LAUSR

Objective: In recent years, there has been a lot of controversy about the factors affecting the penetrance of multiple endocrine neoplasia type 2A(MEN2A). Some studies considered it may be related to gene mutations. In the present study, we aimed to support the hypothesis that RET gene mutation affect the penetrance of MEN2A and study the effects of novel SLC12A3 variants in MEN2A. Design and method: Peripheral blood samples were collected from the proband and his relatives. Whole-exome sequencing and Sanger sequencing were performed to identify the gene mutations. The protein structure prediction with comparative modelling was used to predict the effects of novel gene variants on protein function. We also used the clinical examinations to evaluate the phenotypes of patients comprehensively. Results: Genetic analysis identified RET c.1901G>A and novel variants in SLC12A3 c.3070_3079delinsCAG in the proband and his mother. The patients carrying the novel SLC12A3 variants didn’t show the typical clinical manifestations of Gitelman syndrome because of heterozygosity. But it is theoretically explained that the novel variants of SLC12A3 may affect the function of protein. We also found SLC12A3 gene was not expressed in typical target organs of MEN2A.We are the first to describe compound RET c.1901G>A and SLC12A3 mutations in one family with MEN2A. Our study supports the hypothesis that RET gene mutations affect the penetrance of MEN2A. The novel variants in SLC12A3 may be disease causing, but it is not significantly related to the clinical phenotype of MEN2A in our study. Conclusions: RET gene mutation affect the penetrance of MEN2A. The novel variants in SLC12A3 may affect the function of protein, but it is not significantly related to the clinical phenotype of MEN2A.We need more studies about the phenotypes and related mechanisms of gene mutations to guide individual treatment.