(A) Short-axis cardiac magnetic resonance image of the proband (III-28) 1 decade prior to a sudden cardiac death episode. Dilation of the left ventricle (LV) and right ventricle (RV) and RV wall thinning are clearly evident. (B) Representative images of cardiac biopsy from a second sudden death victim, individual III-26, showing hallmarks of arrhythmogenic cardiomyopathy (ACM), including extensive biventricular myocyte disarray and fibrofatty infiltration. Images show H&E-stained sections (left) and Masson’s trichrome–stained sections (right) from the LV (top) and RV (bottom). Original magnification, ×100. Histology of the RV free wall shows an extensive fatty infiltrate (arrows) and areas of full-thickness replacement of RV myocardium by adipose tissue. The residual muscle is present in a band-like or wave-front pattern (H&E). Trichrome staining highlights transmural fibrofatty infiltration by the fibrotic tissue in blue (arrows). Histology of the LV shows patchy fibrosis (arrows, H&E). Trichrome staining highlights patchy fibrosis (arrows) and mild subepicardial adipose tissue replacement (asterisks). (C) Extended pedigree of proband. White symbols represent unaffected individuals that also lack the DSP R451G mutation. Gray symbols represent individuals that carry the R451G mutation but do not yet show clinical phenotype [G(+)P(–)]. Black symbols with a white center represent mutation positive individuals with clinical symptoms of ACM [G(+)P(+)]. Slashes denote deceased individuals. Asterisks denote individuals who experienced a sudden cardiac death event. Analysis revealed a highly significant linkage between DSP R451G and the ACM phenotype (LOD score 7.65).