Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan

TLDR

The study aimed to compare the phenotypic effects of identical VHL germline mutations across North American, European, and Japanese families. The authors performed germline mutation screening in 469 VHL families from North America, Europe, and Japan. Germline VHL mutations were found in 63 % of the 469 families, comprising 137 distinct variants—most occurring in one or two families—and produced three cancer phenotypes (renal carcinoma alone, renal carcinoma with pheochromocytoma, or pheochromocytoma alone) with similar manifestations across Caucasian and Japanese cohorts, providing a valuable mutation‑phenotype catalog for diagnosis and prognosis.

Abstract

Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1-2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL.