DNA linkage studies in the fragile X syndrome suggest genetic heterogeneity

Previsouly we showed genetic heterogeneity for linkage between the fra(X) locus and a factor IX DNA RFLP (Brown et al, 1985). When fra(X) families were predivided into two classes, one containing those with non‐penetrant (NP) males and one with apparent full penetrance (P), evidence of significant heterogeneity was present. We have now extended this analysis by adding DNA linkage information on 2 additional probes, 52A and ST14, studied in 16 fra(X) kindreds. These data were combined with information on 16 published fra(X) families. There were 7 NP families and 25 P families. We confirmed our previous findings of a higher recombination fraction between factor IX and fra(X) in P families (0 = .32 with lod of .67) compared to as NP familes (0 = .06 with lod of 6.11) which was singnificant at p < .01. In comparing recombination fractions for the additional probes, more recombination between 52A and the other loci was consistently seen in P compared to NP familes which suggested that there may be a higher rate of recombination proximal to the fra(X) locus in P kindreds. A strikingly higher recombination fraction between 52A and factor IX was present in comparing all fra(X) families (.18) to normal families (.02) which was significant at p < .001. These results suggest genetic heterogeneity with respect to recombination is present both among fra(X) pedigrees and between fra(X) and normal pedigrees.