Genetics of cardiomyopathies in children
AbstractCardiomyopathies are diseases of the heart muscle leading to heart failure and/or an increased risk of arrhythmogenic sudden cardiac death. These disorders represent a major cause of morbidity and mortality in children. In childhood forms of cardiomyopathy, genetic etiologies are frequent, but non-genetic or acquired causes, such viral infection, also play a significant role. In the last twenty years, the genetic causes of cardiomyopathies have been increasingly identified and clinical correlations are beginning to be defined. Here we present an overview of the recent advances in our understanding of the genetics of cardiomyopathies in children and what is known about the pathophysiological mechanisms underlying these gene-related forms of disease.
Heron M, Sutton PD, Xu J, et al. Annual summary of vital statistics: 2007. Pediatrics 2010;125:4-15.
Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of pediatric cardiomyopathy in two regions of the United States. N Engl J Med 2003;348:1647–55.
Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807-16.
Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270-6.
Hsu DT, Canter CE. Dilated cardiomyopathy and heart failure in children. Heart Fail Clin 2010;6:415-32.
Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006;296:1867-76.
Ghosh N, Haddad H. Recent progress in the genetics of cardiomyopathy and its role in the clinical evaluation of patients with cardiomyopathy. Curr Opin Cardiol 2011;26:155-64.
Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol 1999;34:181-90.
Towbin JA, Hejtmancik JF, Brink P, et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 1993;87:1854-65.
Towbin, JA. The role of cytoskeletal proteins in cardiomyopathies. Curr Opin Cell Biol 1998;10:131-9.
McBride KL, Garg V. Impact of Mendelian inheritance in cardiovascular disease. Ann N Y Acad Sci 2010;1214:122-37.
Hermans MC, Pinto YM, Merkies IS, et al. Hereditary muscular dystrophies and the heart. Neuromuscul Disord 2010;20:479-92.
Finsterer J, Ramaciotti C, Wang CH, et al. Cardiac findings in congenital muscular dystrophies. Pediatrics 2010;126:538-45.
Cheng J, Morales A, Siegfried JD, et al. SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del. Clin Transl Sci 2010;3:287-94.
Li Z, Ai T, Samani K, et al. A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy. Circ Arrhythm Electrophysiol 2010;3:646-56.
Norton N, Li D, Rieder MJ, et al. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet 2011;88:273-82.
Villard E, Perret C, Gary F, et al. A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy. Eur Heart J 2011;32:1065-76.
Kaski JP, Syrris P, Esteban MT, et al. Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2009;2:436-41.
Schwartz ML, Cox GF, Lin AE, et al. Clinical approach to genetic cardiomyopathy in children. Circulation 1996;94:2021-38.
Morita H, Rehm HL, Menesses A, et al. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 2008;358:1899-908.
Frisso G, Limongelli G, Pacileo G, et al. A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy. Clin Genet 2009;76:91-101.
Towbin JA. Desmosomal gene variants in patients with “possible ARVC”. Heart Rhythm 2011;8:719-20.
Sequeira IB, Kirsh JA, Hamilton RM, et al. Utility of exercise testing in children and teenagers with arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol 2009;104:411-3.
Xu T, Yang Z, Vatta M, et al. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2010;55:587-97.
Vatta M, Marcus FI, Towbin JA. Arrhythmogenic right ventricular cardiomyopathy: a “final common pathway” that defines clinical phenotype. Eur Heart J 2007;28:529-30.
Corrado D, Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: clinical impact of molecular genetic studies. Circulation 2006;113:1634-7.
Azaouagh A, Churzidse S, Konorza T, Erbel R. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a review and update. Clin Res Cardiol 2011;100:383-94.
Gehmlich K, Lambiase PD, Asimaki A, et al. A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions. Heart Rhythm 2011;8:711-8.
Sasano C, Honjo H, Takagishi Y, et al. Internalization and dephosphorylation of connexin43 in hypertrophied right ventricles of rats with pulmonary hypertension. Circ J 2007;71:382-9.
Richards CS, Bale S, Bellissimo DB, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10:294-300.
Weisz SH, Limongelli G, Pacileo G, et al. Left ventricular non compaction in children. Congenit Heart Dis 2010;5:384-97.
Ritter M, Oechslin E, Sütsch G, et al. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997;72:26-31.
Towbin JA. Left ventricular noncompaction: a new form of heart failure. Heart Fail Clin 2010;6:453-69.
Kwiatkowski D, Hagenbuch S, Meyer R. A teenager with Marfan syndrome and left ventricular noncompaction. Pediatr Cardiol 2010;31:132-5.
Martinez HR, Belmont JW, Craigen WJ, et al. Left ventricular noncompaction in Sotos syndrome. Am J Med Genet A 2011;155:1115-8.
McMahon CJ, Chang AC, Pignatelli RH, et al. Left ventricular noncompaction cardiomyopathy in association with trisomy 13. Pediatr Cardiol 2005;26:477-9.
Dod HS, Bhardwaj R, Hummel M, et al. Left ventricular noncompaction: a rare disorder in adults and its association with 1p36 chromosomal anomaly. Am J Med Genet A 2010;152A:191-5.
Gajecka M, Saitta SC, Gentles AJ, et al. Recurrent interstitial 1p36 deletions: Evidence for germline mosaicism and complex rearrangement breakpoints. Am J Med Genet A 2010;152A:3074-83.
Vatta M, Mohapatra B, Jimenez S, et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol 2003;42:2014-27.
Faulkner G, Pallavicini A, Formentin E, et al. ZASP: a new Z-band alternatively spliced PDZ-motif protein. J Cell Biol 1999;146:465-75.
Denfield SW, Webber SA. Restrictive cardiomyopathy in childhood. Heart Fail Clin 2010;6:445-52.
Lewis AB. Clinical profile and outcome of restrictive cardiomyopathy in children. Am Heart J 1992;123:1589-93.
Denfield SW, Rosenthal G, Gajarski RJ, et al. Restrictive cardiomyopathies in childhood: Etiologies and natural history. Tex Heart Inst J 1997;24:38-44.
Cetta F, O’Leary PW, Seward JB, Driscoll DJ. Idiopathic restrictive cardiomyopathy in childhood: diagnostic features and clinical course. Mayo Clin Proc 1995;70:634-40.
Russo LM, Webber SA. Idiopathic restrictive cardiomyopathy in children. Heart 2005;91:1199-202.
Rivenes SM, Kearney DL, Smith EO, et al. Sudden death and cardiovascular collapse in children with restrictive cardiomyopathy. Circulation 2000;102:876-82.
Fitzpatrick AP, Shapiro LM, Rickards AF, Poole-Wilson PA. Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy. Br Heart J 1990;63:114-8.
Denfield SW. Sudden death in children with restrictive cardiomyopathy. Card Electrophysiol Rev 2002;6:163-7.
Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr 2009;10:iii23-33.
Chen SC, Balfour IC, Jureidini S. Clinical spectrum of restrictive cardiomyopathy in children. J Heart Lung Transplant 2001;20:90-2.
Neudorf U, Bolte A, Lang D, et al. Diagnostic findings and outcome in children with primary restrictive cardiomyopathy. Cardiol Young 1996;6:44-7.
Nugent AW, Daubeney PE, Chondros P, et al. The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 2003;348:1639-46.
Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of restrictive cardiomyopathy. Heart Fail Clin 2010;6:179-86.
Weller RJ, Weintraub R, Addonizio LJ, et al. Outcome of idiopathic restrictive cardiomyopathy in children. Am J Cardiol 2002;90:501-6.
Chatterjee K. Diastolic ventricular failure: A clinician’s approach. ACC Curr J Rev 1995;4:50-2.
Wang RY, Bodamer OA, Watson MS, et al. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med 2011;13:457-84.
Yang Z, Vatta M. Danon disease as a cause of autophagic vacuolar myopathy. Congenit Heart Dis 2007;2:404-9.
Taylor MR, Ku L, Slavov D, et al. Danon disease presenting with dilated cardiomyopathy and a complex phenotype. J Hum Genet 2007;52:830-5.
Ren J, Pulakat L, Whaley-Connell A, Sowers JR. Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med (Berl) 2010;88:993-1001.
Holmgren D, Wåhlander H, Eriksson BO, et al. Cardiomyopathy in children with mitochondrial disease; clinical course and cardiological findings. Eur Heart J 2003; 24:280-8.
Capetanaki Y, Bloch RJ, Kouloumenta A, et al. Muscle intermediate filaments and their links to membranes and membranous organelles. Exp Cell Res 2007; 313:2063-76.
Tang S, Batra A, Zhang Y, et al. Left ventricular noncompaction is associated with mutations in the mitochondrial genome. Mitochondrion 2010;10:350-7.
Sibbing D, Pfeufer A, Perisic T, et al. Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. Eur Heart J 2011;32:1121-33.
Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci 2008;1142:133-58.
- Abstract views: 1433
- PDF: 1527
Copyright (c) 2011 Matteo Vatta, Jeffrey A. Towbin
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.