Clinical and Genetic Characterization of Russian Patients with von Hippel-Lindau Syndrome.

VHL

Germline VHL variants: mostly missense (60.3%), about 88% of which affect the HIF-α- and ELOC-binding sites of pVHL

The VHL gene was analysed in 535 Russian patients referred for suspected von Hippel-Lindau syndrome, using Sanger sequencing, MLPA and, in some cases, high-throughput sequencing. In total, 177 causative variants were identified (129 point mutations and 48 large deletions), mostly missense (60.3%) clustered at codons 167, 88 and 78. Carriers had central nervous system (69.7%) and retinal (41.4%) haemangioblastomas, clear-cell renal carcinoma (27.3%) and phaeochromocytoma (7.1%); multi-organ involvement was far more frequent than in patients without a variant (78.8% vs 21.1%), whereas an isolated clear-cell renal carcinoma, even before age 60, had a positive predictive value of only 14.7%. The p.Glu70Lys variant was found only in four patients of East Asian ancestry, and the nonsense variant p.Arg161Ter was more frequent in patients of Turkic than Slavic ethnicity (30.0% vs 2.5%). Testing of 87 relatives identified 41 carriers.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A large national series, useful above all for one figure: the 14.7% positive predictive value of an isolated clear-cell renal carcinoma, which helps prioritise indications for VHL testing. Ancestry-enriched variants (p.Glu70Lys, p.Arg161Ter) are worth knowing for interpretation in under-represented populations. Descriptive study, without follow-up or variant-level penetrance data.

Analysis by Dr Thibaut Benquey