FRAGILE-X GRAY ZONE ALLELES - AGG PATTERNS, EXPANSION RISKS, AND ASSOCIATED HAPLOTYPES

The risk for fragile X ''gray-zone'' alleles to expand appears to depe nd on the absence of stabilizing AGGs, which interrupt the CGG repeat region. To characterize such alleles better, we analyzed a series of 1 01 chromosomes with triplet repeat lengths ranging from 35 to 59 for v ariations 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 relations hip between FMR1 repeat length and the number of interrupting AGGs was observed. Within the range of 35-44 repeats, 98.7% of alleles were fo und to have a pure CGG repeat length (P-CGG) of less than 33. However, among alleles with 45-59 repeats, 50% were found to have 0 or 1 AGG a nd a P-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 len gth associations of P-CGG With 2 flanking microsatellites, DXS548 and FRAXAC1: a P-CGG 120 was strongly associated with haplotype 20-19, whe reas a P-CGG > 20 was more strongly associated with the haplotype 25-2 1. This result could reflect a founder effect or a generalized instabi lity of CGGs and microsatellites. (C) 1996 Wiley-Liss, Inc.