Prenatal Diagnosis of Fragile X Syndrome by Direct Detection of the Unstable DNA Sequence

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Abstract
FRAGILE X syndrome is the most common form of familial mental retardation.1 Its prenatal diagnosis has relied on cytogenetic detection of the fragile X chromosome in cultured amniotic fluid, chorionic-villus cells, or fetal blood obtained by cordocentesis. The rate of misdiagnosis is about 5 percent and is due to rare false positive and more frequent false negative diagnoses.2 A molecular-genetic approach using DNA polymorphisms linked to the fragile site is feasible for diagnosis, but the results are probabilistic rather than absolutely diagnostic.3 , 4 The fragile X syndrome has recently been shown to be characterized by an unstable DNA sequence that can be detected by Southern blot analysis.5 , 6 We report the use of this approach to establish the carrier status of a cytogenetically normal woman in a family with the fragile X syndrome and to diagnose the mutation in her male fetus by detecting the unstable sequence in DNA obtained by chorionic-villus sampling.