Linkage analysis using multiple DNA polymorphic markers in normal families and in families with fragile X syndrome

Linkage data, using the polymorphic markers 52A (DXS51), F9, 4D-8(DXS98), and St14(DXS52), are presented from 14 fragile X pedigrees and from 7 normal pedigrees derived from the collection of the Centre d'Étude du Polymorphisme Humaine. A multipoint linkage analysis indicates that the most probable order of these four loci in normal families is DXS51-F9-DXS98-DXS52. Recombination frequencies (\(\hat \theta \)) corresponding to maximum LOD scores (\(\hat Z\)) were obtained by two-point linkage analysis for a nuber of linkage groups, including: DXS51-F9 (\(\hat Z\)=5.94, \(\hat \theta \)=0.03), F9-DXS98 (\(\hat Z\)=0.51, \(\hat \theta \)=0.26), F9-DXS52 (\(\hat Z\)=0.84, \(\hat \theta \)=0.27), and DXS98-DXS52 (\(\hat Z\)=0.32, \(\hat \theta \)=0.20). A multipoint linkage analysis of these loci, including the fragile X locus, was also performed for the fragile X population and the data support the relative order (DSX51, F9, DXS98)-FRAXA-DXS52. Recombination frequencies and maximum LOD scores, which again were derived from two-point linkage analyses, were obtained for the linkage groups DXS51-F9 (\(\hat Z\)=9.96, \(\hat \theta \)=0) and F9-DXS52 (\(\hat Z\)=0.07, \(\hat \theta \)=0.45), as well as for the groups DXS51-FRAXA (\(\hat Z\)=2.42, \(\hat \theta \)=0.15), F9-FRAXA (\(\hat Z\)=1.30, \(\hat \theta \)=0.18), DXS98-FRAXA (\(\hat Z\)=0.05 \(\hat \theta \)=0.36), and DXS52-FRAXA (\(\hat Z\)=2.42 \(\hat \theta \)=0.15). The linkage data was further tested for the presence of genetic heterogeneity both within and between the fragile X and normal families for the intervals DXS51-F9, F9-DXS52, F9-FRAXA, and DXS52-FRAXA using a modification of the A test. Except for the interval F9-FRAXA (P<0.10) there was no evidence of genetic heterogeneity for each of the various linkage groups examined. The heterogeneity detected for the interval F9-FRAXA, however, was most likely due to one family (Fx-28) that displayed very tight linkage between these two loci.