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(Circulation. 1998;97:2230-2236.)
© 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

Philippe Charron, MD; Olivier Dubourg, MD; Michel Desnos, MD; Mohammed Bennaceur, MD; Lucie Carrier, PhD; Anne-Claude Camproux, PhD; Richard Isnard, MD; Albert Hagege, MD; Jean Marc Langlard, MD; Gisele Bonne, PhD; Pascale Richard, PhD; Bernard Hainque, PhD; Jean-Brieuc Bouhour, MD; Ketty Schwartz, PhD; ; Michel Komajda, MD

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.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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.

Key Words: cardiomyopathy • genetics • myosin • prognosis • hypertrophy

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Familial hypertrophic cardiomyopathy is an autosomal dominant disease characterized by left ventricular hypertrophy, myofibrillar disarray, and the risk of premature sudden death.^{1 2} Clinical expression of the disease and the prognosis of affected subjects vary markedly. One important and unresolved problem is the fact that premature death is difficult to predict from clinical indicators such as the degree of left ventricular hypertrophy, ventricular arrhythmia, and abnormal blood pressure response during exercise.^{1 2 3 4}

The disease is genetically heterogeneous and can be caused by mutations in the ß-MHC,⁵ cardiac troponin T,⁶ -tropomyosin,⁶ MYBPC3,^{7 8} essential and regulatory light chains of myosin,⁹ or cardiac troponin I¹⁰ genes. Differences in clinical manifestations of the disease may be due in part to the genetic heterogeneity resulting from the existence of different disease genes or different mutations within a given gene. Several phenotype-genotype analyses have already been reported in FHC. In families carrying the ß-MHC gene, the prognosis differs according to the mutations involved.^{11 12 13} In families carrying the cardiac troponin T gene, the phenotype is similar and is characterized by mild hypertrophy and a poor prognosis with a high incidence of sudden death before the age of 30 years.^{14 15}

Little information is available on phenotype-genotype associations in FHC that are related to the recently identified MYBPC3 gene. In a pilot study and on the basis of one mutation in the MYBPC3 gene, our results suggested that the prognosis was better than that observed in families with a malignant mutation in the ß-MHC gene.¹⁶ The purpose of the present study was to analyze the detailed phenotype in a large cohort of nine families with seven mutations in the MYBPC3 gene. The phenotype evaluation was performed in two ways: (1) an intragene comparison between the different mutations in the MYBPC3 gene and (2) an intergene comparison between those families carrying the MYBPC3 gene and those families carrying all known mutations in the ß-MHC gene that have been identified thus far in our laboratory.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Determination of Genotype
The phenotype associated with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) was analyzed. For all family members at risk of inheriting the disease gene, informed consent was previously obtained in accordance with a study protocol approved by the Comité d'Ethique du Center Hospitalier Universitaire de la Pitié-Salpêtrière (Paris), blood samples were obtained, and genotype assessment was determined.^{7 17} All subjects bearing a mutation in the MYBPC3 gene (n=76) were also pooled in one group (MYBPC) and compared with subjects (n=52) bearing a mutation in the ß-MHC gene: Asn232Ser, Ile263Thr, Arg403Leu, Arg403Trp, Arg719Trp, Arg723Cys, or Del 930GAG.^{18 19 20}

Clinical Investigations
All genotyped subjects underwent detailed clinical and cardiovascular examination, including a 12-lead ECG; M-mode, two-dimensional echocardiography; and Doppler examination at the time of genotyping. Echocardiography was performed and images were stored on VHS videotape for subsequent analysis. Measurements obtained during three consecutive cardiac cycles were averaged. End-diastolic left ventricular wall thickness measurements were obtained at different locations (anterior and posterior septum, lateral and posterior walls) from the parasternal short-axis view at both the mitral valve and papillary muscle levels and also from the parasternal long-axis view.^{21 22} Left ventricular mass was evaluated by the Spirito-Maron index,²³ which is the sum of maximum thicknesses of four segments in short-axis views. ECG and echocardiographic data were analyzed independently by three observers without knowledge of each subject's genetic status.

Penetrance of the Disease
The penetrance of the disease was determined as previously described.²⁴ In brief, the major criteria used were as follows (in the absence of any known cause of left ventricular hypertrophy): (1) a left ventricular end-diastolic MWT >13 mm in adults or >95% CI of the theoretical value in children²⁵ ; (2) the presence of major abnormalities on the ECG, eg, left ventricular hypertrophy assessed by a Romhilt-Estes score 4,²⁶ Q waves >0.04 second or >1/3 R wave, or significant ST-T–segment changes; or (3) a combination of (1) and (2).

Statistical Analysis
Values were expressed as mean±SD. Differences between two groups were compared with the ² test (or the Fisher test) for categorical variables and with Student's t test (or the Mann-Whitney U test) for continuous variables. For continuous variables, differences among three or more groups were compared by ANOVA (or the Kruskal-Wallis test). The penetrance of FHC was also estimated by a multivariate logistic regression model (SAS software, SAS Institute) that included age, sex, and causative gene as explanatory covariates. Family history was obtained to determine the number of disease-related deaths and the age at which they occurred. The Kaplan-Meier product-limit survival curves²⁷ were constructed with the use of disease-related deaths or cardiac transplantations as time variables. Age at the time of the study was used for all living genetically affected individuals. Product-limit survival functions were compared with the log-rank test. For all comparisons, a value of P<0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Analysis of Seven Mutations in the MYBPC3 Gene
Thirty-six clinical, ECG, and echocardiographic parameters were analyzed with respect to the mutation involved in the MYBPC3 gene. The main results are indicated in Table 1 (see the Appendix for a complete listing of parameters analyzed). Our major findings were the following: (1) Very few disease-related deaths were observed, and no death was reported before the age of 40 years, regardless of the mutation involved. The number of disease-related deaths or cardiac transplantations was 10; the mean age at death or at the time of transplant was 59.6±10 years (range, 44 to 79 years). The cause of death was sudden death in 4 subjects, refractory heart failure in 3, and ischemic cerebrovascular accident in 2. Cardiac transplantation was performed in one subject, who is still alive. Eight of the disease-related deaths or cardiac transplantations occurred in families with the SASint20 mutation, one in the family with the SDSint7 mutation, and one in the family with a deletion in exon 25. Kaplan-Meier survival curves could be constructed for six of the seven mutations because the number of subjects was sufficient; these are shown in Figure 1. (2) No significant differences in phenotype were observed among the seven mutations (Table 1 and data not shown). (3) The penetrance of the disease was incomplete in adults with all mutations except for one small family with three genetically affected adults who carried a branch-point mutation in intron 23. (4) The age at the onset of symptoms was late, especially for the deletion in exon 25 (49.5±4 years) and the branch-point mutation in intron 23 (53±25 years); all subjects were symptom-free in the family with the SDSint23 mutation. (5) The degree of left ventricular hypertrophy was mild to moderate, except for the small family with the branch-point mutation in intron 23.

View this table: [in this window] [in a new window]   Table 1. FHC Phenotype in Adults According to the Mutation Involved in the MYBPC3 Gene

View larger version (16K): [in this window] [in a new window]   Figure 1. Kaplan-Meier product-limit curves for survival in patients with hypertrophic cardiomyopathy associated with six different mutations in MYBPC3 gene.

Comparison Between the MYBPC3 and the ß-MHC Genes
Genetically affected subjects bearing a mutation in the MYBPC gene were pooled in an MYBPC3 group, because there were no significant differences between the seven mutations within the gene. This pooled group was compared with a ß-MHC group, composed of individuals with seven mutations in the ß-MHC gene (including three mutations associated with a very good prognosis, three with a poor prognosis, and one with an undetermined prognosis owing to the small size of the family).^{16 18 19 20} Disease-related deaths and the age at onset of symptoms were analyzed in the total population (children and adults), whereas others parameters such as MWT were analyzed in adults (18 years) only (Table 2). There were 18 disease-related deaths or cardiac transplantations (mean age, 38.5±16 years; range, 15 to 59 years) in the ß-MHC group (for sudden death, n=8; refractory heart failure, n=4; and cardiac transplantation, n=6). The mean age at disease-related death or cardiac transplantation was significantly higher in the MYBPC3 group than in the ß-MHC group (P<0.002). Kaplan-Meier survival curves were constructed to evaluate the prognosis associated with these two genes (Figure 2). Cumulative survival rates at 50 and 60 years of age were 95% and 76% for the MYBPC3 group and 62% and 23% for the ß-MHC group, respectively. Thus, the prognosis was significantly better in the MYBPC3 group than in the ß-MHC group (log-rank test, P<0.0001). The difference was still significant when cardiac transplantations were not considered as end-point events but were censored at the time of the transplantation (log-rank test, P<0.0005). Symptoms were present at the time of the study or before it in 38% of the MYBPC3 group (26/76) and in 44% of the ß-MHC group (21/52, P=NS). The mean age at onset of symptoms was significantly delayed in the MYBPC3 group compared with the ß-MHC group (40.9±19 versus 34.6±17 years, P<0.005). The most important ECG and echocardiographic parameters that were analyzed in adults are indicated in Table 2 (other parameters are listed in the Appendix). No differences were found between the two groups. In particular, the penetrance of the disease was incomplete and the same (71%), and the degree of left ventricular hypertrophy was moderate and similar (mean MWT, 18±6 and 17.2±6 mm). The sensitivity of ECG and echocardiography for the diagnosis was also similar.

View this table: [in this window] [in a new window]   Table 2. Clinical Features Associated With the MYBPC3 and Beta-MHC Genes in Adults (18 Years)

View larger version (12K): [in this window] [in a new window]   Figure 2. Kaplan-Meier product-limit curves for survival in the MYBPC3 group (seven mutations in this gene) compared with ß-MHC group (seven mutations in this gene). Disease-related deaths and cardiac transplantations were considered events. Product-limit survival functions were significantly different between the two groups (P<0.0001) by the log-rank test.

Clinical Features Associated With the Two Genes According to Age
A multivariate logistic regression model that included age and sex as explanatory covariates indicated that disease penetrance was not significantly different between the MYBPC3 and ß-MHC groups. However, the mean age of phenotypically affected subjects (ie, those who had major criteria for the diagnosis) was higher in the MYBPC3 group than in the ß-MHC group (48±18 versus 38±16 years, P<0.02). Moreover, multivariate logistic regression performed within the MYBPC3 group indicated that the penetrance of the disease was significantly related to age (P<0.0003), whereas penetrance was not related to age in the ß-MHC group. Penetrance and MWT before and after 30 years of age are shown in Figure 3. The analyses performed for subjects <30 years of age at the time of the study (age range, 10 to 29 years) are shown in Table 3. The sizes of the groups, mean age, and sex ratio were similar. The penetrance of the disease was lower in the MYBPC3 subjects who were 30 years of age or younger (41% versus 62%), though not statistically different. In the MYBPC3 group, abnormal T waves were less frequent (9% versus 45%, P<0.02); mean MWT was lower (12.4±4 versus 16.3±7 mm, P<0.03), and left ventricular mass (Spirito-Maron index) was also lower (41.2±10 versus 51.7±17 mm, P<0.03) than in the ß-MHC group.

View larger version (38K): [in this window] [in a new window]   Figure 3. Penetrance (major abnormalities as assessed by echocardiography or ECG) and MWT (as assessed by echocardiography) in the MYBPC3 and ß-MHC groups according to two age-groups (before and after 30 years of age). Univariate comparisons performed within genes indicated that differences between age groups were significant only within the MYBPC3 group. Between the two genes and before 30 years of age, MWT was significantly lower in the MYBPC3 group than in the ß-MHC group (P<0.03).

View this table: [in this window] [in a new window]   Table 3. Clinical Features in the MYBPC3 and Beta-MHC Groups Before 30 Years of Age

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
This study is the first extensive report of the detailed phenotypes associated with mutations in the MYBPC3 gene. Little variability was observed in the phenotypes for FHC with respect to the mutations involved (intragene comparison), and no statistical difference was found for the 36 parameters analyzed. By contrast, comparison of the families carrying the MYBPC3 gene with those carrying the ß-MHC gene revealed three major differences. First, the phenotype was milder before 30 years of age in the MYBPC3 group, with low penetrance of the disease, lower MWT and left ventricular mass index on echocardiography, and a lower frequency of abnormal T waves on the ECG. Second, the age at onset of symptoms was significantly delayed in the MYBPC3 group (difference for median age, 19 years). Third, the prognosis associated with the MYBPC3 gene was good before 40 years of age, because no disease-related deaths or cardiac transplantations occurred before this time. Moreover, Kaplan-Meier survival curves indicated a better prognosis in the MYBPC3 group than in the ß-MHC group, even when cardiac transplantations were not considered events but were censored at the time of the transplantation. Only three other families with a mutation in the MYBPC3 gene are described in the literature,^{8 28} and very few data are available on their phenotype. No sudden death occurred in one family,⁸ one such death occurred at 44 years of age in a second family,⁸ and three deaths occurred at 50, 55, and 61 years in the third.²⁸

Our findings are therefore consistent with specific clinical features that appear to be related to the MYBPC3 gene: the phenotype is mild in young subjects, the age at onset of the symptoms is delayed, and prognosis is favorable before 40 years of age. Onset of the disease therefore appears "delayed" in FHC that is related to mutations in the MYBPC3 gene. The cause of these specific clinical features remains unclear, and experimental studies will be necessary to resolve this issue. However, it is interesting to note that most mutations found in the MYBPC3 gene disrupt the reading frame, resulting in stop codons that are expected to produce truncated proteins.¹⁷ In the ß-MHC gene, on the other hand, most of the mutations described are missense mutations, which result in a change of one amino acid of the protein.¹¹ Preliminary data indicate that these missense mutations could act as "poison polypeptides" through a dominant negative effect,²⁹ because they encode a stable protein that is incorporated into the sarcomere, which then interferes in vitro with thick filament assembly. In contrast, mutations in the MYBPC3 gene might act through another mechanism, such as "null" alleles (ie, a quantitative defect of the protein leading to imbalances in stoichiometry) or a third as-yet-undetermined mechanism,²⁸ resulting in less important phenotypic consequences. However, this hypothesis remains speculative, and structure-function analyses are necessary to elucidate the exact mechanisms.

Finally, our results on phenotype-genotype correlations in the MYBPC3 gene may have important clinical implications for FHC: (1) The finding that the onset of clinical disease is late in families carrying the MYBPC3 gene and occurs in middle-aged individuals is at variance with the generally accepted concept that the disease is clinically obvious after adolescence.³⁰ Caution should therefore be applied to the genetic counseling of apparently healthy, young individuals within an FHC family until genotyping is performed and the gene identified. (2) Because FHC families carrying the MYBPC3 gene are characterized by late onset of the disease and a relatively good prognosis, this gene could be frequently involved in hypertrophic cardiomyopathy without obvious autosomal dominant familial transmission, especially in middle-aged or elderly subjects who have an apparently sporadic form of the disease. The particular phenotype associated with the MYBPC3 gene might therefore lead to unrecognized cases of familial forms of hypertrophic cardiomyopathy. This is even more important because, in our experience, the MYBPC3 gene is frequently involved in and accounts for >30% of the FHC families analyzed. (3) Because of the relatively favorable prognosis associated with a mutation in the MYBPC3 gene, genetic testing and identification of a mutation in this gene in a young subject might suggest a low risk of premature death. This information could therefore be particularly useful in the risk stratification of patients and allow better clinical management and genetic counseling in FHC.

Study Limitations
Although our findings are based on a study of nine families, further studies of a larger number of families carrying the MYBPC3 gene will be required to confirm the mild phenotype described in the present investigation, especially because environmental factors or genetic modifier genes could potentially modulate expressivity of the disease. (However, age, sex, ethnic origin, and allele distribution of the insertion/deletion polymorphism in the ACE gene were not different in the two groups that we studied.) Indeed, caution is required, since some exceptions to the general phenotype-genotype correlations have been reported for the ß-MHC gene³¹ and the cardiac troponin T gene.³² This aspect is particularly important before this information can be broadly used as an additional tool in the risk stratification of patients with FHC.

	Selected Abbreviations and Acronyms

 

ß-MHC = ß-myosin heavy chain (gene) FHC = familial hypertrophic cardiomyopathy MWT = maximum wall thickness MYBPC3 = cardiac myosin-binding protein C (gene)

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Complete list of clinical features: disease penetrance in adults; presence of symptoms (at the time of study or in the past), such as syncope, dyspnea, chest pain, palpitations; systolic murmur; and elevated systolic or diastolic blood pressure; on the ECG, PR interval (ms), PR interval >200 ms in adults, left atrial enlargement,³³ atrial fibrillation (at the time of study or in the past), QRS axis, QRS axis <-30° in adults, QRS duration (ms), left ventricular hypertrophy assessed by a Romhilt-Estes score 4,²⁶ abnormal T waves, QT interval (ms), microvoltage assessed by a voltage <5 mV in each limb lead, and the presence of ECG major criteria (as defined in "Methods"); on echocardiography, MWT (mm), interventricular septal thickness (mm), interventricular septum/posterior wall ratio, Spirito-Maron index (mm), left ventricular diastolic diameter (mm), left ventricular systolic diameter (mm), left atrium diameter (mm), presence of systolic anterior motion of the mitral valve, midsystolic aortic closure, gradient >30 mm Hg, mitral valve regurgitation (2/4), E/A wave ratio, isovolumic relaxation time (ms), presence of the major echocardiographic diagnostic criterion (as defined in "Methods"), and the number of disease-related deaths and the age at which they occurred.

	Acknowledgments

 
This work was supported by INSERM (Reseau de recherche clinique No. 4R009B), the Association Française contre les Myopathies, the Fédération Française de Cardiologie, and the Délégation à la recherche clinique AP-HP (Crédits EMUL et IFR Physiopathologie et Génétique Cardio-vasculaire). We are indebted to the family members and their physicians, without whose participation this work could not have been done. We are grateful to Josué Feingold for fruitful discussions.

Received November 25, 1997; revision received January 23, 1998; accepted January 30, 1998.

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