The fra(X) syndrome is one of the most common causes of mental retardation, and validation of the reliability and feasibility of making the prenatal diagnosis of this disorder is important for genetic counseling and prevention. We have received a total of 74 amniotic fluid specimens for prenatal diagnosis of fra(X) from worldwide sources. Results were obtained on 68 specimens of which 43 had a documented family history of the fra(X) syndrome. Of the 43 specimens, 23 were male and 4 were prenatally diagnosed as being affected. On the basis of the results, several conclusions follow: 1.) At least 3 different tissue culture methods should be utilized. 2.) At least 150 cells should be scored, preferably 50 from each of 3 different tissue culture methods or 100 from each method if less than 3 methods are used. 3.) While the test appears to be reliable, it should still be considered to be experimental until larger numbers are obtained with completed follow-up of cases.

Amniotic Fluid↗

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Aneuploidy and the fragile X syndrome.

The possibility that female carriers of the fragile X gene(s) are at increased risk for nondisjunctional events leading to aneuploid offspring has been suggested by several investigators. To better address this question we analyzed pedigrees of 117 families in which the fragile X syndrome is segregating. The 117 pedigrees, originally collected for segregation analyses, included 236 females with offspring whose carrier status was determined by cytogenetic or pedigree analysis or by analyses using flanking DNA markers. These 236 females have had 931 offspring including one 47,XXY and 6 trisomy 21 individuals (1/155). Statistical analysis suggested that the observed rate of trisomy 21 was significantly higher than expected (Fisher's exact test, p less than or equal to 0.05). Assuming a Poisson distribution to calculate the confidence interval for the observed rate of trisomy 21 individuals, we found that the expected rate of 1.6/1000 in this sample fell outside the 99% confidence limits of our observed rate of 1/155. Additional data from a larger sample are needed to replicate these findings.

Aneuploidy↗

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Experience with multiple approaches to the prenatal diagnosis of the fragile X syndrome: amniotic fluid, chorionic villi, fetal blood and molecular methods.

We have had experience with 160 prenatal diagnosis cases for the fragile X syndrome [fra(X)] or Martin-Bell Syndrome. In 140, amniotic fluid was utilized; 98 had a documented family history of fra(X). The 94 completed cases included 4 no growth; 56 males of which 7 were fra(X)-positive and 2 false-negative; 38 females of which 5 were fra(X) positive. There was no fra(X) positive result when a family history of mental retardation was not documented as fra(X). Molecular methods (RFLPs) were utilized in 10 amniotic fluid and 5 chorionic villus specimens (CVS). Percutaneous umbilical blood sampling was used in 2 negative cases and 1 fra(X) positive case because of timing, tissue culture failure or confirmation of another method. CVS were received in 13 cases, and RFLPs were utilized in 5 of the CVS cases. There was no positive fra(X) CVS chromosome result in males, 1 positive result in a female, but 2 false negatives were detected by RFLPs. On the basis of the results, it can be concluded that cytogenetic and molecular methods are complementary and best used together and that multiple approaches can enhance the efficiency and reliability of fra(X) prenatal diagnosis.

Amniocentesis↗

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Conference report: Fourth International Workshop on the fragile X and X-linked mental retardation.

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Female↗