RESEARCH ARTICLE Exome Sequencing Identifies a Novel Gene, WNK1, for Susceptibility to Pelvic Organ

Pelvic organ prolapse (POP) is a common gynecological disorder; however, the genetic components remain largely unidentified. Exome sequencing has been widely used to identi-fy pathogenic gene mutations of several diseases because of its high chromosomal cover-age and accuracy. In this study, we performed whole exome sequencing (WES), for the first time, on 8 peripheral blood DNA samples from representative POP cases. After filtering the sequencing data from the dbSNP database (build 138) and the 1000 Genomes Project, 2 missense variants inWNK1, c.2668G> A (p.G890R) and c.6761C> T (p.P2254L), were identified and further validated via Sanger sequencing. In validation stage, the c.2668G> A (p.G890R) variant and 8 additional variants were detected in 11 out of 161 POP patients. All these variants were absent in 231 healthy controls. Functional experiments showed that fi-broblasts from the utero-sacral ligaments of POP withWNK1mutations exhibited loose and irregular alignment compared with fibroblasts from healthy controls. In sum, our study identi-fied a novel gene,WNK1, for POP susceptibility, expanded the causal mutation spectrums of POP, and provided evidence for the genetic diagnosis and medical management of POP in the future