Genetic testing for hypertrophic cardiomyopathy: ongoing voyage from exploration to clinical exploitation
AbstractMore than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed and expanded, and is now widely available as a potential clinical service in the Western countries. In the meantime, however, the cross-talk between geneticists and clinicians has developed slowly, and still remains unstandardized, with modalities of interaction and degree of mutual comprehension that vary wildly in various settings. In addition, clinicians often question the clinical utility of genetic testing in HCM patients and their families. The apparent lack of practical benefit, in the face of considerable costs, has long hindered large-scale diffusion of genetic testing, particularly in developing countries, and still accounts for understandable (but not always justifiable) resistance on the part of the physicians. However, such resistance is in contrast with considerable evidence supporting a role for molecular diagnosis in tailoring management for HCM patients. We here review several sound clinical reasons in favour of systematic genetic testing in HCM, ranging from identification of complex genotypes, heralding severe disease expression and outcome, to the added benefit of multidisciplinary genetic teamwork, enhancing awareness towards inheritable diseases in the cardiology community. We hope to show that to underestimate the clinical potential of genetic testing in HCM, and to defer its implementation until more advanced knowledge becomes available, is to lose an important opportunity for present improvement in care.
Watkins H, Ashrafian H, Redwood C. Inherited Cardiomyopathies. N Engl J Med 2011; 364:1643-56.
Ho CY. Genetics and clinical destiny: improving care in hypertrophic cardiomyopathy. Circulation 2010;122:2430-40.
Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005;352:362-72.
Ahmad F, Arad M, Musi N, et al. Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation2005;112:3140-8.
Wheeler M, Pavlovic A, DeGoma E, et al. A new era in clinical genetic testing for hypertrophic cardiomyopathy. Cardiovasc Transl Res 2009;2:381-91.
Girolami F, Olivotto I, Passerini I, et al. A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy. J Cardiovasc Med (Hagerstown) 2006;7:601-7.
Charron P, Arad M, Arbustini E, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2010;31:2715-26.
Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ Res 2011;108:743-50.
Maron BJ, Yeates L, Semsarian C. Clinical challenges of genotype positive (+)-phenotype negative (-) family members in hypertrophic cardiomyopathy. Am J Cardiol 2011;107:604-8.
Nagueh SF, Bierig SM, Budoff MJ, et al. American Society of Echocardiography clinical recommendations for multimodality
cardiovascular imaging of patients with hypertrophic cardiomyopathy: Endorsed by the American Society of Nuclear
Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography. J Am Soc Echocardiogr 2011;24:473-98.
Maron MS, Maron BJ, Harrigan C, et al. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:220-8.
Vermes E, Strohm O, Otmani A, et al. Impact of the revision of arrhythmogenic right ventricular cardiomyopathy/dysplasia task force criteria on its prevalence by CMR criteria. JACC Cardiovasc Imaging
Olivotto I, Girolami F, Nistri S, et al. The many faces of hypertrophic cardiomyopathy: from developmental biology to clinical
practice. J Cardiovasc Transl Res 2009;2:349-67.
Ho CY, López B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010;363:552-63.
Maron MS, Olivotto I, Harrigan C, et al. Mitral Valve Abnormalities Identified by Cardiovascular Magnetic Resonance Represent a Primary Phenotypic Expression of Hypertrophic Cardiomyopathy. Circulation 2011 Jun 13. [Epub ahead of print]
Senthil V, Chen SN, Tsybouleva N, et al. Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ Res 2005;97:285-92.
Borry P, Evers-Kiebooms G, Cornel MC, et al. Genetic testing in asymptomatic minors: background considerations towards ESHG Recommendations. Eur J Hum genet 2009;17:711-9.
Wang L, Seidman JG, Seidman CE. Narrative review: harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann Intern Med 2010;152:513-20.
Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America
practice guideline. J Card Fail 2009;15:83-97.
Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 2008;83:630-8.
Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozigosity in hypertrophic
cardiomyopathy. J Am Coll Cardiol 2004; 44:1903-10.
Ingles J, Doolan A, Chiu C, et al. Compound and double mutations in patient with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet 2005;42:e59.
Kelly M, Semsarian C. Multiple mutations in genetic cardiovascular disease; a marker of disease severity. Circ Cardiovasc
Girolami F, Ho CY, Semsarian C, et al. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol 2010;55:1444-53.
Belus A, Piroddi N, Scellini B, et al. The familial hypertrophic cardiomyopathy associated myosin mutation R403Q accelerates tension generation and relaxation of human cardiac myofibrils. J Physiol 2008;586;3639-44.
Olivotto I, Girolami F, Sciagrà R, et al. Microvascular function is selectively impaired in hypertrophic cardiomyopathy patients with sarcomere myofilament gene mutations. Medicine 2010 [Epub ahead of print].
Charron P, Héron D, Gargiulo M, et al. Prenatal molecular diagnosis in hypertrophic cardiomyopathy: report of the first case. Prenat Diagn 2004;24:701-3.
van Langen IM, Birnie E, Leschot NJ, et al. Genetic knowledge and counselling skills of Dutch cardiologists: sufficient for the genomics era? Eur Heart J 2003;24:560-6.
Christiaans I, van Langen IM, Birnie E, etal. Genetic counseling and cardiac care in predictively tested hypertrophic cardiomyopathy
mutation carriers: the patients' perspective. Am J Med Genet A 2009;149A:1444-51.
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