The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats duringtransmission were studied in 139 families in which a full mutation,premutation or intermediate allele at either FRAXA or FRAXE wassegregating. The transmission of alleles at FRAXA, FRAXE and fourmicrosatellite loci were recorded for all individuals. Instability withinthe minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats forFRAXE) was extremely rare; only one example was observed, an increased insize at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles inthe intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) wereunstably transmitted. Instability was more frequent for FRAXA intermediatealleles that had a tract of pure CGG greater than 37 although instabilityonly occurred in two of 13 such transmissions: the changes observed werelimited to only one or two repeats. Premutation FRAXA alleles over 100repeats expanded to a full mutation during female transmission in 100% ofcases, in agreement with other published series. There was no clearcorrelation between haplotype and probability of expansion of FRAXApremutations. Instability at FRAXA or FRAXE was more often observed inconjunction with a second instability at an independent locus suggestinggenomic instability as a possible mechanism by which at least some FRAXAand FRAXE mutations arise.