The fragile X [fra(X)] syndrome is the most common form of inherited mental retardation and one of the most prevalent of all known genetic diseases. One of the many intriguing aspects of this syndrome is the significant degree of phenotypic heterogeneity with which it is associated. The wide spectrum of cognitive and behavioral functioning is particularly impressive; however, the basis for this variability has not yet been identified. Recently, the fra(X) syndrome has been found to be the result of an increased number of CGG triplet repeats found in the 5' untranscribed region of the fra(X) mental retardation-1 gene (FMR-1). Studies of fra(X) families have shown that this region is unstable during meiosis; however, factors affecting this instability are unknown. The purpose of this project is to examine the characteristics of the FMR-1 gene in a school-aged, special needs population in order to test three specific hypotheses involving the prevalence of the fra(X) mutation, the correlation between the FMR-1 genotype and phenotype, and the mutation rates that lead to the clinically expressed syndrome. The targeted study population make this study unique. First, children with special educational needs are at higher risk for carrying the fra(X) mutation than the general population; however, they are not a clinically-referred population. Thus, we can expect adequate sample sizes on which to base genotype-phenotype analyses and also be assured that the phenotype will not be biased towards features of the fra(X) syndrome. Secondly, direct assessment of identified subjects and family members is possible since this is not an anonymous sample. The data gathered from these studies are important from a research, clinical and public health standpoint. The results from the correlation between genotype and phenotype will provide information about the normal functioning of the FMR-1 gene and may shed light on biological factors which underlie other disorders that involve cognitive and behavioral capacity. The characterization of the transmission of the FMR-1 gene in a non-clinically referred population will provide hypotheses concerning the underlying biological mechanisms of instability. As other genes are now found to contain similar repeat regions, the knowledge gained from this study will have a wide application to other disorders. Lastly, evaluation of the prevalence of fra(X) mutation carriers and the range of expression are the first steps that are needed before assessing the feasibility of mass screening for the fra(X) syndrome.
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