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Original Article
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Volume 338:1248-1257 April 30, 1998 Number 18
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Mutations in the Gene for Cardiac Myosin-Binding Protein C and Late-Onset Familial Hypertrophic Cardiomyopathy
Hideshi Niimura, M.D., Linda L. Bachinski, M.D., Somkiat Sangwatanaroj, M.D., Hugh Watkins, M.D., Ph.D., Albert E. Chudley, M.D., William McKenna, M.D., Arni Kristinsson, M.D., Ph.D., Robert Roberts, M.D., Michael Sole, M.D., Barry J. Maron, M.D., J.G. Seidman, Ph.D., Christine E. Seidman, M.D., Ludwig Thierfelder, M.D., John A. Jarcho, M.D., Aris Anastasakis, M.D., Pavlos Toutouzas, M.D., Eleanor Elstein, M.D., Choong-Chin Liew, Ph.D., Jack Liew, Ph.D., John Mably, Ph.D., Harry Rakowski, M.D., E. Douglas Wigle, M.D., Minshun Zhao, Ph.D., Rosemarie Salerni, and Halldora Bjornsdottir, M.D

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ABSTRACT

Background Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown.

Methods DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed.

Results Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly.

Conclusions The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.


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From the Howard Hughes Medical Institute and the Department of Genetics, Harvard Medical School, Boston (H.N., S.S., J.G.S.); the First Department of Internal Medicine, Kagoshima University, Kagoshima, Japan (H.N.); the Molecular Cardiology Unit, Department of Medicine, Baylor College of Medicine, Houston (L.L.B., R.R.); the University of Oxford, Oxford, United Kingdom (H.W.); the Departments of Pediatrics and Human Genetics, University of Manitoba, and the Section of Genetics and Metabolism, Children's Hospital — both in Winnipeg, Canada (A.E.C.); the Department of Cardiological Sciences, St. George's Hospital Medical School, London (W.M.); the Department of Medicine, University Hospital, Reykjavik, Iceland (A.K.); the Center for Cardiovascular Research, Toronto Hospital, University of Toronto, Toronto (M.S.); the Cardiovascular Research Division, Minneapolis Heart Institute Foundation, Minneapolis (B.J.M.); and Howard Hughes Medical Institute and the Cardiovascular Division, Brigham and Women's Hospital, Boston (C.E.S.). Other authors were Ludwig Thierfelder, M.D., Max Delbruck Center for Molecular Medicine, Berlin-Buch, Germany; John A. Jarcho, M.D., Cardiovascular Division, Brigham and Women's Hospital, Boston; Aris Anastasakis, M.D., and Pavlos Toutouzas, M.D., Department of Cardiology, University of Athens, Hippokration Hospital, Athens, Greece; Eleanor Elstein, M.D., Center for Cardiovascular Research, Toronto Hospital, University of Toronto, Toronto, and Division of Cardiology, Royal Victoria Hospital, Montreal; Choong-Chin Liew, Ph.D., Jack Liew, Ph.D., John Mably, Ph.D., Harry Rakowski, M.D., E. Douglas Wigle, M.D., and Minshun Zhao, Ph.D., Center for Cardiovascular Research, Toronto Hospital, University of Toronto, Toronto; Rosemarie Salerni, M.D., University of Pittsburgh–Veterans Affairs Medical Center, Pittsburgh; and Halldora Bjornsdottir, M.D., Division of Cardiology, University Hospital, Reykjavik, Iceland.

Address reprint requests to Dr. Christine Seidman at the Department of Genetics, Alpert Rm. 533, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115.

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