Novel and recurrent germline mutations in the VHL gene in 5 Arab patients with Von Hippel-Lindau disease

Abstract

Inherited germline mutations in the VHL gene cause predisposition to Von Hippel-Lindau (VHL) disease. Patients exhibit benign and cancerous lesions in multiple tissues, including hemangioblastomas, clear cell renal cell carcinoma, cysts in kidneys and pancreas, and pheochromocytomas. Although pathogenic germline mutations in the VHL gene have been widely described in different populations, only a single mutation was previously reported in a family from mixed Arab-Persian ethnicity. Here, we present five Arab patients with two new and two recurrent germline mutations in the VHL gene. These mutations include three in-frame deletions and a missense mutation. Infrequent in-frame deletions in previously described patients from other populations, as well as the presence of new mutations, suggests a distinct spectrum of VHL gene mutations in Arab patients. While pulmonary manifestation has been described rarely in VHL disease, we have identified two patients with a recurrent p.Phe76del in-frame deletion exhibiting multiple nodules in lungs. We also describe a first-ever in-frame deletion in the VHL gene in a patient with VHL type 2C disease, exhibiting bilateral pheochromocytoma. Overall, the study provides an insight into the genotype-phenotype relationship of VHL disease in Arab patients and provides a comparison with previously described patients from other ethnicities.