Coronary Artery Disease, Autosomal Dominant 2

A number sign (#) is used with this entry because of evidence that one form of autosomal dominant coronary artery disease with myocardial infarction and metabolic risk factors is caused by mutations in the LRP6 gene (603507).

For general background information on autosomal dominant coronary artery disease, see entry 608320.

Clinical Features

From a screen of patients and families with coronary artery disease (CAD), Mani et al. (2007) identified an extreme outlier kindred with extraordinary prevalence of early CAD. The kindred, of Iranian ancestry, was ascertained by the proband who presented with myocardial infarction (MI) at the age of 48. His CAD risk factors included hypertension, hyperlipidemia, and diabetes mellitus. He had never smoked, and his body mass index (BMI) was 24. He had critical stenosis of all 3 major coronary arteries, which led to coronary artery bypass grafting. He had progressive atherosclerosis of the grafts and internal carotid arteries. At age 62 he suffered a low impact hip fracture and was found to have severe osteoporosis of unknown cause. He died of a stroke at the age of 72. Among 58 blood relatives of the index case, 28 were diagnosed with early CAD, defined as MI, angina, or sudden cardiac death at or before age 50 in men or 55 in women. Of these, 23 had died from CAD, with a mean age at death of 52 years. In contrast, kindred members without early CAD died at a mean age of 81. Detailed clinical data were obtained for all available kindred members, including 13 affected with early CAD, 5 free of early CAD at or beyond the age threshold, and 9 younger asymptomatic members with a mean age of 35. Cardiac risk factors before or at presentation among affected subjects were surprisingly homogeneous, including high fasting LDL cholesterol in all (mean 176.4 mg/dl, normal less than 130 mg/dl), high fasting triglycerides in 90% (mean 240 mg/dl, normal less than 150 mg/dl), marked hypertension in all (mean 175/103 mm Hg, normal less than 140/90; typically diagnosed after age 40), and type 2 diabetes mellitus (see 125853) in 77% (fasting blood sugar greater than 126 mg/dl; typically diagnosed after hypertension and hyperlipidemia). Despite high triglycerides, HDL levels were normal in all, and only 1 had a history of smoking.

Mapping

Of the 58 members of the large family segregating autosomal dominant CAD described by Mani et al. (2007), 19 were available for genetic studies. Under a stringent model of the trait locus, the maximum multipoint lod score was 4.4 for linkage of CAD within a 2.7-cM interval flanked by SNPs rs2213177 and rs747726. Within the interval were 6 annotated genes, of which LRP6 (603507) was subjected to further analysis.

Molecular Genetics

Mani et al. (2007) found that the index case in the large Iranian family with autosomal dominant CAD studied by them carried an arginine-to-cysteine substitution at codon 611 of the LRP6 gene (R611C; 603507.0001), which lies in the epidermal growth factor-like domain and is conserved among LRP6 orthologs ranging from Xenopus to human. An arginine at this position was also found in mammalian LRP5 (603506), LRP2 (600073), and LRP3 (603159). This mutation precisely cosegregated with early CAD in the kindred and was absent in 400 unrelated Iranian and 3,600 U.S. Caucasian control chromosomes. All 5 mutation carriers studied had low bone density, each with values expected in less than 12.5% of the population (P less than 0.001).

Singh et al. (2013) screened 200 white Americans with early-onset familial CAD and metabolic syndrome and 2,000 healthy northern European controls for nonconservative mutations in the LRP6 gene, and identified 3 missense mutations (603507.0002-603507.0004) that cosegregated with the metabolic traits in the kindreds of the affected individuals. No mutations were identified in the controls. The index cases had extreme phenotypes of angiographically documented early-onset CAD, at less than 55 years of age in males and less than 60 years of age in females, with at least 3 risk factors for metabolic syndrome and a strong family history of CAD and metabolic traits.