From the Service de Cardiologie (P.C., R.I., M.K.), INSERM Unit 153
(L.C., G.B., K.S.), GERC Département de Biomathématiques
(A.-C.C.), and Service de Biochimie (P.R., B.H.), Hôpital
Pitié-Salpêtrière, Paris, France; Service de Cardiologie,
Hôpital Ambroise Paré, Boulogne, France (O.D.); Service de
Cardiologie, Hôpital Boucicaut, Paris, France (M.D., A.H.); and Service
de Cardiologie, Hôpital Laennec, Nantes, France (J.-M.L., J.B.B.).
Correspondence to Michel Komajda, MD, Service de Cardiologie, Pavillon Rambuteau, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris CEDEX 13, France.
Background—Little information is
available on phenotype-genotype correlations in
familial hypertrophic cardiomyopathy that are
related to the cardiac myosin binding protein C (MYBPC3)
gene. The aim of this study was to perform this type of
analysis.
Methods and Results—We studied 76 genetically affected subjects
from nine families with seven recently identified mutations (SASint20,
SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon
25, and a duplication/deletion in exon 33) in the MYBPC3
gene. Detailed clinical, ECG, and echocardiographic
parameters were analyzed. An intergene
analysis was performed by comparing the MYBPC3
group to seven mutations in the ß-myosin heavy-chain gene
(ß-MHC) group (n=52). There was no significant
phenotypic difference among the different mutations in the
MYBPC3 gene. However, in the MYBPC3 group
compared with the ß-MHC group, (1) prognosis was
significantly better (P<0.0001), and no deaths occurred
before the age of 40 years; (2) the age at onset of symptoms was
delayed (41±19 versus 35±17 years, P<0.002); and (3)
before 30 years of age, the phenotype was particularly mild
because penetrance was low (41% versus 62%), maximal wall thicknesses
lower (12±4 versus 16±7 mm, P<0.03), and
abnormal T waves less frequent (9% versus 45%,
P<0.02).
Conclusions—These results are consistent with specific
clinical features related to the MYBPC3 gene: onset of
the disease appears delayed and the prognosis is better than that
associated with the ß-MHC gene. These findings could
be particularly important for the purpose of clinical management and
genetic counseling in familial hypertrophic
cardiomyopathy.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Clinical Features and Prognostic Implications of Familial Hypertrophic Cardiomyopathy Related to the Cardiac Myosin-Binding Protein C Gene
Key Words: cardiomyopathy • genetics • myosin • prognosis • hypertrophy
This article has been cited by other articles:
 |
|
 |
|
  K Zahka, K Kalidas, M A Simpson, H Cross, B B Keller, C Galambos, K Gurtz, M A Patton, and A H Crosby Homozygous mutation of MYBPC3 associated with severe infantile hypertrophic cardiomyopathy at high frequency among the Amish Heart, October 1, 2008; 94(10): 1326 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Kulikovskaya, G. B. McClellan, R. Levine, and S. Winegrad Multiple Forms of Cardiac Myosin-binding Protein C Exist and Can Regulate Thick Filament Stability J. Gen. Physiol., April 30, 2007; 129(5): 419 - 428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Richard, E. Villard, P. Charron, and R. Isnard The Genetic Bases of Cardiomyopathies J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A79 - A89. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Zolk, C. Schenke, and A. Sarikas The ubiquitin-proteasome system: Focus on the heart Cardiovasc Res, June 1, 2006; 70(3): 410 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kubo, H. Kitaoka, M. Okawa, Y. Matsumura, N. Hitomi, N. Yamasaki, T. Furuno, J. Takata, M. Nishinaga, A. Kimura, et al. Lifelong Left Ventricular Remodeling of Hypertrophic Cardiomyopathy Caused by a Founder Frameshift Deletion Mutation in the Cardiac Myosin-Binding Protein C Gene Among Japanese J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1737 - 1743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ackerman, S. L. Van Driest, and M. Bos Are Longitudinal, Natural History Studies the Next Step in Genotype-Phenotype Translational Genomics in Hypertrophic Cardiomyopathy? J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1744 - 1746. [Full Text] [PDF]
|
|
|
|
|
|
A. Sarikas, L. Carrier, C. Schenke, D. Doll, J. Flavigny, K. S. Lindenberg, T. Eschenhagen, and O. Zolk Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants Cardiovasc Res, April 1, 2005; 66(1): 33 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. P. V. Manh, M. Mokrane, E. Georgenthum, J. Flavigny, L. Carrier, M. Semeriva, M. Piovant, and L. Roder Expression of cardiac myosin-binding protein-C (cMyBP-C) in Drosophila as a model for the study of human cardiomyopathies Hum. Mol. Genet., January 1, 2005; 14(1): 7 - 17. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mogensen, R. T. Murphy, T. Kubo, A. Bahl, J. C. Moon, I. C. Klausen, P. M. Elliott, and W. J. McKenna Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2315 - 2325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, J.G. Seidman, and C. E. Seidman Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy J. Am. Coll. Cardiol., December 7, 2004; 44(11): 2125 - 2132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Van Driest, V. C. Vasile, S. R. Ommen, M. L. Will, A. J. Tajik, B. J. Gersh, and M. J. Ackerman Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1903 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Konno, M. Shimizu, H. Ino, M. Yamaguchi, H. Terai, K. Uchiyama, K. Oe, T. Mabuchi, T. Kaneda, and H. Mabuchi Diagnostic value of abnormal Q waves for identification of preclinical carriers of hypertrophic cardiomyopathy based on a molecular genetic diagnosis Eur. Heart J., February 1, 2004; 25(3): 246 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, W. J. McKenna, G. K. Danielson, L. J. Kappenberger, H. J. Kuhn, C. E. Seidman, P. M. Shah, W. H. Spencer III, P. Spirito, F. J. Ten Cate, et al. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1687 - 1713. [Full Text] [PDF]
|
|
|
|
|
|
Writing Committee Members, B. J. Maron, W. J. McKenna, G. K. Danielson, L. J. Kappenberger, H. J. Kuhn, C. E. Seidman, P. M. Shah, W. H. Spencer III, P. Spirito, et al. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines Eur. Heart J., November 1, 2003; 24(21): 1965 - 1991. [Full Text] [PDF]
|
|
|
|
|
|
M. Alders, R. Jongbloed, W. Deelen, A. van den Wijngaard, P. Doevendans, F. Ten Cate, V. Regitz-Zagrosek, H.-P. Vosberg, I. van Langen, A. Wilde, et al. The 2373insG mutation in the MYBPC3 gene is a founder mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands Eur. Heart J., October 2, 2003; 24(20): 1848 - 1853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.J. Marian and R. Roberts To Screen or Not Is Not the Question-- It Is When and How to Screen Circulation, May 6, 2003; 107(17): 2171 - 2174. [Full Text] [PDF]
|
|
|
|
|
|
T. Konno, M. Shimizu, H. Ino, T. Matsuyama, M. Yamaguchi, H. Terai, K. Hayashi, T. Mabuchi, M. Kiyama, K. Sakata, et al. A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients J. Am. Coll. Cardiol., March 5, 2003; 41(5): 781 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Hengstenberg, J Erdmann, and P Charron Outcome of clinical versus genetic family screening in hypertrophic cardiomyopathy with focus on cardiac beta-myosin gene mutations: Prediction of clinical status--is molecular genetics a new tool for the management of hypertrophic cardiomyopathy in clinical practice? Cardiovasc Res, February 1, 2003; 57(2): 298 - 301. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Seidman Genetic Causes of Inherited Cardiac Hypertrophy: Robert L. Frye Lecture Mayo Clin. Proc., December 1, 2002; 77(12): 1315 - 1319. [Abstract] [PDF]
|
|
|
|
|
|
X Jouven, A Hagege, P Charron, L Carrier, O Dubourg, J M Langlard, S Aliaga, J B Bouhour, K Schwartz, M Desnos, et al. Relation between QT duration and maximal wall thickness in familial hypertrophic cardiomyopathy Heart, August 1, 2002; 88(2): 153 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Frustaci, M. Pieroni, and C. Chimenti Late-onset primary LVH HCM versus cardiac fabry variant J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1405 - 1406. [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, J. G. Seidman, and C. E. Seidman Late-onset primary LVHHCM versus cardiac fabry variant: reply J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1406 - 1406. [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Harris, C. R. Bartley, T. A. Hacker, K. S. McDonald, P. S. Douglas, M. L. Greaser, P. A. Powers, and R. L. Moss Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C Knockout Mice Circ. Res., March 22, 2002; 90(5): 594 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Maron Hypertrophic Cardiomyopathy: A Systematic Review JAMA, March 13, 2002; 287(10): 1308 - 1320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Niimura, K. K. Patton, W. J. McKenna, J. Soults, B. J. Maron, J.G. Seidman, and C. E. Seidman Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the Elderly Circulation, January 29, 2002; 105(4): 446 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Andersen, O. Havndrup, H. Bundgaard, J. C. Moolman-Smook, L. A. Larsen, J. Mogensen, P. A. Brink, A. D. Borglum, V. A. Corfield, K. Kjeldsen, et al. Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations J. Med. Genet., December 1, 2001; 38 (12): e43 - e43. [Full Text] [PDF]
|
|
|
|
|
|
C. I. Berul, B. K. McConnell, H. Wakimoto, I. P.G. Moskowitz, C. T. Maguire, C. Semsarian, M. M. Vargas, J. Gehrmann, C. E. Seidman, and J. G. Seidman Ventricular Arrhythmia Vulnerability in Cardiomyopathic Mice With Homozygous Mutant Myosin-Binding Protein C Gene Circulation, November 27, 2001; 104(22): 2734 - 2739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, H. Niimura, S. A. Casey, M. K. Soper, G. B. Wright, J. G. Seidman, and C. E. Seidman Development of left ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations J. Am. Coll. Cardiol., August 1, 2001; 38(2): 315 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Erdmann, J.o. Raible, J. Maki-Abadi, M. Hummel, J. Hammann, B. Wollnik, E. Frantz, E. Fleck, R. Hetzer, and V. Regitz-Zagrosek Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy J. Am. Coll. Cardiol., August 1, 2001; 38(2): 322 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Marian On genetic and phenotypic variability of hypertrophic cardiomyopathy: nature versus nurture J. Am. Coll. Cardiol., August 1, 2001; 38(2): 331 - 334. [Full Text] [PDF]
|
|
|
|
|
|
M. KOMAJDA and P. CHARRON How will the human genome project change cardiovascular medicine? Heart, August 1, 2001; 86(2): 123 - 124. [Full Text] [PDF]
|
|
|
|
|
|
B. K. McConnell, D. Fatkin, C. Semsarian, K. A. Jones, D. Georgakopoulos, C. T. Maguire, M. J. Healey, J. O. Mudd, I. P. G. Moskowitz, D. A. Conner, et al. Comparison of Two Murine Models of Familial Hypertrophic Cardiomyopathy Circ. Res., March 2, 2001; 88(4): 383 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fatkin, R. M. Graham, P. Spirito, and B. J. Maron Prognostic Value of Left Ventricular Hypertrophy in Hypertrophic Cardiomyopathy N. Engl. J. Med., January 4, 2001; 344(1): 63 - 65. [Full Text] [PDF]
|
|
|
|
|
|
A. Karibe, L. S. Tobacman, J. Strand, C. Butters, N. Back, L. L. Bachinski, A. E. Arai, A. Ortiz, R. Roberts, E. Homsher, et al. Hypertrophic Cardiomyopathy Caused by a Novel {{alpha}}-Tropomyosin Mutation (V95A) Is Associated With Mild Cardiac Phenotype, Abnormal Calcium Binding to Troponin, Abnormal Myosin Cycling, and Poor Prognosis Circulation, January 2, 2001; 103(1): 65 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Sorajja, P.M. Elliott, and W.J. Mckenna The molecular genetics of hypertrophic cardiomyopathy: prognostic implications Europace, January 1, 2000; 2(1): 4 - 14. [PDF]
|
|
|
|
|
|
P. M. Elliott, L. D'Cruz, and W. J. McKenna Late-Onset Hypertrophic Cardiomyopathy Caused by a Mutation in the Cardiac Troponin T Gene N. Engl. J. Med., December 9, 1999; 341(24): 1855 - 1856. [Full Text]
|
|
|
|
|
|
Q. Yang, A. Sanbe, H. Osinska, T. E. Hewett, R. Klevitsky, and J. Robbins In Vivo Modeling of Myosin Binding Protein C Familial Hypertrophic Cardiomyopathy Circ. Res., October 29, 1999; 85(9): 841 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Tobacman, D. Lin, C. Butters, C. Landis, N. Back, D. Pavlov, and E. Homsher Functional Consequences of Troponin T Mutations Found in Hypertrophic Cardiomyopathy J. Biol. Chem., October 1, 1999; 274(40): 28363 - 28370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Redwood, J. C. Moolman-Smook, and H. Watkins Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy Cardiovasc Res, October 1, 1999; 44(1): 20 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. L. Doi, H. Kitaoka, N. Hitomi, M. Satoh, A. Kimura, P. Charron, M. Bennaceur, R. Isnard, M. Komajda, L. Carrier, et al. Clinical Expression in Patients With Hypertrophic Cardiomyopathy Caused by Cardiac Myosin-Binding Protein C Gene Mutation • Response Circulation, July 27, 1999; 100 (4): 446 - 449. [Full Text] [PDF]
|
|
|
|
|
|
P. Richard, R. Isnard, L. Carrier, O. Dubourg, Y. Donatien, B. Mathieu, G. Bonne, F. Gary, P. Charron, A. Hagege, et al. Double heterozygosity for mutations in the beta -myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy J. Med. Genet., July 1, 1999; 36(7): 542 - 545. [Abstract] [Full Text]
|
|
|
|
|
|
S. Winegrad Cardiac Myosin Binding Protein C Circ. Res., May 28, 1999; 84(10): 1117 - 1126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Bonne, L. Carrier, P. Richard, B. Hainque, and K. Schwartz Familial Hypertrophic Cardiomyopathy : From Mutations to Functional Defects Circ. Res., September 21, 1998; 83(6): 580 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Witt, B. Gerull, M. J. Davies, T. Centner, W. A. Linke, and L. Thierfelder Hypercontractile Properties of Cardiac Muscle Fibers in a Knock-in Mouse Model of Cardiac Myosin-binding Protein-C J. Biol. Chem., February 9, 2001; 276(7): 5353 - 5359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Burhop, M. Rosol, R. Craig, L. S. Tobacman, and W. Lehman Effects of a Cardiomyopathy-causing Troponin T Mutation on Thin Filament Function and Structure J. Biol. Chem., June 1, 2001; 276(23): 20788 - 20794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Harris, C. R. Bartley, T. A. Hacker, K. S. McDonald, P. S. Douglas, M. L. Greaser, P. A. Powers, and R. L. Moss Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C Knockout Mice Circ. Res., March 22, 2002; 90(5): 594 - 601. [Abstract] [Full Text] [PDF]
|
|