Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel–Lindau (VHL) disease

Hwang, Seong‐Ju; Ku, Cheol Ryong; Lee, Ji I.n.; Hur, Kyu Yeon; Lee, Myung-Shik; Lee, Chul‐Ho; Koo, Kyo Yeon; Lee, Jin Sung; Rhee, Yumie

doi:10.1038/jhg.2014.61

Cited by 14 publications

(22 citation statements)

References 31 publications

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“…The high incidence of Glu70Lys mutation observed in this study (frequency of 23.1 %) and its limited range of manifestations (either CHB or RHB) corresponds well with the findings of Hwang et al [ 20 ]. While previous VHL studies described codons 167, 76, 98, 65, and 78 as frequently mutated regions, there are only a few reports of Glu70Lys mutation in different ethnic groups [ 21 , 22 ].…”

Section: Discussionsupporting

confidence: 92%

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Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma

Lee

et al. 2016

BMC Med Genet

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Backgroundvon 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.MethodsThirteen 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.ResultsWe 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).ConclusionsThis 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.

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Section: Discussionsupporting

confidence: 92%

“…Mettu et al [ 21 ] reported that among the 412 VHL patients studied, only one patient (frequency of 0.24 %) carried the Glu70Lys mutation. Since this mutation is highly frequent in Korean populations [ 20 ], codon 70 seems to be the hot spot region in the ethnic specific mutational spectrum.…”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma

Lee

et al. 2016

BMC Med Genet

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“…Fifteen articles from nine different countries (Chacon‐Camacho et al, ; Chen et al, ; Gergics et al, ; Gomy et al, ; Huang et al, ; Hwang et al, ; Leonardi, Martella, Tosatto, & Murgia, ; Levine, Collins, Horton, & Schimke, ; Prasad et al, ; Rasmussen et al, ; Ruiz‐Llorente et al, ; Vikkath et al, ; Wang et al, ; Wu et al, ; Zhang et al, ) reported a vHL cohort with at least one child/adolescent and a total of more than five patients (Table ). In total, 62 patients were identified with a vHL diagnosis before 18 years, and information about their ages, genotypes, and phenotypes were extracted from the articles when available.…”

Section: Resultsmentioning

confidence: 99%

von Hippel‐Lindau development in children and adolescents

Launbjerg

Bache

Galanakis

et al. 2017

American J of Med Genetics Pt A

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The autosomal dominant von Hippel-Lindau disease (vHL) is associated with a lifelong risk of tumor development, especially retinal and CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma. Knowledge of paediatric vHL development is limited, and current surveillance guidelines are based on expert opinions. We aimed to describe the course of vHL development in children and adolescents, focusing on age at first manifestation, manifestation frequencies, and types. The prevalence of vHL diagnosis as well as manifestations in childhood were evaluated based on 99 patients, who had started surveillance before 18 years: 37 Danish patients from the national vHL research database and 62 international patients reported in 15 articles. Overall, 70% (69 of 99) developed manifestations before 18 years (median age at first manifestation: 12 years (range: 6-17 years)). Thirty per cent (30 of 99) had developed more than one manifestation type; the most frequent were retinal (34%) and CNS (30%) hemangioblastomas. Among the 37 Danish patients, 85% (97 of 116) of their tumors were asymptomatic. Vision outcome is significantly improved in hemangioblastomas that are treated while still asymptomatic. We agree with current guidelines that retinal surveillance be performed from birth. The patients had their first CNS hemangioblastomas at the median ages of 13-14 years (range: 6-17 years). Further, 11% (4 of 37) of the Danish patients had CNS surgery in their teenage years. Although the cohort is too small to make definite conclusions about specific initiation ages, regular CNS surveillance from vHL patients' teenage years seems clinically relevant.

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“…However, the common mutations are varied across different ethnic groups. Hwang et al (2014) reported that Glu70Lys was a high-frequency VHL germline mutation in the Korean population, with nine unrelated patients [16.4% (9/55)] who had the same amino-acid alteration at codon 70 (Glu70Lys) and exhibited VHL type 1 phenotypes. However, in our cohort, the high-frequency mutations included Ser65 (4.81%), Arg161 (5.35%), and Arg167 (12.84%).…”

Section: Discussionmentioning

confidence: 99%

Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel–Lindau Disease

Hong

Zhou

et al. 2019

Front. Genet.

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Von Hippel–Lindau (VHL) disease is a rare autosomal-dominant inherited tumor syndrome. We aimed to analyze the correlations between frequent VHL mutations and phenotypes in Chinese VHL families. We screened 540 patients from 187 unrelated Chinese VHL families for 19 frequent VHL mutations. The penetrance and mean age at onset for VHL-associated susceptible organs were calculated and compared. The overall survival of VHL patients was described with Kaplan–Meier curves. Among the 19 frequent germline mutations, there were four hotspot mutation sites (194, 481, 499, and 500). Missense mutations were the most common types of mutations (70.0%) followed by nonsense mutations (20.0%) and splicing mutations (10.0%). Due to the diversity of these mutations, the penetrance for each organ and the age at onset are distinct. Even in cases of similar mutations, variance in the penetrance and age at onset was observed. The mean age at death for the patients in this cohort was 42.4 ± 13.5 years, and variability was observed in the Kaplan–Meier curves. We present a precise summary of the phenotypes for the frequent VHL mutations in the largest Chinese VHL cohort, which provides valuable strategies for genetic counseling and clinical surveillance of VHL individuals.

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Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel–Lindau (VHL) disease

Cited by 14 publications

References 31 publications

Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma

Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma

von Hippel‐Lindau development in children and adolescents

Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel–Lindau Disease

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