76. Von Hippel-Lindau syndrome in a patient with negative germline testing

Aly Abdelkareem

Patricia Hernandez

I am a Clinical Pathology resident at Washington University in St. Louis and I will continue my training as Molecular Genetic Pathology and Informatics fellow. My interests include cancer diagnosis and prognosis features, constitutional diseases, and informatics.


Patricia Hernandez, Andrea Stacy, Yang Cao

Washington University in St. Louis, St. Louis, MO, United States

The VHL gene is a tumor suppressor gene that plays a critical role in regulating cell growth and division. Pathogenic variants in the VHL gene can lead to the development of tumors in various organs, including the kidneys, adrenal glands, and pancreas. The most well-known disease associated with VHL gene pathogenic variants is von Hippel-Lindau disease (VHL disease), an inherited disorder that increases the risk of developing multiple tumors and cysts in different parts of the body.

Here, we present the case of an individual with a clinical diagnosis of VHL disease where germline NGS testing results were negative twice, using genomic DNA obtained from both blood and saliva. No clinically significant variants were identified on the germline common Hereditary Cancers Panel or von Hippel-Lindau Syndrome panel (including VHL gene). The strong clinical suspicion for VHL motivated a VHL gene targeted next-generation sequencing to be performed on formalin-fixed paraffin embedded from the resected brain tissue (hemangioblastoma). DNA was extracted and sequenced with a coverage of >3000x. A pathogenic VHL variant (p.Arg161X) was found, indicating VHL mosaicism. 95-100% of individuals with clinical features of VHL present a positive germline VHL variant. In rare events where there is clinical suspicion for VHL without a VHL germline variant detected, somatic mosaicism as demonstrated in our case is a possible explanation to elucidate the diagnosis.

This report of a rare case of VHL mosaicism highlights the value of high depth NGS testing on affected tissues in VHL variant negative cases.