Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease

摘要: Context von Hippel-Lindau disease, comprising renal cancer, hemangioblastoma and/or pheochromocytoma (PHEO) is caused by missense or truncating variants of the VHL tumor suppressor gene, which involved in degradation hypoxia inducible factors (HIFs). However, role synonymous disease unclear. Objective We evaluated a variant patients with familial PHEO without detectable pathogenic mutation. Design performed genetic and transcriptional analyses leukocytes tumors from affected unaffected individuals splicing existing cancer databases. Results identified variant(c.414A>G, p.Pro138Pro) as driver event five independent individuals/families PHEOs syndrome. This promotes exon 2 skipping and, hence, abolishes expression full-length transcript. Exon spans HIF binding domain, required for VHL. Accordingly, carrying this display hyperactivation typical loss. Moreover, other TCGA pan-cancer datasets are biased toward transcript that excludes exon, supporting broader impact spliced variant. Conclusion A recurrent (c.414A>G, confers susceptibility to through splice disruption, leading dysfunction. finding indicates certain may be clinically relevant should considered testing surveillance settings. The observation coding can exclude suggests dysregulated an underappreciated mechanism VHL-mediated tumorigenesis.