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