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CLINICAL RESEARCH: HEART FAILURE

A Novel Locus for Dilated Cardiomyopathy, Diffuse Myocardial Fibrosis, and Sudden Death on Chromosome 10q25-26

Patrick T. Ellinor, MD, PhD^_*,, Sabine Sasse-Klaassen, MD, Susanne Probst, MSc, Brenda Gerull, MD, Jordan T. Shin, MD, PhD^_*,, Andrea Toeppel, PhD, Arnd Heuser, MD, Beate Michely, MD, Danita M. Yoerger, MD, Bong-Seok Song, MD, Bernhard Pilz, MD^||, Gregor Krings, MD^¶, Bruce Coplin, MD^_**, Peter E. Lange, MD, G. William Dec, MD, Hans Christian Hennies, PhD, Ludwig Thierfelder, MD^,||, and Calum A. MacRae, MB, ChB, PhD^_*,,_*

^_* Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts
Max-Delbrueck Center for Molecular Medicine, Berlin, Germany
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
^|| Franz-Volhard Clinic, HELIOS Clinics GmbH, Charité, Humboldt University Berlin, Berlin, Germany
^¶ Clinic for Pediatrics, Cardiology Division, Charité, Humboldt University Berlin, Berlin, Germany
^_** Albany Associates in Cardiology, Albany, New York
Department of Congenital Heart Disease, German Heart Institute Berlin, Berlin, Germany
Cologne Center for Genomics, Cologne, Germany.

Manuscript received November 3, 2005; revised manuscript received December 30, 2005, accepted January 9, 2006.

^_* Reprint requests and correspondence to: Dr. Calum A. MacRae, Cardiovascular Research Center, 149 13th Street, 4th Floor, Charlestown, Massachusetts 02129. (Email: lthier{at}mdc-berlin.de).

Dr. Ludwig Thierfelder, Max Delbrueck Center for Molecular Medicine, Robert Rossle Strasse 10, 13092 Berlin, Germany. (Email: cmacrae{at}partners.org).

OBJECTIVES: We sought to identify the genetic locus for an inherited form of dilated cardiomyopathy (DCM) that is characterized by diffuse myocardial fibrosis and sudden death.

BACKGROUND: Genetic studies have mapped multiple loci for DCM, which is a major cause of nonischemic heart failure; however, the genes responsible for the majority of cases have yet to be identified.

METHODS: Sixty-six family members were evaluated by 12-lead electrocardiogram (ECG), echocardiogram, and laboratory studies. Individuals with echocardiographically documented DCM were defined as affected. Subjects were considered unaffected if they were older than 20 years of age, had a normal ECG and echocardiogram, no personal history of heart failure, and had no affected offspring. Genotyping was performed using polymorphic markers.

RESULTS: Genome-wide linkage analysis identified a novel locus for this inherited phenotype on chromosome 10q25.3-q26.13. Peak two-point logarithm of the odds scores >3.0 were obtained independently with each family using the markers D10S1773 and D10S1483, respectively. Haplotype analyses defined a critical interval of 14.0 centiMorgans between D10S1237 and D10S1723, corresponding to a physical distance of 9.5 megabases. Multipoint linkage analyses confirmed this interval and generated a peak logarithm of the odds score of 8.2 indicating odds of >100,000,000:1 in favor of this interval as the location of the gene defect responsible for DCM in these families.

CONCLUSIONS: We have mapped a novel locus for cardiomyopathy, diffuse myocardial fibrosis, and sudden death to chromosome 10q25-q26. The identification of the causative gene in this interval will be an important step in understanding the fundamental mechanisms of heart failure and sudden death.

Abbreviations and Acronyms   CM = cardiomyopathy   DCM = dilated cardiomyopathy   HCM = hypertrophic cardiomyopathy   LOD = logarithm of the odds

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