Frequency of Von Hippel‐Lindau germline mutations in classic and non‐classic Von Hippel‐Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation‐dependent probe amplification

Hes, Frederik J.; Luijt, Rob B. van der; Janssen, Ann; Zewald, R. A.; Jong, G. J. de; Lenders, Jacques W.M.; Links, Thera P.; Luyten, Gré P.M.; Sijmons, Rolf H.; Eussen, H. J.; Halley, Dicky; Lips, C. J. M.; Pearson, P. L.; Ouweland, Ans M.W. van den; Majoor‐Krakauer, Danielle

doi:10.1111/j.1399-0004.2007.00827.x

Cited by 63 publications

(71 citation statements)

References 19 publications

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“…Thus, it is recommended that ''mutationnegative'' patients also be routinely screened with quantitative PCR analysis, for example, multiplex ligation-dependent probe amplification (MLPA). Hes et al [2007] were the first to apply this method for VHL mutation screening, combining it with Southern blot and sequencing to achieve 95% mutation detection. Interestingly, Cho et al [2009] detected 100% of 15 VHL patients screened with sequencing and MLPA for detecting large deletions; the latter was described as more sensitive and easier than FISH and quantitative Southern analysis.…”

Section: Diagnosismentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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Section: Diagnosismentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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“…7 vHL is normally diagnosed on a genetic basis, frequently presymptomatic in familial cases. However, diagnosis of isolated vHL cases is often delayed compared with familial cases, 8 and may never be recognized, as a clinical diagnosis requires at least two manifestations, often involving multiple medical specialists. 4 A timely diagnosis is essential to establish surveillance and offer genetic counselling to at-risk family members.…”

Section: Introductionmentioning

confidence: 99%

Prevalence, birth incidence, and penetrance of von Hippel–Lindau disease (vHL) in Denmark

et al. 2016

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Von Hippel-Lindau disease (vHL) is a rare hereditary tumour predisposition with multiorgan involvement that is not always easily recognized. The disease is reported to be almost fully penetrant at age 60 years. Previous estimates of vHL prevalence and incidence are all regional and vary widely. Most are 420 years old and prone to selection bias because of inclusion of only clinically affected vHL patients who were diagnosed before genetic testing was available. In an unselected cohort of all known Danish carriers of a disease-causing VHL variant, we assessed vHL penetrance on a national basis. We further used national health registers to identify individuals who fulfilled the clinical diagnostic vHL criteria based on their registered diagnostic codes, but had not been diagnosed with vHL. We also assessed the medical histories of first-degree relatives to identify familial cases. This study gives the first national estimates of vHL prevalence (1 in 46 900 individuals) and birth incidence (1 in 27 300 live births). vHL has been underdiagnosed in Denmark, and as many as 25% of the overall vHL cohort (diagnosed+undiagnosed patients) have a missed diagnosis in spite of fulfilling the international diagnostic criteria. We found an overall penetrance of 87% at age 60 years. When considering only vHL patients who have not attended surveillance, 20% will still be asymptomatic at age 60 years. This should be considered in the context of genetic counselling, especially when assessing the risk of vHL in asymptomatic adult first-degree relatives who are often not genetically tested.

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“…In many hereditary diseases, the implementation of MLPA in molecular diagnostics has led to the detection of new disease causing mutations. 4,5 In the Database of Genomic Variants 6 a copy number variant (CNV), which includes the MEFV gene has been reported. Thus far, it is unknown if large rearrangements within in the MEFV gene are associated with FMF.…”

Section: Introductionmentioning

confidence: 99%

Search for copy number alterations in the MEFV gene using multiplex ligation probe amplification, experience from three diagnostic centres

et al. 2008

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Familial mediterranean fever (FMF) is a hereditary autoinflammatory autosomal recessive disease caused by mutations in the MEFV gene. Despite the identification of many disease associated MEFV mutations, often the clinical diagnosis cannot be genetically confirmed. The currently used diagnostic sequencing techniques only allow the detection of point mutations, small deletions or duplications. The question as to whether larger genetic alterations are also involved in the pathophysiology of FMF remains to be answered. To address this question, we used multiplex ligation-dependent probe amplification (MLPA) on a total of 216 patients with FMF symptoms. This careful analysis revealed that not a single deletion/ duplication could be detected in this large cohort of patients. This result suggests that single or multiexon MEFV gene copy number changes do not contribute substantially, if at all, to the MEFV mutation spectrum.

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Frequency of Von Hippel‐Lindau germline mutations in classic and non‐classic Von Hippel‐Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation‐dependent probe amplification

Cited by 63 publications

References 19 publications

Genetic analysis of von Hippel-Lindau disease

Genetic analysis of von Hippel-Lindau disease

Prevalence, birth incidence, and penetrance of von Hippel–Lindau disease (vHL) in Denmark

Search for copy number alterations in the MEFV gene using multiplex ligation probe amplification, experience from three diagnostic centres

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