Familial dilated cardiomyopathy locus maps to chromosome 2q31

Background-Inherited gene defects are an important cause of dilated cardiom yopathy. Although the chromosome locations of some defects and I disease ge ne (actin) have been identified, the genetic etiologies of most cases of fa milial 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 dilat ion during the teenage years and congestive heart failure during the third decade of life). The disease was nonpenetrant in 2 obligate carriers, To id entify the causal gene defect, linkage studies were performed, A new dilate d cardiomyopathy locus was identified on chromosome 2 between loci GCG and D2S72 (maximum logarithm of odds [LOD] score=4.86 at theta=0). Because the massive gene encoding titin, a cytoskeletal muscle protein, resides in this disease interval, sequences encoding 900 amino acid residues of the cardia c-specific (N2-B) domain were analyzed. Five sequence variants were identif ied, 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-cau sing mutation is not present in its cardiac-specific N2-B domain.