MOLECULAR ANALYSIS OF 53 FRAGILE-X FAMILIES WITH THE PROBE-STB12.3

Fifty-three pedigrees with the fragile X syndrome have been studied fo r amplification of the CGG repeat sequence adjacent to the CpG island in the FMR1 gene. Probe StB12.3 allowed direct detection of affected m ales, carrier females, normal transmitting males, as well as prenatal diagnosis. Comparison of our molecular data with our previous linkage data from 38 families indicates the effectiveness of direct DNA analys is. A total of 325 individuals were studied and no new mutation was fo und. All daughters of males with a premutation had a premutation. When the mother had a full mutation no children had a premutation. In prem utated mothers, the size of the premutation seems to be a determining factor for the transition to the full mutation. All affected males had a full mutation or mosaicism and only 42% of the females with a full mutation were mentally impaired. Analysis of large families over 3 gen erations illustrated clearly the Sherman paradox. Furthermore, the ana lysis of these families is in reasonable agreement with the multiallel ic model of Morton and Macpherson [Proc Natl Acad Sci USA 89:4215-4217 , 1992]. Mosaic cases in the offspring of the mothers with a full muta tion suggest a maternal germinal mosaicism. Then an abnormal methylati on and a somatic heterogeneity established in very early steps of embr yogenesis could explain these cases. (C) 1994 Wiley-Liss, Inc.