Impact of Mendelian inheritance in cardiovascular disease
Kim L. McBride,
Vidu Garg,
Kim L. McBride
Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
Center for Molecular and Human Genetics, Research Institute at Nationwide Children's Hospital
Search for more papers by this authorVidu Garg
Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
The Heart Center and Center for Cardiovascular and Pulmonary Research, Research Institute at Nationwide Children's Hospital, Columbus, Ohio
Search for more papers by this author
Kim L. McBride,
Vidu Garg,
Kim L. McBride
Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
Center for Molecular and Human Genetics, Research Institute at Nationwide Children's Hospital
Search for more papers by this authorVidu Garg
Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
The Heart Center and Center for Cardiovascular and Pulmonary Research, Research Institute at Nationwide Children's Hospital, Columbus, Ohio
Search for more papers by this author
Addresses for correspondence: Vidu Garg, M.D., The Heart Center and Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, 700 Children's Drive W302, Columbus, OH 43205. [email protected]; and Kim L. McBride, M.D., Center for Molecular and Human Genetics, Research Institute at Nationwide Children's Hospital, 700 Children's Drive W410, Columbus, OH 43205. [email protected]
Abstract
Cardiovascular disease is a leading cause of mortality worldwide. While the etiology for the majority of cardiovascular disease is presumed to be a combination of genetic and environmental factors, developments in understanding the basic biology of cardiac disorders have been greatly advanced through discoveries made studying heart diseases that exhibit Mendelian forms of inheritance. Most of these diseases primarily affect children and young adults and include cardiomyopathies, arrhythmias, aortic aneurysms, and congenital heart defects. The discovery of the genetic etiologies for these diseases have had significant impact on our understanding of more complex forms of cardiovascular disease and in some cases have led to novel diagnostic and treatment modalities. In this review, we will summarize these seminal genetic discoveries, highlighting a few that have resulted in significant impact on human disease, and discuss the potential utility of studying Mendelian-inherited heart disease with the development of new genetic technologies and our increased understanding of the human genome.
References
- 1 Heron, M. et al . 2010. Annual summary of vital statistics: 2007. Pediatrics 125: 4–15.
- 2 Lloyd-Jones, D. et al . 2010. Executive summary: heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation 121: 948–954.
- 3 Gaziano, T.A. et al . 2010. Growing epidemic of coronary heart disease in low- and middle-income countries. Curr. Probl. Cardiol. 35: 72–115.
- 4 Centers for Disease Control and Prevention. 2007. Hospital stays, hospital charges, and in-hospital deaths among infants with selected birth defects–United States, 2003. MMWR Morb. Mortal. Wkly. Rep. 56: 25–29.
- 5 Marelli, A.J. et al . 2007. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation 115: 163–172.
- 6 Pillutla, P., K.D. Shetty & E. Foster. 2009. Mortality associated with adult congenital heart disease: trends in the US population from 1979 to 2005. Am. Heart J. 158: 874–879.
- 7 Arking, D.E. & A. Chakravarti. 2009. Understanding cardiovascular disease through the lens of genome-wide association studies. Trends Genet. 25: 387–394.
- 8 Maron, B.J. et al . 2003. 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. 42: 1687–1713.
- 9 Maron, B.J. et al . 1995. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 92: 785–789.
- 10 Maron, B.J. et al . 2009. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation 119: 1085–1092.
- 11 Teare, D. 1958. Asymmetrical hypertrophy of the heart in young adults. Br. Heart J. 20: 1–8.
- 12 Geisterfer-Lowrance, A.A. et al . 1990. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 62: 999–1006.
- 13 Bowles, N.E., K.R. Bowles & J.A. Towbin. 2000. The “final common pathway” hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins in dilated cardiomyopathy. Herz 25: 168–175.
- 14 Morita, H. et al . 2008. Shared genetic causes of cardiac hypertrophy in children and adults. N. Engl. J. Med. 358: 1899–1908.
- 15 Saltzman, A.J. et al . 2010. Short communication: the cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy. Circ. Res. 106: 1549–1552.
- 16 Bos, J.M., J.A. Towbin & M.J. Ackerman. 2009. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 54: 201–211.
- 17 Niimura, H. et al . 2002. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 105: 446–451.
- 18 Watkins, H. et al . 1992. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N. Engl. J. Med. 326: 1108–1114.
- 19 Ackerman, M.J. et al . 2002. Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective. J. Am. Coll. Cardiol. 39: 2042–2048.
- 20 Moolman, J.C. et al . 1997. Sudden death due to troponin T mutations. J. Am. Coll. Cardiol. 29: 549–555.
- 21 Varnava, A.M. et al . 2001. Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. Circulation 104: 1380–1384.
- 22 Watkins, H. et al . 1995. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N. Engl. J. Med. 332: 1058–1064.
- 23 Olivotto, I. et al . 2008. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin. Proc. 83: 630–638.
- 24 Ingles, J. et al . 2005. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J. Med. Genet. 42: e59.
- 25 Girolami, F. et al . 2010. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J. Am. Coll. Cardiol. 55: 1444–1453.
- 26 Richard, P. et al . 2003. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 107: 2227–2232.
- 27 Van Driest, S.L. et al . 2004. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 44: 1903–1910.
- 28 Fitzgerald-Butt, S.M. et al . 2009. Parental knowledge and attitudes toward hypertrophic cardiomyopathy genetic testing. Pediatr. Cardiol. 31: 195–202.
- 29 Christiaans, I. et al . 2009. Quality of life and psychological distress in hypertrophic cardiomyopathy mutation carriers: a cross-sectional cohort study. Am. J. Med. Genet. A. 149A: 602–612.
- 30 Ingles, J. et al . 2008. Psychosocial impact of specialized cardiac genetic clinics for hypertrophic cardiomyopathy. Genet. Med. 10: 117–120.
- 31 Mestroni, L. et al . 1999. Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur. Heart J. 20: 93–102.
- 32 Jefferies, J.L. & J.A. Towbin. 2010. Dilated cardiomyopathy. Lancet 375: 752–762.
- 33 Codd, M.B. et al . 1989. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation 80: 564–572.
- 34 Towbin, J.A. et al . 2006. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 296: 1867–1876.
- 35 Burkett, E.L. & R.E. Hershberger. 2005. Clinical and genetic issues in familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 45: 969–981.
- 36 Michels, V.V. et al . 1992. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N. Engl. J. Med. 326: 77–82.
- 37 Baig, M.K. et al . 1998. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J. Am. Coll. Cardiol. 31: 195–201.
- 38 Grunig, E. et al . 1998. Frequency and phenotypes of familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 31: 186–194.
- 39 Keeling, P.J. et al . 1995. Familial dilated cardiomyopathy in the United Kingdom. Br. Heart J. 73: 417–421.
- 40 Morales, A. et al . 2010. Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy. Circulation 121: 2176–2182.
- 41 van Spaendonck-Zwarts, K.Y. et al . 2010. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 121: 2169–2175.
- 42 Towbin, J.A. & N.E. Bowles. 2002. The failing heart. Nature 415: 227–233.
- 43 Hershberger, R.E. et al . 2008. Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin. Transl. Sci. 1: 21–26.
- 44 Parks, S.B. et al . 2008. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am. Heart J. 156: 161–169.
- 45 Kamisago, M. et al . 2000. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N. Engl. J. Med. 343: 1688–1696.
- 46 van Tintelen, J.P. et al . 2007. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am. Heart J. 154: 1130–1139.
- 47 Maron, B.J. et al . 2006. 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 113: 1807–1816.
- 48 Basso, C. et al . 2009. Arrhythmogenic right ventricular cardiomyopathy. Lancet 373: 1289–1300.
- 49 Scaglia, F. et al . 2004. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 114: 925–931.
- 50 Wilcken, D.E. 2003. Overview of inherited metabolic disorders causing cardiovascular disease. J. Inherit. Metab. Dis. 26: 245–257.
- 51 Finsterer, J. & C. Stollberger. 2008. Primary myopathies and the heart. Scand. Cardiovasc. J. 42: 9–24.
- 52 Beaudet, A.L. & J.W. Belmont. 2008. Array-based DNA diagnostics: let the revolution begin. Annu. Rev. Med. 59: 113–129.
- 53 Fokstuen, S. et al . 2008. A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. Hum. Mutat. 29: 879–885.
- 54 Waldmuller, S. et al . 2008. Array-based resequencing assay for mutations causing hypertrophic cardiomyopathy. Clin. Chem. 54: 682–687.
- 55 Zimmerman, R.S. et al . 2010. A novel custom resequencing array for dilated cardiomyopathy. Genet. Med. 12: 268–278.
- 56 Lupski, J.R. et al . 2010. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N. Engl. J. Med. 362: 1181–1191.
- 57 Okou, D.T. et al . 2007. Microarray-based genomic selection for high-throughput resequencing. Nat. Methods 4: 907–909.
- 58 Albert, T.J. et al . 2007. Direct selection of human genomic loci by microarray hybridization. Nat. Methods 4: 903–905.
- 59 Gnirke, A. et al . 2009. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat. Biotechnol. 27: 182–189.
- 60 Elefteriades, J.A. & E.A. Farkas. 2010. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J. Am. Coll. Cardiol. 55: 841–857.
- 61 Clouse, W.D. et al . 2004. Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture. Mayo Clin. Proc. 79: 176–180.
- 62 Keane, M.G. & R.E. Pyeritz. 2008. Medical management of Marfan syndrome. Circulation 117: 2802–2813.
- 63 De Paepe, A. et al. 1996. Revised diagnostic criteria for the Marfan syndrome. Am J. Med. Genet. 62: 417–426.
10.1002/(SICI)1096-8628(19960424)62:4<417::AID-AJMG15>3.0.CO;2-R CASPubMedWeb of Science®Google Scholar
- 64 Dietz, H.C. et al . 1991. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352: 337–339.
- 65 Maslen, C.L. et al . 1991. Partial sequence of a candidate gene for the Marfan syndrome. Nature 352: 334–337.
- 66 Lee, B. et al . 1991. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 352: 330–334.
- 67 Stheneur, C. et al . 2009. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur. J. Hum. Genet. 17: 1121–1128.
- 68 Faivre, L. et al . 2007. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am. J. Hum. Genet. 81: 454–466.
- 69 Neptune, E.R. et al . 2003. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33: 407–411.
- 70 Loeys, B.L. et al . 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37: 275–281.
- 71 Loeys, B.L. et al . 2006. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N. Engl. J. Med. 355: 788–798.
- 72 Callewaert, B. et al . 2008. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract. Res. Clin. Rheumatol. 22: 165–189.
- 73 McDonnell, N.B. et al . 2006. Echocardiographic findings in classical and hypermobile Ehlers-Danlos syndromes. Am. J. Med. Genet. A. 140: 129–136.
- 74 Wenstrup, R.J. et al . 2002. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet. Med. 4: 112–117.
- 75 Nicod, P. et al . 1989. Familial aortic dissecting aneurysm. J. Am. Coll. Cardiol. 13: 811–819.
- 76 Biddinger, A. et al . 1997. Familial thoracic aortic dilatations and dissections: a case control study. J. Vasc. Surg. 25: 506–511.
- 77 Coady, M.A. et al . 1999. Familial patterns of thoracic aortic aneurysms. Arch. Surg. 134: 361–367.
- 78 Milewicz, D.M. et al . 1998. Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections. Am. J. Cardiol. 82: 474–479.
- 79 Albornoz, G. et al . 2006. Familial thoracic aortic aneurysms and dissections–incidence, modes of inheritance, and phenotypic patterns. Ann. Thorac. Surg. 82: 1400–1405.
- 80 Davies, R.R. et al . 2007. Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve. Ann. Thorac. Surg. 83: 1338–1344.
- 81 Keane, M.G. et al . 2000. Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions. Circulation 102: III35–III39.
- 82 Biner, S. et al . 2009. Aortopathy is prevalent in relatives of bicuspid aortic valve patients. J. Am. Coll. Cardiol. 53: 2288–2295.
- 83 Jiang, X. et al . 2000. Fate of the mammalian cardiac neural crest. Development 127: 1607–1616.
- 84 Tran-Fadulu, V. et al . 2009. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J. Med. Genet. 46: 607–613.
- 85 Guo, D.C. et al . 2007. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat. Genet. 39: 1488–1493.
- 86 Pannu, H. et al . 2005. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 112: 513–520.
- 87 Zhu, L. et al . 2006. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat. Genet. 38: 343–349.
- 88 McKellar, S.H. et al . 2007. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J. Thorac. Cardiovasc. Surg. 134: 290–296.
- 89 Guo, D.C. et al . 2009. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am. J. Hum. Genet. 84: 617–627.
- 90 Habashi, J.P. et al . 2006. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312: 117–121.
- 91 Brooke, B.S. et al . 2008. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N. Engl. J. Med. 358: 2787–2795.
- 92 Gambarin, F.I. et al . 2009. Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations. J. Cardiovasc. Med. (Hagerstown) 10: 354–362.
- 93 Lacro, R.V. et al . 2007. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am. Heart J. 154: 624–631.
- 94 Radonic, T. et al . 2010. Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial. Trials 11: 3.
- 95 Keating, M.T. & M.C. Sanguinetti. 2001. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104: 569–580.
- 96 Schwartz, P.J. et al . 1993. Diagnostic criteria for the long QT syndrome. An update. Circulation 88: 782–784.
- 97 Crotti, L. et al . 2008. Congenital long QT syndrome. Orphanet. J. Rare Dis. 3: 18.
- 98 Goldenberg, I., W. Zareba & A.J. Moss. 2008. Long QT syndrome. Curr. Probl. Cardiol. 33: 629–694.
- 99 Romano, C., G. Gemme & R. Pongiglione. 1963. Rare cardiac arrythmias of the pediatric age. II. Syncopal attacks due to paroxysmal ventricular fibrillation. (Presentation of 1st case in Italian Pediatric Literature). Clin. Pediatr. (Bologna) 45: 656–683.
- 100 Ward, O.C. 1964. A new familial cardiac syndrome in children. J. Ir. Med. Assoc. 54: 103–106.
- 101 Jervell, A. & F. Lange-Nielsen. 1957. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am. Heart J. 54: 59–68.
- 102 Tawil, R. et al . 1994. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann. Neurol. 35: 326–330.
- 103 Tristani-Firouzi, M. et al . 2002. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J. Clin. Invest. 110: 381–388.
- 104 Splawski, I. et al . 2004. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119: 19–31.
- 105 Wang, Q. et al . 1995. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80: 805–811.
- 106 Curran, M.E. et al . 1995. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80: 795–803.
- 107 Hedley, P.L. et al . 2009. The genetic basis of long QT and short QT syndromes: a mutation update. Hum. Mutat. 30: 1486–1511.
- 108 Lehnart, S.E. et al . 2007. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation 116: 2325–2345.
- 109 Schwartz, P.J. et al . 2001. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 103: 89–95.
- 110 Moss, A.J. et al . 1995. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 92: 2929–2934.
- 111 Moss, A.J. et al . 2000. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 101: 616–623.
- 112 Antzelevitch, C. et al . 2003. Brugada syndrome: 1992–2002: a historical perspective. J. Am. Coll. Cardiol. 41: 1665–1671.
- 113 Brugada, P. & J. Brugada. 1992. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J. Am. Coll. Cardiol. 20: 1391–1396.
- 114 Chen, Q. et al . 1998. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392: 293–296.
- 115 Hedley, P.L. et al . 2009. The genetic basis of Brugada syndrome: a mutation update. Hum. Mutat. 30: 1256–1266.
- 116 Leenhardt, A. et al . 1995. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 91: 1512–1519.
- 117 Reid, D.S. et al . 1975. Bidirectional tachycardia in a child. A study using His bundle electrography. Br. Heart J. 37: 339–344.
- 118 Mohamed, U., C. Napolitano & S.G. Priori. 2007. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J. Cardiovasc. Electrophysiol. 18: 791–797.
- 119 Swan, H. et al . 1999. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J. Am. Coll. Cardiol. 34: 2035–2042.
- 120 Laitinen, P.J. et al . 2001. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 103: 485–490.
- 121 Priori, S.G. et al . 2001. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103: 196–200.
- 122 Wehrens, X.H. et al . 2003. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 113: 829–840.
- 123 Wehrens, X.H., S.E. Lehnart & A.R. Marks. 2005. Ryanodine receptor-targeted anti-arrhythmic therapy. Ann. N.Y. Acad. Sci. 1047: 366–375.
- 124 Cerrone, M. et al . 2007. Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ. Res. 101: 1039–1048.
- 125 Knollmann, B.C. et al . 2006. Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. J. Clin. Invest. 116: 2510–2520.
- 126 Watanabe, H. et al . 2009. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat. Med. 15: 380–383.
- 127 Kannankeril, P.J. & D.M. Roden. 2007. Drug-induced long QT and torsade de pointes: recent advances. Curr. Opin. Cardiol. 22: 39–43.
- 128 Splawski, I. et al . 2002. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 297: 1333–1336.
- 129 Tester, D.J. & M.J. Ackerman. 2009. Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children. Annu. Rev. Med. 60: 69–84.
- 130 Bruneau, B.G. 2008. The developmental genetics of congenital heart disease. Nature 451: 943–948.
- 131 Hoffman, J.I. & S. Kaplan. 2002. The incidence of congenital heart disease. J. Am. Coll. Cardiol. 39: 1890–1900.
- 132 Oyen, N. et al . 2009. National time trends in congenital heart defects, Denmark, 1977–2005. Am. Heart J. 157: 467–473.
- 133 Ferencz, C. 1993. Epidemiology of Congenital Heart Disease: The Baltimore-Washington Infant Study 1981–1989. Futura Publishing. Mount Kisco , NY .
- 134 Jenkins, K.J. et al . 2007. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115: 2995–3014.
- 135 Pierpont, M.E. et al . 2007. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115: 3015–3038.
- 136 Olson, E.N. 2006. Gene regulatory networks in the evolution and development of the heart. Science. 313: 1922–1927.
- 137 Srivastava, D. 2006. Making or breaking the heart: from lineage determination to morphogenesis. Cell 126: 1037–1048.
- 138 Basson, C.T. et al . 1994. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N. Engl. J. Med. 330: 885–891.
- 139 Basson, C.T. et al . 1997. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat. Genet. 15: 30–35.
- 140 Chen, B. et al . 2000. Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat. Genet. 24: 296–299.
- 141 Tartaglia, M. et al . 2001. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 29: 465–468.
- 142 Aoki, Y. et al . 2008. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum. Mutat. 29: 992–1006.
- 143 Schubbert, S., G. Bollag & K. Shannon. 2007. Deregulated Ras signaling in developmental disorders: new tricks for an old dog. Curr. Opin. Genet. Dev. 17: 15–22.
- 144 Li, L. et al . 1997. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet. 16: 243–251.
- 145 Oda, T. et al . 1997. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat. Genet. 16: 235–242.
- 146 McDaniell, R. et al . 2006. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am. J. Hum. Genet. 79: 169–173.
- 147 Satoda, M. et al . 2000. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat. Genet. 25: 42–46.
- 148 Gebbia, M. et al . 1997. X-linked situs abnormalities result from mutations in ZIC3. Nat. Genet. 17: 305–308.
- 149 Purandare, S.M. et al . 2002. A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129: 2293–2302.
- 150 Zhu, L., J.W. Belmont & S.M. Ware. 2006. Genetics of human heterotaxias. Eur. J. Hum. Genet. 14: 17–25.
- 151 Schott, J.J. et al . 1998. Congenital heart disease caused by mutations in the transcription factor NKX2–5. Science 281: 108–111.
- 152 Garg, V. et al . 2003. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424: 443–447.
- 153 Ching, Y.H. et al . 2005. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat. Genet. 37: 423–428.
- 154 Kodo, K. et al . 2009. GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc. Natl. Acad. Sci. USA 106: 13933–13938.
- 155 Kirk, E.P. et al . 2007. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am. J. Hum. Genet. 81: 280–291.
- 156 Garg, V. et al . 2005. Mutations in NOTCH1 cause aortic valve disease. Nature 437: 270–274.
- 157 McBride, K.L. et al . 2008. NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Hum. Mol. Genet. 17: 2886–2893.
- 158 Goldmuntz, E., E. Geiger & D.W. Benson. 2001. NKX2.5 mutations in patients with tetralogy of fallot. Circulation 104: 2565–2568.
- 159 Rajagopal, S.K. et al . 2007. Spectrum of heart disease associated with murine and human GATA4 mutation. J. Mol. Cell Cardiol. 43: 677–685.
- 160 Schluterman, M.K. et al . 2007. Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease. Am. J. Med. Genet. A. 143A: 817–823.
- 161 Tomita-Mitchell, A. et al . 2007. GATA4 sequence variants in patients with congenital heart disease. J. Med. Genet. 44: 779–783.
- 162 Greenway, S.C. et al . 2009. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat. Genet. 41: 931–935.
- 163 Redon, R. et al . 2006. Global variation in copy number in the human genome. Nature 444: 444–454.
- 164 Richards, A.A. et al . 2008. Cryptic chromosomal abnormalities identified in children with congenital heart disease. Pediatr. Res. 64: 358–363.
- 165 Roach, J.C. et al . 2010. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328: 636–639.
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