Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene

Human Molecular Genetics
F M RichardsE R Maher

Abstract

VHL disease is a dominantly inherited familial cancer syndrome with variable expression and age-dependent penetrance. The diagnosis of isolated cases is often delayed compared with familial cases, and estimates of the new mutation rate have varied more than 20-fold. To investigate the frequency and origin of de novo VHL gene mutations we have analysed: (i) families with identical mutations to determine if there is a common haplotype, and (ii) apparent new mutation cases to determine whether the clinical diagnosis of such cases is reliable and to define the parental origin of de novo VHL gene mutations. Haplotyping of 12 VHL mutations occurring in two or more families (total 42 kindreds) revealed that for most mutations there was no evidence of a founder effect. A marked bias for a paternal origin of new mutations has been reported in other familial cancer syndromes such as neurofibromatosis type 1 (NF1), multiple endocrine neoplasia (MEN) 2B and bilateral retinoblastoma, but it is unclear whether this bias results from a greater susceptibility for mutagenesis during male gametogenesis because of the larger number of cell divisions compared with that in oogenesis, or from genomic imprinting effects. Analysis of 13 de novo VHL mu...Continue Reading

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