The Fragile X [fra(X)] syndrome is a type of non-specific X-linked mental retardation (MR) which is characterized by a unique cytogenetic marker, a fragile site located on the long arm of the X chromosome. Approximately 1 in 1500 males and 1 in 2000 females are mentally retarded because of the fra(X), making this the most common inherited form of MR in man. The inheritance of the fra(X) syndrome is different from all known X-linked disorders and, as yet, no genetic model fully explains its transmission. This has practical as well as theoretical consequences since the absence of an appropriate model greatly complicates genetic counseling. Thus, delineation of the population parameters which describe the fra(X) syndrome and characterize the mutation will have far-reaching implications in the field of medical genetics. The purpose of this proposal is to determine the prevalence of the fra(X) syndrome and estimate recurrence risks in order to define the genetic model which best explains the inheritance of fra(X) syndrome and to provide accurate parameters for genetic counseling. Specifically, this five-year study proposes to collect and analyze: prospective data on pregnancy outcomes of women who carry the fra(X) mutation or have an affected son; fra(X) families obtained from screening mentally impaired school age children from a defined population; and, retrospective fra(X) family data collected in our and other laboratories. We propose to: 1) Estimate recurrence risks based on the phenotype of the carrier parent, family history and grandparental origin of the fra(X) mutation. 2) Estimate parameters that are necessary to calculate model-dependent mutation rates for the fra(X) syndrome. 3) Use the empirical estimates to test current models. 4) Provide a meaningful set of empirical recurrence risks for the fra(X) syndrome for use in genetic counseling.
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