REVERSE MUTATIONS IN THE FRAGILE-X SYNDROME

Three females were identified who have apparent reversal of fragile X premutations. Based on haplotype analysis of nearby markers, they were found to have inherited a fragile X chromosome from their premutation carrier mothers, and yet had normal size FMR1 repeat alleles. The cha nges in repeat sizes from mother to daughter was 95 to 35 in the first , 145 to 43 in the second, and 82 to 33 in the third. In the first fam ily, mutations of the nearby microsatellites FRAXAC2 and DXS548 were a lso observed. In the other two, only mutations involving the FMR1 repe ats were found. We suggest differing mutational mechanisms such as gen e conversion versus DNA replication slippage may underlie such reversi ons. We estimate that such revertants may occur among 1% or less of pr emutation carrier offspring. Our results indicate that women identifie d to be carriers by linkage should be retested by direct DNA analysis. (C) 1996 Wiley-Liss, Inc.