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. 2016 Jul 20;17(1):48.
doi: 10.1186/s12881-016-0306-2.

Genotype-phenotype Analysis of Von Hippel-Lindau Syndrome in Korean Families: HIF-α Binding Site Missense Mutations Elevate Age-Specific Risk for CNS Hemangioblastoma

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Free PMC article

Genotype-phenotype Analysis of Von Hippel-Lindau Syndrome in Korean Families: HIF-α Binding Site Missense Mutations Elevate Age-Specific Risk for CNS Hemangioblastoma

Jee-Soo Lee et al. BMC Med Genet. .
Free PMC article

Abstract

Background: von Hippel-Lindau (VHL) disease is a rare hereditary tumor syndrome caused by VHL gene mutations that is characterized by heterogeneous phenotypes such as benign/malignant tumors of the central nervous system, retina, kidney, adrenal gland, and pancreas. The genotype-phenotype correlation has not been well characterized in the Korean population so far. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Korean VHL patients.

Methods: Thirteen unrelated subjects with VHL mutations were included. Direct sequencing and multiplex ligation-dependent probe amplification were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated.

Results: We identified 10 different VHL mutations. The c.160_161delAT frameshift mutation was novel. Missense mutations clustered in 2 domains (α domain in exon 1; β domain in exon 3). The most frequently observed mutation was c.208G > A (p.Glu70Lys). Milder phenotypes were observed in subjects with de novo mutations. Age-specific risk for CNS hemangioblastoma was significantly higher in subjects carrying missense mutations within the HIF-α binding site (P < 0.05).

Conclusions: This study provides insight into the genotype-phenotype correlation in that amino acid substitutions in the HIF-α binding site may predispose patients to age-related risks of CNS hemangioblastoma.

Keywords: Genotype-phenotype correlation; Hypoxia-inducible factor 1; von Hippel-Lindau Tumor suppressor protein; von Hippel-Lindau disease.

Figures

Fig. 1
Fig. 1
Pedigrees of VHL families (family 1, 3, 5, 9, 11, 12 and 13). Black symbols represent the affected subjects. Probands are marked with arrows. A further family history assessment of family 4 was not available
Fig. 2
Fig. 2
Distribution of germline mutations in VHL patients. Three exons are shown by boxes and α/β domains are indicated by colored boxes. The horizontal bars indicate binding domains. A splice site mutation, c.464-1G > T is not shown in this figure
Fig. 3
Fig. 3
Phenotypic traits of Korean VHL patients. a Number of VHL-related tumors in 2 groups of VHL patients (de novo mutation vs. familial mutation). The patients are represented on the x-axis. bd Age-related penetrance of CHB in VHL mutations. b HIF-α binding site vs. elongin C binding site. c Missense mutations vs. other mutations. d Missense mutations within the HIF-α binding site vs. other mutations

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