The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, the authors show that the mutations in E1' induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. A patient of family F7, was found to have a germline mutation in the VHL gene, c.340+816A>C in a homozygous state. This patient was diagnosed with erythrocytosis at 7 years old. This patient's asymptomatic parents were also genetically tested and both were found to have the same germline variant.