Effects Of VHL And EGLN1 Gene Mutations On Clinical Phenotypes In A Family Of VHL Syndrome

Objective: To investigate the mutations of VHL gene(c.208 g > A)and EGLN1 gene(c.380 g > C)in a Han family with Von-hipple Lindau(VHL)syndrome,a Han family in Guizhou Province,and compare it with the clinical table.Type comparison and analysis to clarify the effect of VHL(c.208G>A)and EGLN1(c.380G>C)gene mutations on the clinical phenotype.Methods: Collect peripheral blood from 9 members of a family with VHL syndrome,extract genomic DNA,and screen patients with VHL syndrome and healthy members of the family with pathogenic genes through Whole Exome Sequencing(WES),gene annotation and control analysis check.Sanger sequencing method was used to amplify gene fragments by Polymerase Chain Reaction(PCR)and sequence the VHL gene and EGLN1 gene to understand the mutations of the two genes in the family members.Investigate the clinical data of family members,and compare and analyze the differences in clinical phenotypes of family members.Results:(1)By comparing the Whole Exome Sequencing(WES)of patients with VHL c.208G>A gene mutation(Ⅱ 6)and healthy members of different generations(Ⅲ 19,Ⅳ 4),the suspicious pathogenic genes: VHL c.208G>A and EGLN1 c.380G>C were screened out,which were consistent with the mutation results of VHL gene and EGLN1 gene of Sanger sequencing family members.(2)Four VHL syndrome patients(Ⅱ3,Ⅱ6,Ⅲ12,Ⅲ17)were found to have VHL c.208G>A gene mutations.All family members with VHL c.208G>A gene mutation had clinical phenotypes.(3)Among the family members,the elder sister of the proband’s mother(Ⅱ 2)and the elder son of the elder brother of the proband’s mother(Ⅲ 7)had EGLN1 c.380G>C gene mutation.No clinical phenotype was found in the family members with EGLN1 c.380G>C gene mutation.(4)Four patients with VHL syndrome in the family had EGLN1 c.380G>C gene mutation,and the clinical phenotype of each patient was significantly different.The elder brother of the mother of the proband(Ⅱ3)only showed renal cyst.The other three patients presented with clinical phenotype of retinal hemangioblastoma,and only the proband(Ⅲ 17)developed a rare clinical phenotype of polycythemia.Conclusion:(1)The mutation site of the pathogenic gene in this family of VHL syndrome is VHL c.208G>A.(2)The mutation of EGLN1 c.380G>C gene alone does not cause disease,and the simultaneous mutation of VHL c.208G>A gene can produce different clinical phenotypes.