PRENATAL-DIAGNOSIS OF FRAGILE-X SYNDROME - (CGG)(N) EXPANSION AND METHYLATION OF CHORIONIC VILLUS SAMPLES

Fragile X syndrome is the most common form of inherited mental retarda tion, due to an expansion of the (CGG)(n) trinucleotide repeat in the FMR-1 gene and hypermethylation of its 5' upstream CpG island. Two maj or problems remain to be resolved for fragile X prenatal diagnosis: th e abnormal methylation patterns of chorionic villus samples (CVS) and the inability to predict the mental status of females with the full mu tation. We present here the results of ten prenatal diagnoses of fragi le X syndrome using Southern blotting and polymerase chain reaction (P CR) amplification, and the analysis of 50 further CVS to test the meth ylation status of the CpG island of the FMR-1 gene. In the ten 'at-ris k' CVS, eight normal (five males and three females) and two affected m ale fetuses were detected. Absence of methylation in the CVS was obser ved in two cases, which was not found upon subsequent examination of t he newborn or of fetal tissues. In the 50 CVS not 'at risk' for fragil e X syndrome, abnormal fragment patterns for probe StB12.3 were detect ed in 32 per cent for female and 24 per cent for male fetuses. This ab normal pattern could be due to absent or partial methylation of the Cp G island of the FMR-1 gene in chorionic villus tissues.