimed at identification rare damaging variants within 46 EM-associated genes novel candidates. WES analysis detected 63 rare, predicted, heterozygous 24 in 63% patients. In particular, (1) total 43% carried 13 recurrent (FCRL3, LAMA5, SYNE1, SYNE2, GREB1, MAP3K4, C3, MMP3, MMP9, TYK2, VEGFA, VEZT, RHOJ); (2) 8.8% private eight (KAZN, IL18, WT1, CYP19A1, IL1A, IL2RB, LILRB2, ZNF366); (3) 24% three candidates (ABCA13, NEB, CSMD1). Finally, to deepen polygenic architecture EM, comprehensive evaluation analysed performed, revealing higher burden (p < 0.05) harbouring than controls. These results highlight new insights into genetics, allowing for definition genotype–phenotype correlations, thereby contributing, long-term perspective, development personalised care