Germline mutations in the von Hippel-Lindau disease (VHL) gene in mainland Chinese families

Abstract

Background: von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. To date, more than 500 VHL families have been reported worldwide. However, few information is available about VHL germline mutations in mainland Chinese families.

Objective: To provide some preliminary information about the germline VHL mutations in mainland Chinese population.

Methods: A total of 27 index patients suspected of having VHL disease from unrelated Chinese families were studied by using direct DNA sequencing analysis and universal primer quantitative fluorescent multiplex polymerase chain reaction.

Results: The VHL germline mutations were detected in 26 (96%) probands. A total of 20 intragenic mutations (77%) were identified consisting of 12 missenses, 5 nonsenses, 2 micro-deletions and 1 novel intron mutation (IVS1-38C>T). Six large deletions (23%) were detected including four partial deletions and two complete deletions. Furthermore, a C>T substitution at nucleotide 470 (Pro86Leu) was observed in two unrelated Chinese families. Of note, two mutations (Asn78Ser and Ser80Ile) previously characterized as VHL type I mutations in Western VHL were associated with the type II Chinese family. In addition, a VHL germline mutation was also identified in a proband who did not fulfill the clinical diagnostic criteria for VHL disease.

Conclusions: The spectrum of VHL germline mutations in mainland Chinese population is similar to that observed in Western population, and Genetic testing can be powerful in diagnosis and clinical management of VHL disease.

Fig. 1

Genotyper traces of a normal control and three deletions. Peaks corresponding to deleted exons are indicated by arrows. Peaks are labeled by the name of the amplified region. The β-globin gene and the GPR15 gene are two reference genes

Fig. 2

Pedigree of the proband 9 with asynchronous bilateral renal clear cell carcinomas, multiple renal cysts and pancreatic cysts and with no positive family history. The analysis of the VHL germline mutation showed a Pro86Leu mutation and identified an asymptomatic patient and a carrier in the family 9

Fig. 3

The genotype and phenotype in the large Chinese family with VHL disease. a The pedigree of the family 6 with 18 affected patients. b DNA sequence analysis showing a A–G transition at nucleotide 446. The change results in the mutation from Asn to Ser in codon78. c 46-year-old woman from the family (individual III-14). Computed tomography of the abdomen demonstrates a cystic lesion in right adrenal and a solid tumor in right kidney. Pathological results confirm pheochromocytoma and clear cell carcinaoma