IDENTIFICATION OF A COMMON LOW-DENSITY-LIPOPROTEIN RECEPTOR MUTATION (R329X) IN THE SOUTH OF ENGLAND - COMPLETE LINKAGE DISEQUILIBRIUM WITHAN ALLELE OF MICROSATELLITE D19S394

Familial hypercholesterolaemia is commonly caused by mutations in the low density lipoprotein receptor (LDLR) gene and more than 300 differe nt mutations have been described worldwide. Some mutations occur at re latively higher frequency in certain populations, reflecting both chan ce and demography, most evident in founder populations. As part of a s tudy of kindreds of 78 probands from Southampton and south west Hampsh ire, we identified the same mutation (R329X) in 9/78 (11.5%) probands. In all (100%) of these probands, length allele 259nt of the 17 allele microsatellite D19S394, sited approximately 250 kilobases telomeric a nd 5' to the LDLR gene, was observed, although in the general populati on this allele has a prevalence of only 16.1%. A simple diagnostic ass ay for R329X was constructed in conjunction with more detailed family studies. Both the R329X and linked D19S394 allele also cosegregated wi th the FH phenotype within each kindred. Although R329X involves a CpG site, it is highly likely that the families are identical by descent for R329X, we surmise with a common ancestor within 500 to 1000 years, although the mutation is not restricted to this geographical area. Th is relationship illustrates that the linkage disequilibrium of gene LD LR with marker D19S394 will enable rapid recognition using D19S394 gen otype of possible common FH mutation(s) within a cohort of FH patients from a particular locality or ethnic group.