Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred.

Monogenically inherited hypercholesterolemia is most commonly caused by mutations at the low density lipoprotein receptor (LDLR) locus causing familial hypercholesterolemia (FH) or at the apolipoprotein B (APOB) locus causing the disorder familial defective apoB (FDB). Probands from 47 kindreds with a strict clinical diagnosis of FH were selected from the Cardiovascular Genetics Research Lipid Clinic, Utah, for molecular genetic analysis. Using a combination of single-strand conformation polymorphism (SSCP) and direct sequencing, 12 different LDLR gene mutations were found in 16 of the probands. Three of the probands were carriers of the APOB R3500Q mutation. In five of the remaining 28 pedigrees where no mutation had been detected, samples from enough relatives were available to examine co-segregation with the LDLR region using the microsatellite marker D19S221, which is within 1 Mb centromeric of the LDLR locus, and D19S394, sited within 150 kb telomeric of the LDLR locus. In four of the families there was strong evidence for co-segregation between the LDLR locus and the phenotype of hypercholesterolemia, but in one large family with 18 living affected members and clear-cut bimodal hypercholesterolemia, there were numerous exclusions of co-segregation. Using length polymorphic markers within and outside the APOB gene, linkage of phenotype in this family to the APOB region was similarly excluded. In this large family, the degree of hypercholesterolemia, prevalence of tendon xanthomata, and occurrence of early coronary disease were indistinguishable from the other families studied. In summary, the data provide unequivocal evidence that a third locus can be etiological for monogenic familial hypercholesterolemia and should be reinvigorating to research in this field.