RESUMEN
BACKGROUND: Familial hypercholesterolemia(FH) is an autosomal dominant metabolic disorder caused by the mutation in low density lipoprotein receptor(LDLR) gene. However, direct genetic diagnosis of LDLR gene mutation is not easily available because more than 300 mutations have been described in LDLR gene of FH patients. Therefore indirect genetic diagnosis using the genetic markers can be used to follow the inheritance of defective gene in FH families. The purpose of this study was to evaluate the usefulness of indirect genetic markers for detecting identical-by-descent LDLR gene abnormalities in FH families. METHODS: We examined the allele frequency, heterozygosity, polymorphism information content(PIC) of each genetic markers(D19S394, Taq I, Hinc II, Ava II, ATn, D19S221) in 94 unrelated healthy subjects. The genetic polymorphic haplotypes in 3 FH families were also determined. RESULTS: The heterozygosity and PIC values of RFLP's(Taq I, Hinc II, Ava II) were 0.51/0.344, 0.25/0.223, 0.28/0.233 and microsatellite markers(D19S394, ATn, D19S221) were 0.64/0.558, 0.56/0.455, 0.60/0.475. Hinc II and Ava II were significantly linked(|D|=0.72, p< 0.05). The cumulative PIC values of Taq I+Hinc II, Taq I+Hinc II+ATn, D19S394+ATn were 0.520, 0.814, 0.813, respectively. When applied in the FH pedigree, the genetic diagnosis using only one marker was not available in most cases. However, combination of two or more genetic markers could successfully discriminate the affected and unaffected members in FH families. Among the several combinations of the genetic markers, the combination of D19S394 and ATn was supposed to be the most effective and informative. Because one case of recombination was suspected in D19S221 allele, it was thought to be carefully used for genetic diagnosis of FH. CONCLUSION: We concluded that indirect genetic diagnosis using intragenic or extragenic genetic markers was useful for detecting identical-by-descent LDLR gene abnormalities in FH families and the most effective and informative combination of genetic marker seemed to be D19S394 and ATn.