THE USEFULNESS OF 3 BIALLELIC RESTRICTION-FRAGMENT-LENGTH-POLYMORPHISMS VERSUS A POLYMORPHIC DINUCLEOTIDE TANDEM REPEAT POLYMORPHISM AT THELOW-DENSITY-LIPOPROTEIN RECEPTOR GENE LOCUS FOR DIAGNOSIS OF FAMILIALHYPERCHOLESTEROLEMIA

Indirect molecular diagnosis of familial hypercholesterolemia is possi ble based on genetic linkage analysis of DNA polymorphisms at the low- density-lipoprotein receptor gene locus in family studies. The use of biallelic restriction fragment length polymorphisms, however, is restr icted by their low degree of heterogeneity, and therefore several of t hese markers have to be combined, To overcome these restrictions we ex amined the value and applicability of an (AT)(n) tandem repeat polymor phism at the 3' untranslated region of the gene, alone and in combinat ion with three biallelic restriction fragment length polymorphisms in 35 independent healthy subjects and in familial hypercholesterolemia f amilies with 23 parents and 52 children. For each family one of the pa rents had the clinical diagnosis of familial hypercholesterolemia. The probands were genotyped using the TaqI, HincII and NcoI restriction f ragment length polymorphism and the (AT)(n) tandem repeat polymorphism of the gene. The heterozygosity index (0.60) and the polymorphism inf ormation content (PIG value) (0.53) of the AT(n) repeat polymorphism w ere higher compared to each single biallelic restriction fragment leng th polymorphism (heterozygosity index 0.26-0.54; PIC value 0.24-0.36). The combined PIC value of all three biallelic restriction fragment le ngth polymorphisms (0.79) was comparable to the combination of the Hin cII and the AT(n) polymorphism (0.74). Using these two markers, a defi nitive molecular diagnosis could be made in 36 children from 15 parent s compared to just 12 parents and their children using the three biall eleic restriction fragment length polymorphisms. We conclude that the AT(n) tandem repeat polymorphisms is useful for indirect molecular dia gnosis of familial hypercholesterolemia in affected families.