Familial hypercholesterolemia in Utah kindred with novel R103W mutations in exon 4 of the LDL receptor gene

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causi ng twice normal low-density lipoprotein cholesterol levels early in childho od and very early coronary disease in both men and women. Previously publis hed blood cholesterol criteria greatly under-diagnosed new cases of FH amon g members of known families with FH and over-diagnosed FH among participant s of general population screening. Thus, there is a need for accurate and g enetically validated criteria for the early diagnosis of heterozygous FH. I n the course of investigations of coronary artery disease in Utah, we ident ified a family whose proband showed elevated plasma levels of LDL cholester ol. To carry out molecular genetic diagnosis of the disease, we screened DN A samples for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein (LDL) receptor gene. Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 36 9, causing substitution of Tryptophan for Arginine at codon 103 in exon 4 o f the LDL receptor gene. The SSCP method was used to examine seven members of the family recruited for the diagnosis. This method helped to unequivoca lly diagnose only the proband as heterozygous for this particular LDL recep tor mutation while excluding the remaining six individuals from carrier sta tus with FH.