Familial dilated cardiomyopathy (FDCM), an inherited primary form of myocardial disease, is a significant cause of morbidity and mortality at all ages and a leading cause of transplantation. Although typically inherited as an autosomal dominant disorder, all forms of inheritance have been recognized. Recently, two loci in families with autosomal dominant FDCM were mapped. In one family with conduction abnormalities and FDCM the locus was mapped to 1p1-1q1, while a disease locus in other families with pure FDCM was mapped to 9q13-q22. Neither gene has been identified.

Clinical evaluation of one family with pure FDCM was performed. Standard clinical and echocardiographic criteria were used for diagnosis. Other diseases potentially causing secondary cardiac dysfunction were excluded in all patients. Blood was obtained from 19 of the 26 family members for linkage analysis and cell immortalization. Eleven patients were affected with FDCM, 8 were normal, and seven had uncertain status. We analyzed this family for linkage to 1p1-1q1 and 9q13-q22 as well as the entire genome using parametric linkage analysis with short tandem repeat markers (STRs, heterozygosity>0.70).

Linkage to 1p1-1q1 and 9q13-q22 was excluded (lod scores<-2.0). Further linkage analysis of this family using 169 STRs, which excluded 50% of the genome, demonstrated linkage of FDCM to 10q21-q23. Linkage was found to markers D10S605 and D10S201 with a pairwise lod score=3.01, θ=0, for both markers. The 10q21-q23 region contains several candidate genes, including muscle membrane proteins (vinculin, metavinculin, actin, ankyrin, and laminin), energy-producing proteins (ATP synthase), and proteins involved in energy transport (perforin). Vinculin and metavinculin have been excluded as candidates by single-stranded conformation polymorphism (SSCP) analysis. The remaining genes are still under study.

We conclude that (1) genetic heterogeneity exists for FDCM and (2) an FDCM gene is localized to 10q21-q23 in one family with pure autosomal dominant FDCM.