Whole-Exome Sequencing Reveals Novel Variations in Patients with Familial Von Hippel−Lindau Syndrome

Von Hippel−Lindau (VHL) syndrome is a rare disease that occurs in an autosomal-dominant genetic pattern. Due to the high genetic variability of VHL diseases, current studies have limited clinical value. Moreover, casual genetic variations in patients with VHL syndrome are still unclear. Here, we performed whole-exome sequencing of 25 individuals to identify reliable disease-related variations. Systemic computational analysis was performed for variant detection, and Sanger sequencing was used to validate detected mutations. Most of the known mutations in the VHL gene were observed in the studied population. In addition, a large fragment deletion in VHL exon 2 in the immediate family members of the last family was detected. This had not been reported earlier. Moreover, we identified 3 novel mutation sites in the MAP2K3 gene that may be involved in the occurrence and development of the VHL disease. These results demonstrated that the heterogeneous nature of VHL syndrome and novel mutational signatures may help to improve the diagnostic ability of VHL syndrome.