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Familial Dilated Cardiomyopathy Locus Maps to Chromosome 2q31

1999; Lippincott Williams & Wilkins; Volume: 99; Issue: 8 Linguagem: Inglês

10.1161/01.cir.99.8.1022

1524-4539

Benjamin L. Siu, Hideshi Niimura, John A. Osborne, Diane Fatkin, Calum A. MacRae, Scott Solomon, D. Woodrow Benson, J.G. Seidman, Christine E. Seidman,

Cardiac electrophysiology and arrhythmias

Background —Inherited gene defects are an important cause of dilated cardiomyopathy. Although the chromosome locations of some defects and 1 disease gene (actin) have been identified, the genetic etiologies of most cases of familial dilated cardiomyopathy remain unknown. Methods and Results —We clinically evaluated 3 generations of a kindred with autosomal dominant transmission of dilated cardiomyopathy. Nine surviving and affected individuals had early-onset disease (ventricular chamber dilation during the teenage years and congestive heart failure during the third decade of life). The disease was nonpenetrant in 2 obligate carriers. To identify the causal gene defect, linkage studies were performed. A new dilated cardiomyopathy locus was identified on chromosome 2 between loci GCG and D2S72 (maximum logarithm of odds [LOD] score=4.86 at θ=0). Because the massive gene encoding titin, a cytoskeletal muscle protein, resides in this disease interval, sequences encoding 900 amino acid residues of the cardiac-specific (N2-B) domain were analyzed. Five sequence variants were identified, but none segregated with disease in this family. Conclusions —A dilated cardiomyopathy locus (designated CMD1G ) is located on chromosome 2q31 and causes early-onset congestive heart failure. Although titin remains an intriguing candidate gene for this disorder, a disease-causing mutation is not present in its cardiac-specific N2-B domain.