VHL mosaicism: the added value of multi-tissue analysis

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Von Hippel-Lindau (VHL) disease is an inherited disorder.
• It's caused by VHL gene variants, leading to various tumors.
• Germline VHL variants are usually found in affected individuals.

Purpose of the Study:

• To report a rare case of VHL disease.
• To highlight diagnostic challenges when blood DNA testing is negative.
• To emphasize the importance of tissue analysis in diagnosing VHL.

Main Methods:

• Clinical diagnosis of VHL disease.
• Peripheral blood DNA sequencing.
• Tumor tissue DNA sequencing (ccRCC, pheochromocytoma, lung, liver).
• Re-analysis of peripheral blood DNA.
• Immunohistochemical analysis (alpha-inhibin, CAIX, pVHL).

Main Results:

• Peripheral blood DNA analysis initially failed to detect a VHL variant.
• Sequencing of four tumor tissues identified a VHL c.593T>C (p.Leu198Pro) variant.
• The variant was present in tumors at varying allele fractions (10-55%).
• Re-examination detected the variant at a low allele fraction (6%) in peripheral blood.
• Tumor analysis confirmed VHL-related pseudohypoxia.

Conclusions:

• This case demonstrates VHL mosaicism.
• Tissue testing is crucial for diagnosing VHL in variant-negative cases.
• Low-level mosaicism can be missed by standard blood DNA testing.