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(Circulation. 2006;113:2186-2192.)
© 2006 American Heart Association, Inc.

Genetics

Novel Locus for an Inherited Cardiomyopathy Maps to Chromosome 7

Lei Song, MD, PhD; Steven R. DePalma, PhD; Maria Kharlap, MD; Andrey G. Zenovich, MSc; Allison Cirino, MS; Richard Mitchell, MD; Barbara McDonough, RN; Barry J. Maron, MD; Christine E. Seidman, MD; J.G. Seidman, MD; Carolyn Y. Ho, MD

From the Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Mass (L.S., S.R.D., B.M., C.E.S., J.G.S.); Department of Clinical Electrophysiology, A.L. Myasnikov Institute of Clinical Cardiology, Cardiology Research Center, Moscow, Russia (M.K.); Minneapolis Heart Institute Foundation, Minneapolis, Minn (A.G.Z., B.J.M.); and Cardiovascular Division (A.C., C.E.S., C.Y.H.) and Department of Pathology (R.M.), Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Carolyn Y. Ho, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail cho{at}partners.org

Received October 24, 2005; de novo received January 24, 2006; revision received March 1, 2006; accepted March 3, 2006.

Background— Genetic mutations are the most common cause of hypertrophic cardiomyopathy (HCM) and an increasingly recognized cause of dilated cardiomyopathy. Autosomal dominant HCM is caused by mutations in sarcomere proteins; such mutations are not universally present, however, and fail to account for &40% of cases of phenotypic HCM. To add further complexity, other genetic origins can mimic the gross clinical phenotype of HCM, and mutations in sarcomere genes have been demonstrated to cause dilated cardiomyopathy.

Methods and Results— To explore novel genetic causes of inherited cardiomyopathies, genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death. Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM. Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified. Linkage was then established to a novel locus on chromosome 7 (7p12.1-7q21). A maximum 2-point logarithm of odds score of 4.11 was obtained. Recombination events refine the disease interval between D7S506 and D7S3314, corresponding to a distance of 27.2 megabases.

Conclusions— The discovery of a novel genetic locus in this family provides more evidence that molecular pathways leading to inherited cardiac hypertrophy extend beyond the sarcomere. Identification of the causal gene mutation and additional genotype-phenotype correlation studies will provide fundamental insight into mechanisms of cardiac remodeling.

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