Familial hypercholesterolemia in Utah kindred with novel 2412-6 ins G mutations in exon 17 of the LDL receptor gene

Familial hypercholesterolemia (FH) is a monogenic disorder associated with primary hypercholesterolemia. FH is characterized by autosomal co-dominant inheritance with strikingly elevated LDL-cholesterol, the presence of xanth oma and premature atherosclerosis. in the course of investigations of coron ary artery disease in Utah, we identified a family whose proband showed ele vated plasma levels of LDL cholesterol. To determine the genetic etiology o f the lipoprotein abnormalities, we screened DNA samples from the family fo r mutations in all 18 exons and the exon- intron boundaries of the low-dens ity lipoprotein receptor (LDLR) gene. Novel point mutations were identified in the proband: a one-base insertion of G to a five-G stretch at nucleotid es 2412-6 (codons 783-785), causing a frameshift in exon 17 of the LDL rece ptor gene. The direct sequencing method was used to examine six members of the family recruited for the diagnosis. This method helped to unequivocally diagnose the five individuals as heterozygous for this particular LDL rece ptor mutation. This method also helped us to diagnose with FH, or to exclud e from carrier status, three children between ages 6 and 11.