Investigation of a family with autosomal dominant dilated cardiomyopathy defines a novel locus on chromosome 2q14-q22

Abstract

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most frequent indication for heart transplantation in young patients. Probably >25% of DCM cases are of familial etiology. We report here genetic localization in a three-generation German family with 12 affected individuals with autosomal dominant familial DCM characterized by ventricular dilatation, impaired systolic function, and conduction disease. After exclusion of known DCM loci, we performed a whole-genome screen and detected linkage of DCM to chromosome 2q14-q22. Investigation of only affected individuals defines a 24-cM interval between markers D2S2224 and D2S2324; when unaffected individuals are also included, the critical region decreases to 11 cM between markers D2S2224 and D2S112, with a peak LOD score of 3.73 at recombination fraction 0 at D2S2339. The identification of an additional locus for familial autosomal dominant DCM underlines the genetic heterogeneity and may assist in the elucidation of the causes of this disease.

Figure 1

Pedigree of family with autosomal dominant DCM, with most likely marker haplotypes from the linked region on chromosome 2q. Key recombination events were observed with marker D2S2224, in individual 004; with marker D2S112, in individual 003; and with marker D2S2324, in individual 010.

Figure 2

Part of genetic map of human chromosome 2q. The region including the DCM gene is marked. Genetic distances between markers are given (in cM). Microsatellite loci were obtained from the final Généthon linkage map (Dib et al. 1996). The locations of nebulin (NEB), the disease gene of autosomal recessive nemaline myopathy 2 (NEM2), titin (TTN), and the adjacent CMD1G locus are shown.