EDITORIAL COMMENT
Are Longitudinal, Natural History Studies the Next Step in Genotype-Phenotype Translational Genomics in Hypertrophic Cardiomyopathy?*
Michael J. Ackerman, MD, PhD, FACC*,
Sara L. Van Driest, BA and
Martijn Bos, MD
Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics and the Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota.
* Reprint requests and correspondence: Dr. Michael J. Ackerman, Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, Rochester, Minnesota 55905. (Email: ackerman.michael{at}mayo.edu).
Over the past 15 years of translational genomics research, enormous strides have occurred in understanding the molecular underpinnings of hypertrophic cardiomyopathy (HCM). Clinical studies have shown that HCM is a common disease (affecting 1 in 500 persons) with a highly variable phenotype (1,2). Clinical outcomes are documented to range from an entirely asymptomatic course with normal longevity to chronic progressive heart failure or sudden cardiac death (SCD). Genetic studies have led to the understanding of HCM as principally a disease of the sarcomere or more specifically a disease of the cardiac myofilament. Currently, over 200 different HCM-associated mutations are scattered throughout 8 different myofilament encoding genes, including: 1) thick filament comprised of MYH7-encoded beta-myosin heavy chain, MYL2-encoded regulatory myosin light chain, and MYL3-encoded essential myosin light chain; 2) intermediate filament comprised of MYBPC3-encoded myosin binding protein C; and 3) thin filament comprised of TNNT2-encoded cardiac troponin T, TPM1-encoded alpha-tropomyosin, TNNI3-encoded cardiac troponin I, and ACTC-encoded actin (2–6). Recent studies have also implicated mutations in Z-disk components, like muscle LIM protein (CSRP3) (7) and telethonin (TCAP) (8) as well as glycogen storage diseases, such as AMP-activated protein kinase gamma 2 (PRKAG2) (9) and lysosome-associated membrane protein 2 (LAMP2) (9) in the pathogenesis of HCM. Numerous genotype-phenotype correlative studies have been reported, with conflicting and sometimes confusing conclusions (4–6,10–15). One shortfall of these previous studies lies in the fact that nearly all of the genotype-phenotype data gathered to date have provided a "snapshot view" of individual HCM patients with different causative mutations. There is a relative paucity of data correlating genotype to disease progression over time.
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Clinical course of a founder MYBPC3 mutation
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In this issue of the Journal, Kubo et al. (16) provide a concise and comprehensive longitudinal observation of the clinical manifestations of a founder effect mutation involving the MYBPC3-encoded cardiac myosin binding protein C, which is perhaps the most common genotype for myofilament-HCM (17). The V592fs/8 frameshift mutation was initially identified in 15 of 94 Japanese probands. Analysis for this specific mutation in family members of these 15 probands identified 24 additional V592fs/8-MYBPC3 genotype positive individuals. Thirty of the 39 genotype positive subjects had a demonstrable HCM phenotype based upon echocardiographic and/or electrocardiographic findings. Disease penetrance for the V592fs/8 mutation was 100% in patients over 50 years of age and 65% in patients younger than 50 years of age. Over a mean follow up period of 9.2 ± 5.5 years, seven patients were hospitalized for treatment of heart failure, three patients died of HCM-related causes, and one patient had an implantable cardioverter-defibrillator (ICD) discharge.
In contrast to some studies that described the course of MYBPC3-HCM as generally favorable (18–22), Kubo et al. (16) show that the course of patients with this particular MYBPC3 frameshift mutation often, although at an advanced age, leads to severe heart disease, which is supported by previous observations from our center (6). We found that 63 (16%) of 389 unrelated patients with HCM harbored a mutation in MYBPC3; a subset that was phenotypically indistinguishable from patients with thick filament-HCM (6). Notably, this Japanese founder mutation was not observed in our predominantly Caucasian cohort of HCM subjects.
One key aspect not addressed by this communication is that other common and intriguing characteristics of MYBPC3 may be contributing to the progression of disease in Japanese patients. Besides being the most common HCM-associated gene, MYBPC3 has also been implicated as the most common gene to harbor mutations leading to protein truncation (frameshift or nonsense mutation) (6). These mutations have been associated with a more severe disease phenotype than those hosting missense mutations in MYBPC3 (15,23). In addition, an estimated 5% to 10% of patients with myofilament-HCM possess two distinct HCM-associated mutations, with MYBPC3 being the most likely myofilament gene to host one or both concomitant sarcomeric mutations (compound heterozygosity). Such patients with multiple sarcomeric/myofilament mutations have been reported to be diagnosed at a younger age and to have more severe hypertrophy (6). Either of these factors could contribute to the malignant course seen in the patients described in the present study by Kubo et al. (16).
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Future directions
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The methodology used by Kubo et al. (16) does open a new door in HCM genotype-phenotype research. The longitudinal study of a relatively large group of patients with an identical HCM-susceptibility mutation provides an opportunity to explore the possibility that different mutations may predispose to very different natural histories. Additionally, Kubo et al. (16) are in the unique position to use their finding of a founder mutation among several unrelated families to explore the effect of polymorphisms or disease modifiers on the severity of the disease, as previously demonstrated by Ortlepp et al. (24) in a single family with MYBPC3-HCM.
However, the results, as reflected accurately by Kubo et al. (16) in their study limitations, do not shed light on several other important issues. For example, what is the cellular function of myosin-binding protein C? Why is MYBPC3 in comparison with other HCM-associated genes more susceptible to micro-insertions and deletions resulting in premature truncations of this intermediate myofilament? Do the patients with worse outcomes harbor additional HCM-associated mutations? To what degree did lifestyle and environment contribute to disease outcome? Although this longitudinal study is an important step to take, research in this avenue alone will not fulfill the ultimate goal of understanding the crucial question, "Why do these patients die?" Indeed, the answer to this question will come when data converge from several research fronts.
From the arena of HCM genomics, headway must be made in defining the full spectrum of HCM-causing and HCM-modifying genetic variants. Without this data, we cannot ascertain the full genetic context of any individual patient with HCM. From clinical studies, we must determine the environmental and physiologic factors that play a role in disease progression. Hypertension, smoking, and alcohol use are obvious candidates for environmental triggers for disease progression, but in many studies these variables are either not assessed, or patients with these risk factors are excluded from study. From the basic science laboratories, a better understanding of the downstream effects, common final pathways, and post-translational events occurring in the cardiac myocytes with HCM-causing genetic mutations must be established. In addition, the cellular function(s) of both the MYBPC3-encoded intermediate myofilament and other HCM-associated proteins must be elucidated.
As the foundation of HCM genomics is built upon with further genetic, clinical, and basic science insights, we can strive for critical insights that may one day lead toward the effective prediction, treatment, and perhaps even the prevention of this disease. Kubo et al. (16) should be commended for providing an important stepping stone to pave the way toward achieving these lofty goals.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4,111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults Circulation 1995;92:785-789.[Abstract/Free Full Text]
2. Maron BJ. Hypertrophic cardiomyopathya systematic review. JAMA 2002;287:1308-1320.[Abstract/Free Full Text]
3. Seidman JG, Seidman C. The genetic basis for cardiomyopathyfrom mutation identification to mechanistic paradigms. Cell 2001;104:557-567.[CrossRef][Web of Science][Medline]
4. Van Driest SL, Ellsworth EG, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ. Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy Circulation 2003;108:445-451.[Abstract/Free Full Text]
5. Van Driest SL, Jaeger MA, Ommen SR, et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy J Am Coll Cardiol 2004;44:602-610.[Abstract/Free Full Text]
6. Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy J Am Coll Cardiol 2004;44:1903-1910.[Abstract/Free Full Text]
7. Geier C, Perrot A, Ozcelik C, et al. Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy Circulation 2003;107:1390-1395.[Abstract/Free Full Text]
8. Hayashi T, Arimura T, Itoh-Satoh M, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy J Am Coll Cardiol 2004;44:2192-2201.[Abstract/Free Full Text]
9. Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy N Engl J Med 2005;352:362-372.[Abstract/Free Full Text]
10. Ackerman MJ, Van Driest SV, Ommen SR, et al. Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T gene in hypertrophic cardiomyopathya comprehensive outpatient perspective. J Am Coll Cardiol 2002;39:2042-2048.[Abstract/Free Full Text]
11. Jaaskelainen P, Kuusisto J, Miettinen R, et al. Mutations in the cardiac myosin-binding protein C gene are the predominant cause of familial hypertrophic cardiomyopathy in eastern Finland J Mol Med 2002;80:412-422.[CrossRef][Web of Science][Medline]
12. Jaaskelainen P, Soranta M, Miettinen R, et al. The cardiac beta-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population J Am Coll Cardiol 1998;32:1709-1716.[Abstract/Free Full Text]
13. Van Driest SV, Ackerman MJ, Ommen SR, et al. Prevalence and severity of "benign" mutations in the beta myosin heavy chain, cardiac troponin-T, and alpha tropomyosin genes in hypertrophic cardiomyopathy Circulation 2002;106:3085-3090.[Abstract/Free Full Text]
14. Morner S, Richard P, Kazzam E, et al. Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden J Mol Cell Cardiol 2003;35:841-849.[CrossRef][Web of Science][Medline]
15. Erdmann J, Daehmlow S, Wischke S, et al. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy Clin Genet 2003;64:339-349.[CrossRef][Web of Science][Medline]
16. Kubo T, Kitaoka H, Okawa M, 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 2005;46:1737–43..
17. Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ. Sarcomeric genotyping in hypertrophic cardiomyopathy Mayo Clin Proc 2005;80:463-469.[Abstract/Free Full Text]
18. Fay WP, Taliercio CP, Ilstrup DM, Tajik AJ, Gersh BJ. Natural history of hypertrophic cardiomyopathy in the elderly J Am Coll Cardiol 1990;16:821-826.[Abstract]
19. Alders M, Jongbloed R, Deelen W, 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 2003;24:1848-1853.[Abstract/Free Full Text]
20. Charron P, Dubourg O, Desnos M, et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene(comment) Circulation 1998;97:2230-2236.[Abstract/Free Full Text]
21. Konno T, Shimizu M, Ino H, 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 2003;41:781-786.[Abstract/Free Full Text]
22. Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy(comment) N Engl J Med 1998;338:1248-1257.[Abstract/Free Full Text]
23. Erdmann J, Raible J, Maki-Abadi J, et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy J Am Coll Cardiol 2001;38:322-330.[Abstract/Free Full Text]
24. Ortlepp JR, Vosberg HP, Reith S, et al. Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathya study of five polymorphic genes in a family with a disease causing mutation in the myosin binding protein C gene. Heart 2002;87:270-275.[Abstract/Free Full Text]
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