Background —Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease of unknown etiology that causes arrhythmias, heart failure, and sudden death. Diagnosis can be difficult, and this hampers investigation of its molecular basis. Forms of ARVC in which gene penetrance and disease expression are greater should facilitate genetic study. We undertook a clinical and genetic investigation of Naxos disease, originally described by Protonotarios in 1986. This disease constitutes the triad of ARVC, diffuse nonepidermolytic palmoplantar keratoderma, and woolly hair. Methods and Results —We evaluated the population of Naxos, Greece, to identify probands, which was followed by family screening. Twenty-one affected persons from 9 families of 150 persons were identified. Linkage analysis was performed with microsatellite markers. The disease locus mapped to 17q21. A peak 2-point LOD score of 3.62 at θ=0.0 was found with a marker within intron 4 of the keratin 9 gene, a member of the type I (acidic) keratin family. A preserved homozygous disease haplotype was identified. Haplotype analysis delimited the disease interval. Conclusions —Hair and skin abnormalities were found to be reliable markers of subsequent heart disease. This suggests the presence of a single mutant gene with novel cardiac, skin, and hair function or two or more tightly linked disease genes. Recessive inheritance of Naxos disease and a founder effect were demonstrated. Identification of a fully informative genetic marker linked to the disease and uncommon in the background population may be of use as a test to identify disease gene carriers.

Coronary artery disease (CAD) patients (n=235), comprising minimal (CAD", n=124) and severe (CAD + , n = l l l ) CAD, were recruited on the basis of their angiographic scores. Male control subjects (n=123) were selected randomly from the Caerphilly Heart Study cohort. Subjects were genotyped for the Ser*"-Ter mutation and HindlUJPvu II restriction fragment length polymorphisms of the lipoprotein lipase gene and investigated for associations with severity and development of CAD and lipid and lipoprotein levels. The Ser*"-Ter mutation showed no significant associations with CAD or dyslipidemia but was related to favorable lipid and lipoprotein profiles. The H2H2 genotype (P<.05) and H2 allele (P=.O5) were significantly more frequent in CAD + versus CAD" and control subjects versus CAD". H2H2 sub-

The DD genotype is a linkage marker for an etiologic mutation at or near the ACE gene that may confer risk of CAD detectable in subjects previously unidentifiable with "classic" risk factors. However, this risk may be quantitatively small among the general male population.