Prenatal diagnosis of fragile X syndrome: identification of a male fetus mosaic for a premutation on chorionic villus sampling - management and follow-up

Abstract

Families at risk to have a child with fragile X syndrome are routinely counselled regarding the limitations of performing prenatal analysis via chorionic villus sampling (CVS) due to incomplete methylation status at this point in gestation. However, this testing option appeals to families due to the timing of the prenatal procedure. Here we report on the identification of a male fetus, by polymerase chain reaction (PCR) and Southern blot analysis, mosaic for a premutation. The mother carries a premutation allele with a (CGG)_n repeat size of 101 and was identified as a carrier after her first son was diagnosed with fragile X syndrome (630 repeats). Analysis of direct CVS in the current pregnancy identified a male fetus. Molecular analysis revealed a fetus mosaic for FMR-1 alleles with (CGG)_n repeat sizes ranging from 130-170. After counselling, the couple chose to pursue amniocentesis to confirm that the expansion in the extraembryonic tissue accurately reflected the somatic expansion size in the fetus and to assess FMR-1 methylation status. Amniocentesis revealed a male with an unmethylated premutation and a (CGG)n repeat size of 170 repeats. Based on these findings we predict that the fetus is unlikely to be affected with fragile X syndrome. At birth, cord blood will be analyzed to confirm the above findings. The majority of published recommendations regarding the identification of a male carrier of fragile X syndrome on CVS suggest confirmation of this result through amniocentesis or cordocentesis. Additional cases describing the accurate diagnosis of male carriers of fragile X syndrome by CVS need to be reported to facilitate the development of evidence-based protocols regarding the management of these cases. This could potentially alleviate the need for a second invasive prenatal procedure.