CDHR2 c.2233C > T Is Involved in Human Familial Ovarian Immature Teratoma With BMP15 c.262C > T

We previously identified the germline mutation c.262C > T in BMP15 as a genetic susceptibility factor of hereditary ovarian immature teratoma (OIT). However, not all female carriers in that family had OIT. In this study, we analyzed the genetic differences among these individuals, aiming to explore whether any genes may be copathogenic with BMP15. The subjects were recruited from two three-generation pedigrees of hereditary OIT. Whole-exome sequencing (WES) was performed, and the candidate variants were subsequently tested by Sanger sequencing. Moreover, bioinformatics was used to assess the mutation with MutationTaster and Combined Annotation Dependent Depletion (CADD), and pathogenicity was predicted according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The effect of the mutation on CDHR2 expression was evaluated by RT-qPCR, Western blotting, and immunofluorescence with confocal microscopy. WES revealed that, unlike the two unaffected sisters, both affected second-generation individuals harbored a germline mutation in CDHR2 (c.2233C > T, p.R745X) in addition to the mutation in BMP15 (c.262C > T, p.R86C). CDHR2 c.2233C > T is a truncating mutation that was predicted to be deleterious by MutationTaster and CADD and classified as pathogenic according to the ACMG criteria. Our in vitro experiments revealed that mRNA and protein expression levels were significantly lower in cells with the 2233T allele than in those with the 2233C allele. Moreover, the localization of the mutant product in cells was significantly different from that of the wild-type protein. The mutant group exhibited abnormal accumulation of small-molecule metabolites, along with aberrant activation of the HIPPO signaling cascade. Our findings suggest that the CDHR2 c.2233C > T variant may have a synergistic effect with BMP15 in hereditary OIT or act as a modifier gene in OIT development.