(Circulation. 2000;101:1396.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
A Newly Created Splice Donor Site in Exon 25 of the MyBP-C Gene Is Responsible for Inherited Hypertrophic Cardiomyopathy With Incomplete Disease Penetrance
From the Department of Experimental Cardiology, Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Germany (J.A.M., K.U., S.B., B.J., H.-P.V.); the Department of Medical Physiology, University of Stellenbosch, Republic of South Africa (J.A.M.); the Department of Cardiology, Medizinische Klinik I, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany (S.R., J.O., H.K.); the Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (C.F.); the Department of Cardiological Sciences, St George’s Hospital Medical School, London, UK (W.J.M.); and European Molecular Biology Laboratory, Heidelberg, Germany (M.G.).
Background—Hypertrophic cardiomyopathy is a myocardial disorder resulting from inherited sarcomeric dysfunction. We report a mutation in the myosin-binding protein-C (MyBP-C) gene, its clinical consequences in a large family, and myocardial tissue findings that may provide insight into the mechanism of disease.
Methods and Results—History and clinical status (examination,
ECG, and echocardiography) were assessed in 49
members of a multigeneration family. Linkage analysis
implicated the MyBP-C gene on chromosome 11. Myocardial mRNA, genomic
MyBP-C DNA, and the myocardial proteins of patients and healthy
relatives were analyzed. A single guanine
nucleotide insertion in exon 25 of the MyBP-C gene resulted
in the loss of 40 bases in abnormally processed mRNA. A 30-kDa
truncation at the C-terminus of the protein was predicted, but a
polypeptide of the expected size (
95 kDa) was not detected by
immunoblot testing. The disease phenotype in this
family was characterized in detail: only 10 of 27 gene carriers
fulfilled diagnostic criteria. Five carriers showed
borderline hypertrophic cardiomyopathy, and 12
carriers were asymptomatic, with normal ECG and
echocardiograms. The age of onset in symptomatic patients
was late (29 to 68 years). In 2 patients, outflow obstruction required
surgery. Two family members experienced premature sudden cardiac death,
but survival at 50 years was 95%.
Conclusions—Penetrance of this mutation was incomplete and age-dependent. The large number of asymptomatic carriers and the good prognosis support the interpretation of benign disease.
Key Words: genes • cardiomyopathy • diagnosis
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