Basic article

Genetics of cardiomyopathyand channelopathy

Connie R. BezzinaHeart Failure Research Center, Department of Experimental Cardiology, AMC, Amsterdam, The Netherlands

Correspondence: C. R. Bezzina, Heart Failure Research Center, Department of Experimental Cardiology,Room L2-108-1, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

E-mail: C.R.Bezzina@amc.uva.nl

Conflicts of interest: None.

Abstract

During the past 20 years, we have witnessed a dramatic increase in our knowledge of the genetic basis ofthe cardiomyopathies and the primary electrical disorders (‘‘ion channelopathies’’). This review aims toprovide an overview of the different genes linked to these disorders to date.

Heart Metab. 2008;41:5–10.

Keywords: Arrhythmia, cardiomyopathy, channelopathy, mutation, sudden cardiac death

Introduction

During the past 20 years, we have witnessed adramatic increase in our knowledge of the geneticbasis of cardiac disease. The greatest advancementshave undoubtedly taken place in the understanding ofthe genetic basis of the cardiomyopathies and theprimary electrical disorders, the latter commonlyreferred to as the ‘‘ion channelopathies’’. Recognitionof the genetic substrate in cardiomyopathy and chan-nelopathy not only has provided clues to the under-lying molecular mechanisms, but, importantly, hasenabled the introduction of genetic diagnostic testing,providing new opportunities for patient managementsuch as early, presymptomatic, identification ofpatients at risk of developing fatal arrhythmias. Thisreview aims to provide an overview of the differentgenes linked to these disorders to date.

Cardiomyopathy

Cardiomyopathy is typically divided into several sub-types: hypertrophic cardiomyopathy, glycogen cardi-

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omyopathy, dilated cardiomyopathy, restrictivecardiomyopathy, and arrhythmogenic right ventric-ular cardiomyopathy.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a relativelycommon disorder with a prevalence of about 1 : 500[1]. It is recognized clinically by the presence ofcardiac hypertrophy in the absence of an increasedexternal load [2]. Echocardiographically, it is associ-ated with preserved systolic, but impaired diastolic,function. Hypertrophy is asymmetric in about two-thirds of cases, with the septum being the predomi-nant site of involvement. Significant left ventricularoutflow tract obstruction is observed in approximatelyone-quarter of cases.

HCM is usually inherited as an autosomal dominanttrait [3,4]. The first gene linked to HCM was reportedin 1990 [5]. This was the gene encoding cardiacb-myosin heavy chain (MYH7), a component of thesarcomere, the contractile unit within the cardiomyo-cyte. The sarcomere is an immense protein complexthat is organized into thick and thin filaments that, in

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Basic articleConnie R. Bezzina

Figure 1. The structure of the cardiomyocyte showing structural components involved in cardiomyopathies. AMPK, AMP-activated protein kinase; Ca, calcium; LAMP2, lysosome-associated membrane protein; SERCA, sarcoplasmic reticulumCa2þ-ATPase. (From Ahmad et al [3], with permission.) Copyright � [2005] Massachusetts Medical Society. All rightsreserved.

the presence of calcium and ATP, slide pasteach other, thereby generating contractile force(Figure 1). After the discovery of mutations inMYH7, mutations in another 10 sarcomeric geneswere linked to HCM, leading to the proposition thatHCM was a disease of the sarcomere (Table I). Mostcommonly affected are the MYH7 and the MYBPC3genes, with the other genes accounting for far fewercases. Mutations in sarcomeric genes account forabout 60% of cases of HCM [6]. More recently,mutations have also been described in genes encod-ing sarcomere-associated proteins such as muscle LIMprotein [7]. However, mutations in these genes appearto be rare.

Glycogen cardiomyopathy

Cardiac hypertrophy can also be triggered by defectsin genes of metabolism [3]. Glycogen deposition is ashared feature of these metabolic cardiomyopathies.A number of features distinguish this form of cardio-

Table I. Genes encoding sarcomeric proteins involved in hypertrophic

Gene Protein name

TNNT2 Cardiac troponin T2TTN TitinMYL3 Essential myosin light chainTNNC1 Cardiac troponin CMYBPC3 Cardiac myosin binding proMYL2 Regulatory myosin light chaMYH7 Beta myosin heavy chainMYH6 Alpha myosin heavy chainACTC Cardiac actinTPM1 Alpha tropomyosinTNNI3 Cardiac troponin I

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myopathy from the sarcomere-related type. Histo-logic features associated with sarcomere-relatedhypertrophy (myocyte and myofiber disarray, myo-cyte hypertrophy, fibrosis) are notably absent in theglycogen cardiomyopathies, which, in contrast,contain myocyte vacuoles containing glycogen.Furthermore, patients with metabolic gene defectsusually present with electrophysiological dysfunc-tion.

Mutations in three lysosomal proteins produce suchglycogen cardiomyopathy. Recessively inherited lyso-somal acid a 1,4-glucosidase (GAA) deficiency causesPompe disease, X-linked lysosome-associated mem-brane protein (LAMP2) deficiency causes Danon dis-ease, and X-linked lysosomal hydrolase a galactosi-dase A (GLA) deficiency causes Fabry disease; thesethree diseases are systemic disorders. Another geneassociated with glycogen storage disease is PRKAG2,encoding the g2 subunit of AMP-activated proteinkinase (AMPK) [8]. AMPK functions as a metab-olite-sensing protein kinase that is activated under

cardiomyopathy.

Chromosomal location

1q322q313p213p21–p14

tein C 11p11.2in 12q23–q24

14q1214q1215q1415q2219q13.4

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Basic articleGenetics of cardiomyopathy and channelopathy

conditions of energy depletion, manifested byincreased concentrations of cellular AMP. Pompe,Danon, and Fabry diseases. Because the g2 subunithas cardiac-specific expression, extracardiac manifes-tations do not occur in PRKAG2 cardiomyopathy,distinguishing this from other forms of glycogenstorage cardiomyopathies.

Dilated cardiomyopathy

Dilated cardiomyopathy (DCM) [9] is characterizedby left ventricular chamber enlargement and systolicdysfunction, with normal or a modest increase inventricular wall thickness. It has an estimated preva-lence of 1 : 2500. Affected individuals graduallydevelop heart failure, often in association with life-threatening atrial or ventricular arrhythmias.

The disease is familial in about 35% of cases,pointing to an important role of genetics in diseasepathogenesis [10]. In such cases, inheritance is mostcommonly autosomal dominant, but autosomalrecessive, X-linked, or matrilinear (mitochondrial)inheritances also occur. DCM has been linked to25 different chromosomal loci and genes. Knownmutations affect proteins with a wide range of unre-lated functions. Mutations have been identified inseveral components of the myocyte cytoskeleton,which, through a complex network of proteins, linksthe sarcomere to the sarcolemma and extracellularmatrix and functions to transmit force generatedduring contraction (Figure 1). Cytoskeletal com-ponents found to be associated with DCM includecardiac muscle LIM protein (MLP), cypher/ZASP(LBD3), d-sarcoglycan (SGCD), desmoplakin (DSP),desmin (DES), dystrophin (DMD), telethonin (TCAP),and vinculin (VCL).

Mutations in the ubiquitously expressed nuclearenvelope protein lamin A/C (LMNA) cause DCMassociated with conduction disease [11]. A myriadof phenotypes, besides DCM, are associated withlamin A/C mutation, including Emery–Dreifuss mus-cular dystrophy type B1 and Charcot–Marie–Toothdisease. Several genes encoding sarcomeric proteinslinked to HCM, including TTN, ACTC, TPM1, MYH7and TNNT2, may also cause DCM. Other geneslinked to DCM include genes encoding ion channelsubunits. One of these is SCN5A, which encodes thepore-forming subunit of the cardiac sodium channel.Conduction disease and atrial fibrillation are a com-mon finding in patients with DCM harboringmutations in SCN5A [12]. Another ion channel genesubunit linked to DCM is the sulfonylurea receptor 2A(SUR2A), which is the regulatory subunit of KATP

channels in the heart. DCM is also caused by mutationin phospholamban (PLN), which has an essential rolein calcium metabolism by modulating calcium-ATPase activity.

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Restrictive cardiomyopathy

Restrictive cardiomyopathy is a rare disorder charac-terized by a normal or decreased volume of bothventricles, associated with bi-atrial enlargement,impaired ventricular filling with restrictive physi-ology, normal myocardial wall thickness, and normalor near-normal systolic function. A mutation has beendescribed in cardiac troponin I (TNNTI3) in a family inwhich carriers exhibited restrictive or hypertrophiccardiomyopathy. Additional TNNTI3 mutations werealso found in unrelated patients with restrictive car-diomyopathy [2,3].

Arrhythmogenic right ventricularcardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy(ARVC) involves predominantly the right ventricle,with progressive loss of myocytes and fatty or fibrofattytissue replacement – a process that appears to begin atthe epicardium and gradually extends towards thesubendocardium [13]. Left ventricular involvement isnow commonly recognized. Significant advances inthe understanding of the genetic basis of this disorderhave been made over the past few years.

Mutations in five different desmosomal components�

(plakoglobin, desmoplakin, plakophilin-2, desmo-glein-2, desmocollin-2) have been described, leadingto the notion that ARVC is a disease of the desmo-some. Desmosomes form specialized intercellularjunctions that anchor intermediate filaments to thecytoplasmic membrane in adjoining cells, impartingmechanical strength. Mutations have also beendescribed in two extradesmosomal genes. One ofthese is RYR2, encoding the cardiac ryanodine recep-tor. However, one could argue that the phenotype ofthese patients more closely resembles that of cat-echolaminergic polymorphic ventricular tachycardia(CPVT, see below), which also is caused by mutationin RYR2. The other extradesmosomal gene in whichmutations have been described is TGF-b3, encodingtransforming growth factor-b3. The contribution ofmutations in this gene to the overall genetic profileof ARVC is not known with certainty.

Channelopathy

The cardiac action potential is mediated by the excep-tionally well orchestrated activity of a diversity of ionchannels. Cardiac ion channels are protein complexesin the membrane of cardiomyocytes which, via highlyregulated opening and closing (gating), conduct aselective and rapid flow of ions through a centralpore. Spatial heterogeneity of ion channel expressionunderlies the different action potential morphology of

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Basic articleConnie R. Bezzina

the different parts of the heart, which in turn ensures acoordinated contraction. The maintenance of normalcardiac rhythm is dependent on the correct movementof ions mediating the action potential in each cardiaccompartment. Abnormalities in ion channel functioncan have disastrous consequences that manifest them-selves as abnormalities of the electrocardiogram(ECG) and arrhythmias. These disorders of ion chan-nels, commonly referred to as ‘‘cardiac channelopa-thies’’, have been brought into focus in recent years,as mutations in genes coding for specific ion channelswere shown to underlie specific forms of heritablearrhythmogenic disorders occurring in the structurallynormal heart. These include long-QT syndrome(LQTS), short-QT syndrome, Brugada syndrome, con-duction disease, sinus node dysfunction, and CPVT,discussed here.

Long-QT syndrome

LQTS, estimated to affect 1 in 5000 individuals, is arepolarization disorder identified by prolongation ofthe QT interval on the ECG [14]. It has long beenrecognized as a familial disorder, frequently present-ing in childhood with syncopal episodes and poten-tially lethal torsades de pointes tachyarrhythmias,which occur in a significant proportion of untreatedpatients. Inheritance of the disease is either autosomaldominant or recessive. The autosomal recessive form(Jervell and Lange-Nielsen syndrome) is also associ-ated with deafness.

Mutations in eight different genes encoding potass-ium (Kþ), sodium (Naþ), or calcium (Ca2þ) ion channelsubunits have been associated with the disorder (TableII). The pore-forming subunits of the slowly and rapidlyactivating repolarizing potassium currents (KCNQ1and KCNH2 genes, respectively) are most oftenaffected. Mutations affecting the potassium channelsubunits (KCNQ1, KCNH2, KCNE1, KCNE2) prolongaction potential repolarization – and, consequently,the QT interval on the ECG – by a net reduction inoutward repolarizing Kþ current. Mutations in SCN5A,which encodes the pore-forming subunit of the sodiumchannel, lead to an increased inward Naþ currentduring the action potential plateau, shifting the balanceto prolonged repolarization. Mutations in SCN4B, anancillary subunit of the sodium channel, have recentlybeen reported in one family with LQTS [15].

Mutations associated with LQTS have also beendescribed in genes encoding linker/adapter proteins.These include the membrane adapter protein ankyrin-B (ANK2), caveolin 3 (CAV3 – a major component ofcaveolae that constitute microdomains of the plasma-lemma [16]), A-kinase anchoring protein 9 (AKAP9)[17], and a1-syntrophin (SNTA1), a member of thefamily of dystrophin-associated proteins containingseveral protein interaction motifs [18].

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Jervell and Lange-Nielsen syndrome is caused byhomozygosity (because of consanguineous parents) orcompound heterozygosity for mutations in KCNQ1 orKCNE1. These genes are expressed in marginal cells ofthe stria vascularis, where they are believed to play apart in the homeostasis of Kþ in the endolymph, a Kþ-rich fluid of the inner ear. This explains the deafnessthat is associated with this disorder.

Mutations in the KCNJ2 gene that encodes theinward rectifier Kþ channel Kir2.1 in both heart andstriated muscle cause Andersen syndrome, a raredisorder that, besides mild prolongation of the QTinterval, also exhibits extracardiac features, includingskeletal muscle periodic paralysis and developmentalproblems. Another disorder manifesting with pro-longation of the QT interval and extracardiac featuresis Timothy syndrome. This disorder combines,amongst other defects, severe prolongation of theQT-interval with syndactyly, autism, mental retar-dation, and facial dysmorphism. Considering thewidespread expression of the CACNA1C gene andthe importance of Ca2þ as an intracellular signalingmolecule, the widespread cellular and organ defectsin this disorder are not unexpected.

Short-QT syndrome

The short-QT syndrome presents with a high rate ofsudden death and exceptionally short QT intervals(QTc typically �300 ms). To date, only 30–40patients have been described. In contrast to LQTS,in SQTS repolarization is hastened by an enhancedoutward current during repolarization. Gain-of-func-tion mutations in the KCNH2, KCNQ1, and KCNJ2genes were identified in patients with the disorder(Table II). QT-interval shortening in the KCNJ2 sub-type seems less severe than that for the other twosubtypes.

Brugada syndrome

The Brugada syndrome is characterized by ST-segment elevation in the right precordial leads, withor without conduction abnormalities, and a significantrisk of sudden cardiac death. The disorder is endemicin East and Southeast Asia, where it underlies thesudden unexpected death syndrome. Brugada syn-drome is familial in about one-third of patients, inwhich case an autosomal dominant mode of inheri-tance is observed.

Genes involved in pathogenesis of Brugadasyndrome encode the pore-forming and auxiliarysubunits of the cardiac Naþ channel encoded,respectively, by SCN5A and SCN1B [14,19](Table II). The functional effects of Brugada syndromeon the sodium current are opposite to those foundin LQTS. Loss-of-function mutations underlie

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Basic articleGenetics of cardiomyopathy and channelopathy

Table II. Summary of genes for inherited cardiac arrhythmia syndromes.

Subtypea Gene Protein/Aliases InheritanceIonic currentaffected

Effect oncurrent

Long-QT syndrome LQT1 KCNQ1 KvLQT1 Dominant IKs #LQT2 KCNH2 HERG Dominant IKr #LQT3 SCN5A Nav1.5 Dominant INa "LQT4 ANK2 Ankyrin-B Dominant SeveralLQT5 KCNE1 minK, Isk Dominant IKs #LQT6 KCNE2 MiRP1 Dominant IKr #LQT7 KCNJ2 kir2.1, IRK1 Dominant IK1 #LQT8 CACNA1C Cav1.2 De novo ICa-L "LQT9 CAV3 Caveolin-3 Dominant INa "LQT10 SCN4B Navb.4 Dominant INa "LQT11 AKAP9 AKAP9/yotiao Dominant IKs #LQT12 ANTA1 a-Syntrophin Dominant INa "JLN1 KCNQ1 KvLQT1 Recessive IKs #JLN2 KCNE1 minK, Isk Recessive IKs #

Short-QT syndrome SQT1 KCNH2 HERG Dominant IKr "SQT2 KCNQ1 KvLQT1 Unknown IKs "SQT3 KCNJ2 Kir2.1, IRK1 Dominant IK1 "

Brugada syndrome BS1 SCN5A Nav1.5 Dominant INa #BS2 GPD1L Dominant INa #BS3 CACNA1C Cav1.2 Dominant ICa-L #BS4 CACNB2b Cavb2b Dominant ICa-L #BS5 SCN1B Navb.1 Dominant INa #

Catecholaminergicpolymorphicventriculartachycardia

CPVT1 RYR2 Dominant SR Ca2þ release "CPVT2 CASQ2 Recessive SR Ca2þ release

"

Sick sinussyndrome

SSS1 HCN4 Unknown If #SSS2 SCN5A Nav1.5 Recessive INa #

Cardiac conductiondisease

CCD1 Unknown DominantCCD2 SCN5A Nav1.5 Dominant INa #CCD3 Unknown DominantCCD4 SCN1B Navb.1 Dominant INa #

Brugada syndrome and the frequently associated(mild) conduction disorders. Mutations in GPD1L,which encodes glycerol-3-phosphate dehydrogenase1-like protein, also lead to Brugada syndrome byattenuation of the sodium current, an effect probablycaused by interference with cell membrane expres-sion of the channel [20]. Recently, loss-of-functionmutations in two subunits of the cardiac Ca2þ

channel complex (CACNA1C and CACNB2) wereassociated with Brugada syndrome, in combinationwith somewhat shorter-than-normal QT intervals[21].

Cardiac conduction disease and sinus nodedysfunction

Loss-of-function mutations in components of the car-diac Naþ channel complex, namely SCN5A andSCN1B, also lead to cardiac conduction disease[19]. It is unknown why such mutations leading toloss of Naþ channel function lead to conductiondisease in some patients and Brugada syndrome (with

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conduction defects) in others. Mutations in SCN5Aleading to loss of Naþ channel function also cause arecessive form of sick sinus syndrome. Mutations inHCN4, which encodes the cardiac pacemaker chan-nel, cause autosomal dominant sinus node dysfunc-tion [14].

Catecholaminergic polymorphic ventriculartachycardia

Arrhythmias in the setting of CPVT are, typically,bidirectional and polymorphic ventricular tachycar-dia, exclusively triggered by adrenergic stimuli. Thephenotype often presents in early childhood. In themajority of cases, CPVT displays an autosomal domi-nant mode of inheritance and is caused by mutationsin the gene encoding the ryanodine receptor channel(RYR2; Table II). This is an intracellular Ca2þ-releasechannel on the sarcoplasmic reticulum that releasesCa2þ in response to the entry of Ca2þ through mem-brane Ca2þ channels. A recessive form of CPVT iscaused by homozygous mutation in the CASQ2 gene

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Basic articleConnie R. Bezzina

(Table II), which encodes calsequestrin, a protein thatserves as the major Ca2þ reservoir within the lumen ofthe sarcoplasmic reticulum. Symptoms are apparentlymore severe in CASQ2-related CPVT, including anearlier age of onset.

Concluding remarks

The identification of the mutation within a familyaffected by inherited cardiac disorders allows diag-nosis in other family members independently of echo-cardiographic features, ECG features, or arrhythmicmanifestations. This has led to the realization thatinherited cardiac disorders exhibit variability inclinical expression [22,23]. As in the case of manyother Mendelian disorders, reduced penetrance andvariable expression are more the rule than the excep-tion. Hence, not all carriers of mutations are clinicallyaffected to the same degree by the disorders. Clinicalexpression is probably influenced by several factors,including age, sex, and environmental factors such aslifestyle, exercise, and blood pressure. Genetic modi-fiers are also expected to modulate disease penetranceand expression. Although some genetic modifiersare beginning to be uncovered [22,24], the natureof such modifiers remains, largely, unknown. Theidentification of genetic modifiers is regarded as themajor next step in genetic studies of inherited cardiacdisorders.�See glossary for definition of this term.

REFERENCES

1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild

DE. Prevalence of hypertrophic cardiomyopathy in a generalpopulation of young adults. Echocardiographic analysis of4111 subjects in the CARDIA Study. Coronary Artery RiskDevelopment in (Young) Adults. Circulation. 1995;92:785–789.

2. Maron BJ, Towbin JA, Thiene G, et al., for the American HeartAssociation; Council on Clinical Cardiology, Heart Failureand Transplantation Committee; Quality of Care and Out-comes Research and Functional Genomics and TranslationalBiology Interdisciplinary Working Groups; Council on Epide-miology and Prevention. Contemporary definitions and clas-sification of the cardiomyopathies: an American HeartAssociation Scientific Statement from the Council on ClinicalCardiology, Heart Failure and Transplantation Committee;Quality of Care and Outcomes Research and FunctionalGenomics and Translational Biology Interdisciplinary Work-ing Groups; and Council on Epidemiology and Prevention.Circulation. 2006;113:1807–1816.

3. Ahmad F, Seidman JG, Seidman CE. The genetic basis forcardiac remodeling. Annu Rev Genomics Hum Genet.2005;6:185–216.

10

4. Keren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopa-thy: the genetic determinants of clinical disease expression.Nat Clin Pract Cardiovasc Med. 2008;5:158–168.

5. Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A mole-cular basis for familial hypertrophic cardiomyopathy: a betacardiac myosin heavy chain gene missense mutation. Cell.1990;62:999–1006.

6. Marian AJ, Roberts R. The molecular genetic basis for hyper-trophic cardiomyopathy. J Mol Cell Cardiol. 2001;33:655–670.

7. Geier C, Gehmlich K, Ehler E, et al. Beyond the sarcomere:CSRP3 mutations cause hypertrophic cardiomyopathy. HumMol Genet. 2008 Jun 2 [Epub ahead of print].

8. Arad M, Benson DW, Perez-Atayde AR, et al. Constitutivelyactive AMP kinase mutations cause glycogen storage diseasemimicking hypertrophic cardiomyopathy. J Clin Invest.2002;109:357–362.

9. Karkkainen S, Peuhkurinen K. Genetics of dilated cardiomyo-pathy. Ann Med. 2007;39:91–107.

10. Grunig E, Tasman JA, Kucherer H, Franz W, Kubler W, KatusHA. Frequency and phenotypes of familial dilated cardiomyo-pathy. J Am Coll Cardiol. 31:186–194.

11. Sylvius N, Tesson F. Lamin A/C and cardiac diseases. CurrOpin Cardiol. 2006;21:159–165.

12. Bezzina CR, Remme CA. Dilated cardiomyopathy due tosodium channel dysfunction; what is the connection? Circula-tion: Arrhythmia and Electrophysiology. 2008;1:80–82.

13. Sen-Chowdhry S, Syrris P, McKenna WJ. Role of geneticanalysis in the management of patients with arrhythmogenicright ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol.2007;50:1813–1821.

14. Wilde AA, Bezzina CR. Genetics of cardiac arrhythmias.Heart. 2005;91:1352–1358.

15. Medeiros-Domingo A, Kaku T, Tester DJ, et al. SCN4B-en-coded sodium channel beta4 subunit in congenital long-QTsyndrome. Circulation. 2007;116:134–142.

16. Vatta M, Ackerman MJ, Ye B, et al. Mutant caveolin-3 inducespersistent late sodium current and is associated with long-QTsyndrome. Circulation. 2006;114:2104–2212.

17. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ,Kass RS. Mutation of an A-kinase-anchoring protein causeslong-QT syndrome. Proc Natl Acad Sci U S A. 2007;104:20990–20995.

18. Ueda K, Valdivia C, Medeiros-Domingo A, et al. Syntrophinmutation associated with long QT syndrome through activa-tion of the nNOS-SCN5A macromolecular complex. Proc NatlAcad Sci U S A. 2008;105:9355–9360.

19. Watanabe H, Koopmann TT, Le Scouarnec S, et al. Sodiumchannel beta1 subunit mutations associated with Brugadasyndrome and cardiac conduction disease in humans. J ClinInvest. 2008;118:2260–2268.

20. London B, Michalec M, Mehdi H, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreasescardiac NaR current and causes inherited arrhythmias. Cir-culation. 2007;116:2260–2268.

21. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie anew clinical entity characterized by ST-segment elevation,short QT intervals, and sudden cardiac death. Circulation.2007;115:442–449.

22. Scicluna BP, Wilde AAM, Bezzina CR. The primary arrhyth-mia syndromes: same mutation, different manifestations. Arewe starting to understand why? J Cardiovasc Electrophysiol.2008;19:445–452.

23. Keren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopa-thy: the genetic determinants of clinical disease expression.Nat Clin Pract Cardiovasc Med. 2008;5:158–168.

24. Warwick Daw E, Chen NE, Czernuszewicz G, et al. Genome-wide mapping of modifier chromosomal loci for humanhypertrophic cardiomyopathy. Hum Mol Genet. 2007;16:2463–2471.

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