Fra(X) frequency on the active X-chromosome and phenotype in heterozygous carriers of the fra(X) form of mental retardation

Abstract

Female heterozygotes of the fra(X) form of mental retardation show variable degrees of mental impairment and phenotype expression of the disorder. This might be an effect of inactivation of the X-chromosome which carries the fra(X)(q). Prior replication studies in heterozygous carriers gave contradictory results with respect to possible genotype-phenotype correlation. In the interpretation of these studies it is important to understand the effect of BrdU on the fra(X)(q) expression. In a group of 13 hemizygous patients with fra(X)(q) and 7 heterozygous carriers we studied the effect of BrdU on fra(X) expression. In the heterozygous carriers the use of BrdU resulted in a significant suppression of the fra(X)(q), while in hemizygous patients no difference in fra(X)(q) frequency with or without BrdU could be observed. It can be concluded that BrdU suppresses the fra(X)(q) preferentially on the inactive X-chromosome. Thus the fra(X)(q) frequency on the active X-chromosome is of primary importance in phenotype correlation studies among heterozygous carriers. In our group of heterozygous carriers we observed a negative correlation between (IQ) phenotype and fra(X)(q) expression on the active X-chromosome. This suggests that the gene for the fra(X)(q) form of mental retardation is on the X-chromosome and undergoes inactivation.