| Institution: | 1. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;2. Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada;3. Fred A Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, Ontario, Canada;4. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada;5. Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands;6. Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada;7. Advanced Molecular Diagnostics Laboratory, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada;8. Department of Medicine, University Health Network, Toronto, Ontario, Canada;9. Section 6 on Endocrinology and Genetics, National Institutes of Health, Bethesda, Mary Land;10. McMaster University, Hamilton, Ontario, Canada;11. Department of Ophthalmology and Vision Sciences, University Health Network, University of Toronto, Toronto, Ontario, Canada;12. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada;13. Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada;14. Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada;15. Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada;16. Department of Paediatics, Hospital for Sick Children, Toronto, Ontario, Canada;17. Department of Biostatistics, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada |
| Abstract: | Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL. |
