CLINICAL STUDY
Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy
Jeanette Erdmann, PhD*,
J.örg Raible*,
Jaleh Maki-Abadi*,
Manfred Hummel,
Jan Hammann, MD*,
Bernd Wollnik, MD ,
Eckart Frantz, MD*,
Eckart Fleck, MD*,
Roland Hetzer, MD and
Vera Regitz-Zagrosek, MD*
* Departments of Internal Medicine and Cardiology, Charité, Campus Virchow-Klinikum, Humboldt University and Deutsches Herzzentrum, Berlin, Germany
Department of Medical Genetics, Child Health Institute, University of Istanbul, Istanbul, Turkey
Manuscript received February 23, 2000;
revised manuscript received April 10, 2001,
accepted April 12, 2001.
Reprint requests and correspondence: Dr. V. Regitz-Zagrosek, Kardiologie, Charité, Campus Virchow-Klinikum und Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany
zagrosek{at}dhzb.de
OBJECTIVES
We studied the clinical and genetic features of hypertrophic cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent.
BACKGROUND
Mutations in the MYBPC3 gene represent the cause of HCM in  15% of familial cases. MYBPC3 mutations were reported to include mainly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French families. We investigated the features that characterize MYBPC3 variants in a large, unrelated cohort of consecutive patients.
METHODS
The MYBPC3 gene was screened by single-strand conformational polymorphism analysis and sequencing. The clinical phenotypes were analyzed using rest and 24-h electrocardiography, electrophysiology, two-dimensional and Doppler echocardiography and angiography.
RESULTS
We identified 13 mutations in the MYBPC3 gene: one nonsense, four missense and three splicing mutations and five small deletions and insertions. Of these, 11 were novel, and two were probably founder mutations. Patients with MYBPC3 mutations presented a broad range of phenotypes. In general, the 16 carriers of protein truncations had a tendency toward earlier disease manifestations (33 ± 13 vs. 48 ± 9 years; p = 0.06) and more frequently needed invasive procedures (septal ablation or cardioverter-defibrillator implantation) compared with the 9 carriers of missense mutations or in-frame deletions (12/16 vs. 1/9 patients; p < 0.01).
CONCLUSIONS
Multiple mutations, which include missense, nonsense and splicing mutations, as well as small deletions and insertions, occur in the MYBPC3 gene. Protein truncation mutations seem to cause a more severe disease phenotype than missense mutations or in-frame deletions.
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Abbreviations and Acronyms
| | del | = deletion | | HCM | = hypertrophic cardiomyopathy | | ICD | = implantable cardioverter-defibrillator | | ins | = insertion | | IVS | = intervening sequence (intron) | | MHC | = myosin heavy chain | | MyBPC | = myosin-binding protein C | | MYBPC3 | = myosin-binding protein C gene | | PCR | = polymerase chain reaction | | TASH | = transcoronary ablation of septal hypertrophy %*The single-letter amino acid code is used for description of mutations. |
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