173: Ethnic variability in FMR1 CGG repeat size distribution predicts differences in inter-ethnic fragile X syndrome incidence

Previous large studies have reported pan-ethnic fragile X syndrome (FXS) frequency of 1 in 4000-6000. There have been some indications of ethnic predilection, but this has not been well defined to date. FXS incidence is affected not only by premutation carrier frequency, but also by CGG repeat size, since the risk for next-generation expansion to full mutation corresponds to increasing size. Taking into account both of these factors, we report predicted incidence of FXS by ethnicity derived from our population based carrier screening data. Samples were considered only if no family history, known carrier status, or infertility history were reported. We also excluded samples originating from ART clinics to avoid bias from premutation-induced fragile X premature ovarian insufficiency. We report data from 134,840 individuals passing the above filters, including over 2700 in each of ten self-reported ethnicities. FMR1 5'UTR CGG repeat size was assessed by PCR and capillary electrophoresis. Predicted incidence in the offspring of our tested population was calculating by assigning a reproductive risk to each CGG repeat size, based on the frequency of that size in the tested population and the described probability of next-generation expansion to full mutation (Yrigollen 2012). These risks were then summed to determine a single reproductive risk (incidence) of FXS in each ethnic group. Table 1 details, by ethnic groups, the frequency of any premutation, the distribution of CGG repeat sizes and the predicted incidence. All of these figures demonstrated substantial ethnic variability. As an example of the impact of repeat size distribution, even though the premutation frequency was higher in N Europeans (1/315) than S Europeans (1/412), the latter’s repeat distribution more heavily favored alleles with high transmission risk: 18.2% of premutations were between 90-200 repeats, compared with 4.1%. The outcome of this phenomenon is actually a higher absolute risk for fragile X syndrome in Southern Europeans, 1/2224, compared to 1/3805. Premutation frequency and repeat length must be considered in tabulating risk for fragile X syndrome. This provides a more accurate indication of reproductive risk than reliance on simple carrier frequency.