Effect of X inactivation on fragile X frequency and mental retardation

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Abstract
The probability of a heterozygote being affected was estimated from the distribution of frequencies of early‐replicating fragile X [fra(X)] chromosome in normal and mentally retarded heterozygotes, taking into account the prior probabilities of 0.35 for mental retardation and 0.65 for normality. The estimated probability of a heterozygote with 100% early‐replicating fra(X) being mentally retarded was 78%, which coincides with the value of penetrance in males. Therefore, the manifestation of retardation in females seems to differ from that in males due solely to X inactivation. The frequencies of early‐replicating fra(X) were significantly increased among the heterozygotes with the highest frequencies of fra(X) both in the normal group and in the mentally retarded. The mean frequencies of early‐replicating fra(X) were 0.42 and 0.68 for normal and mentally retarded heterozygotes, respectively. Considering the overall frequency of retarded heterozygotes as 0.35, the mean frequency of early‐replicating fra(X) obtained for all heterozygotes was 0.51, which is in accordance with the hypothesis of random X inactivation. Thus the fragile site appears to have equal chances of being detected when located either on the early‐ or on the late‐replicating X. This leads to the conclusion that the frequency of the fragile site is a consequence of the proportion of cells with the active Martin‐Bell syndrome (MBS) gene and not the result of a better visualization of the site on the early‐replicating X.