Hotspot mutations and tumour spectrum in von Hippel-Lindau syndrome: genotype-phenotype analysis of a large Chinese cohort

VHL

Recurrent germline VHL variants (codon 65 missense, exon 2 deletion, c.481C>T, c.224_226del) associated with distinct tumour profiles

This retrospective single-centre Chinese study includes 674 patients with von Hippel-Lindau disease from 283 unrelated families, aiming to refine mutation-specific risk stratification, as the traditional classification relies mainly on pheochromocytoma penetrance. Four recurrent hotspot subtypes were analysed: codon 65 missense, exon 2 deletion, c.481C>T and c.224_226del. Codon 65 missense variants were associated with a lower risk of retinal angioma and pheochromocytoma, whereas exon 2 deletion was characterised by more frequent and earlier retinal angiomas and worse renal cell carcinoma-specific survival. c.481C>T was associated with increased risks of central nervous system hemangioblastoma, renal cell carcinoma and pancreatic lesions, and c.224_226del with a hemangioblastoma-predominant phenotype, earlier onset, lower pancreatic lesion risk but higher overall mortality. These four subtypes cover 19.6% of patients.

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

The value lies in moving from a clinical-type classification to variant-tailored counselling, useful for adjusting surveillance in carriers of these four recurrent subtypes. Its scope remains limited: the stratification covers only one patient in five, the cohort is single-centre and Chinese, and transferability to populations with different recurrent variants remains to be established.

Analysis by Dr Thibaut Benquey