Fragile X CGG repeat structures among African-Americans: identification ofa novel factor responsible for repeat instability

The cryptic CGG repeat responsible for the fragile X syndrome, located in t he 5'-UTR of FMR1, is unique compared with the many other triplet repeat-ca using diseases, making it ideal for identifying factors involved in repeat expansion that may be common to other triplet repeat diseases. To date, a n umber of factors have been identified which may influence repeat instabilit y, including the number and position of interspersed AGGs, length of the 3' pure CGG repeat and haplotype background, However, nearly all such data we re derived from studies of Caucasians, Using a large African-American popul ation, we present the only comprehensive examination of factors associated with CGG repeat instability in a non-Caucasian population. Among Caucasians , susceptible alleles were thought to come from those in the intermediate r epeat range (41-60 repeats); however, we find that susceptible alleles may come from a larger repeat pool (35-60 repeats) and are better defined by th eir pure CGG repeat and/or presence of only one AGG interruption, These res ults demonstrate the existence of different susceptible alleles among world populations and may account for the similar prevalence of the fragile X sy ndrome in African-Americans compared with Caucasians despite the lower freq uency of intermediate sized alleles in the African-American population. Fin ally, we show that repeat structures among unaffected African-Americans wit h the most frequent fragile X haplotype background are either pure or conta in a single distal interruption. We propose that the lack of a proximal mos t interruption is a novel factor involved in CGG repeat instability.