Fragile X “gray zone” alleles: AGG patterns, expansion risks, and associated haplotypes

Abstract

The risk for fragile X {open_quotes}gray-zone{close_quotes} alleles to expand appears to depend on the absence of stabilizing AGGs, which interrupt the CGG repeat region. To characterize such alleles better, we analyzed a series of 101 chromosomes with triplet repeat lengths ranging from 35 to 59 for variations in their AGG interspersion patterns. Among these, 11.9% had 3 AGGs, 59.3%, had 2, 24.8% had 1, and 4.0% had 0. An inverse relationship between FMR1 repeat length and the number of interrupting AGGs was observed. Within the range of 35-44 repeats, 98.7% of alleles were found to have a pure CGG repeat length (P{sub CGG}) of less than 33. However, among alleles with 45-59 repeats, 50% were found to have 0 or 1 AGG and a P{sub CGG} of more than 33. Thus, gray-zone alleles with 45-59 repeats frequently have a long stretch of pure CGGs and thus are more likely to be unstably inherited than alleles with 35-44 repeats. We found length associations of P{sub GCC} with 2 flanking microsatellites, DXS548 and FRAXAC 1: a P{sub CGG} 20 was more strongly associated with the haplotype 25-21. This resultmore » could reflect a founder effect or a generalized instability of CGGs and microsatellites. 28 refs., 2 figs., 4 tabs.« less