Prenatally detected fragile X females: long-term follow-up studies show high risk of mental impairment.

The prenatal detection of a positive fragile X [fra(X)] female raises difficult counseling issues. In order to address questions regarding the long term outlook, we have conducted follow-up studies on 4 fra(X) positive females which were carried to term. Three were prenatally detected, and one was a false negative. The subjects were between 3 and 7 years old when follow-up investigation of mental status was conducted. The first case age, 6 and 9/12 years, had an IQ of 106. On measures of achievement she had some difficulty with arithmetic. The second and third cases were clearly affected. They were judged to be mildly to moderately mentally retarded. The fourth case was borderline normal. The prenatal amniocentesis cytogenetic frequencies had a mean of 3.74% (range 0-8.5%). On postnatal follow-up testing of blood, the mean cytogenetic frequency increased to 31.75% (range 24-47%), an 8.5 fold increase. Follow-up DNA samples from 3 of the 4 subjects were analyzed for underlying DNA mutations using probe StB12.3 which detects insertions and methylation status of the FMR-1 gene. All 3 showed an affected female genotype with a large insert (greater than 500bp) and complete CpG island methylation. We conclude: (1) prenatally detected cytogenetic frequencies of females increase by an average 8.5 fold on follow-up postnatal studies, (2) genetic counseling should indicate the risks to be affected are approximately 75% when a positive female is prenatally detected, (3) DNA testing can help determine carrier status but may not accurately predict whether a female will be mentally affected.