Denaturing high-performance liquid chromatography (DHPLC)-based prenatal diagnosis for tuberous sclerosis

Tuberous sclerosis (TSC) is a frequent autosomal-dominant condition (affect ing 1 in 6000 individuals) caused by various mutations in either the hamart in (TSC1) or the tuberin gene (TSC?). This allelic and nonallelic heterogen eity makes genetic counseling and prenatal diagnosis difficult, especially as a significant proportion of TSC cases are due to de novo mutations. For this reason the identification of the disease causing mutation is mandatory for accurate counseling, yet current mutation detection methods such as si ngle-strand conformation polymorphism (SSCP) or denaturing gradient gel ele ctrophoresis (DGGE) are labor intensive with limited detection efficiency. Denaturing high-performance liquid chromatography (DHPLC) is a high-through put, semi-automated mutation detection system with a reported mutation dete ction rate close to 100% for PCR fragments of up to 800 bp. We used a recen tly described DHPLC assay allowing the efficient detection of mutations in TSC1 to analyze the DNA extracted from a chorion villus sample in order to perform a prenatal diagnosis for TSC. The fetus was found not to have inher ited the deleterious mutation and the DHPLC diagnosis was confirmed by hapl otype analysis. This represents the first DHPLC-based prenatal diagnosis of a genetic disease. Copyright (C) 2001 John Wiley & Sons, Ltd.